TAP Vol 6 Issue 1 by Harborside Press LLC

Brentuximab Vedotin in Hodgkin Lymphoma 3, 5 | Triple-Negative Breast Cancer

| Nivolumab in Melanoma

23, 93, 94

VOLUME 6, ISSUE 1

JANUARY 25, 2015

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

ASH Annual Meeting

Carfilzomib-Based Triplet Yields ‘Unprecedented’ Duration of Remission in Relapsed Myeloma By Caroline Helwick

By Chandrakanth Are, MBBS, MBA, FRCS, FACS

he phase III global ASPIRE trial documented an “unprecedented” duration of remission in relapsed multiple myeloma patients receiving carfilzomib (Kyprolis) plus a standard-of-care doublet, according to Keith Stewart, MB, ChB, Professor of Medicine at the Mayo Clinic in Scottsdale, Arizona, who presented the findings at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition in San Francisco.1 ASPIRE enrolled 792 relapsed or refractory patients from 20 countries. Patients had received one to three prior regimens (on average, two).

Key Findings Patients who received carfilzomib plus lenalidomide (Revlimid) and low-dose dexamethasone (KRd) achieved a median progression-free survival of 26.3 months, whereas patients in the control arm, who received lenalidomide/dexamethasone alone (Rd), had a

median progression-free survival of only 17.6 months—a 31% reduction in risk (P < .0001), Dr. Stewart reported. Furthermore, no significant increase was observed in cardiac, renal, or pulmonary toxicity, providing evidence from a large clinical Keith Stewart, MB, ChB trial that the drug can be safely administered, Dr. Stewart said. “By adding carfilzomib to the gold standard in multiple myeloma therapy, we are observing an unprecedented duration of remission, without additional toxicity, in relapsed and heavily pretreated patients,” he said. “The best result ever reported in this population,” he told journalists at a press briefing, was a median progression-free survival of just 19 months, which was continued on page 12

San Antonio Breast Cancer Symposium

Ovarian Suppression Plus Hormonal Therapy May Be Practice-Changing in Premenopausal Hormone Receptor–Positive Early-Stage Breast Cancer By Alice Goodman

What Is a Physician? Call a Spade a Spade

esults of the large International Breast Cancer Study Group (IBCSG)-coordinated SOFT trial present a convincing argument for the addition of ovarian function suppression to adjuvant hormonal therapy to reduce the risk of tumor recurrence in younger women with hormone receptor–positive early-stage breast cancer at high enough risk to be treated with chemotherapy and who remain premenopausal. Compared with tamoxifen alone,

ovarian function suppression plus exemestane achieved a greater reduction in the risk of tumor recurrence than ovarian function suppression plus tamoxifen. In the cohort of premenopausal women younger than age 35, substantial benefits were seen with ovarian suppression. In the cohort of women who had not received chemotherapy, tamoxifen alone was just as effective as tamoxifen plus ovarian function suppression. Thus, tamoxifen appears to be sufficient therapy to reduce the risk of tumor I believe this trial is practicerecurrence for premenopausal women with low-risk changing. If I see a woman under age cancers not requiring che35 with hormone receptor–positive motherapy. This group of premenopausal women was breast cancer, I will know how to older with predominantly advise her. small node-negative tumors —Prudence Francis, MD of low to intermediate grade.

nyone who has awoken from a decadeslong amnestic spell can be forgiven for thinking that physicians cannot do anything right nowadays. Compared with decades ago, when physicians did mostly right, we now seem to be nowhere close to correctness. Nearly every malady that befalls the health-care environment is blamed on physicians. We are a befuddled bunch who collectively amount to nothing good, as evident from what is portrayed in the media and literature. continued on page 185

Dr. Are is Associate Professor of Surgical Oncology, Vice Chair of Education, and Program Director of the General Surgery Residency Program at University of Nebraska Medical Center, Omaha. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO. Some details have been changed to protect patient privacy.

MORE IN THIS ISSUE Oncology Meetings Coverage ASH Annual Meeting �� 1, 3–5, 11–13, 116–118 SABCS �� 1, 14, 19–22, 28–30, 78–92 American College of Sugeons ��35 Symposium in Thoracic Oncology �� 37, 41, 44, 46–47 Molecular Pathology �� 47, 50 FDA Updates �� 23–27, 61, 101, 114 John Marshall, MD, on Colorectal Cancer �� 51 Direct From ASCO �� 71–74 Jacek Jassem, MD, PhD, and Rafat Dziadziuszko, MD, PhD, on Crizotinib in NSCLC �� 100 Daniel F. Hayes, MD, FASCO, Elected 2016–2017 ASCO President �� 101

continued on page 14

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The ASCO Post | JANUARY 25, 2015

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PAGE 3

ASH Annual Meeting Hematology

Brentuximab Vedotin Added to Standard Therapy for Advanced-Stage Hodgkin Lymphoma May Improve Results By Caroline Helwick

everal studies presented at the 2014 ASH Annual Meeting supported the use of brentuximab vedotin (Adcetris) in Hodgkin lymphoma. The Reed-Sternberg cells of classical Hodgkin lymphoma typically express CD30, which is targeted by brentuximab vedotin, an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E.

Active in Combination With AVD As initial therapy for patients with advanced-stage Hodgkin lymphoma, the addition of brentuximab vedotin to doxorubicin, vinblastine, dacarbazine (AVD) led to highly durable responses and a 3-year overall survival rate of 100%, in a study from the British Columbia Cancer Agency, the Mayo Clinic, MD Anderson Hospital, and the University of North Carolina.1 “Brentuximab vedotin plus AVD has a high level of activity. Although brentuximab vedotin can be safely combined with AVD, it should never be combined with bleomycin (ABVD),” said lead author of the study Joseph M. Connors, MD. In the phase I study, brentuximab vedotin plus ABVD led to a 44% rate of pulmonary toxicity, including two deaths, whereas no patients receiving AVD and brentuximab vedotin developed this side effect.

At the 2014 ASH Annual Meeting, Dr. Connors and colleagues reported safety and efficacy results for 51 newly diagnosed advanced-disease (80% stage III/ IV) patients who received brentuximab vedotin in combination with ABVD or the same regimen without bleomycin (AVD) in a multicenter dose-escalation study. Patients received doses of 0.6, 0.9, or 1.2 mg/kg of brentuximab vedotin with standard doses of ABVD or 1.2 mg/ kg with AVD on days 1 and 15 of each 28day cycle for up to six cycles of therapy. The investigators previously reported that 95% of patients given ABVD and brentuximab vedotin achieved a complete response, as did 96% of patients given AVD and brentuximab vedotin. However, toxicity was a concern with the ABVD regimen. “We established that brentuximab vedotin cannot be safely combined with bleomycin,” Dr. Connors said, adding that this had not been suspected from other studies of brentuximab vedotin or bleomycin. “We saw it when we combined these drugs.” Pulmonary toxicity occurred in 11 patients, typically during the second half of treatment, and it resolved in 9 patients with standard approaches and treatment discontinuation (8 switched to AVD and brentuximab vedotin). In two patients, however, the toxicity proved fatal.

We hope with this trial [ECHELON-1] to definitively establish brentuximab vedotin [plus AVD] front line as a new, less toxic gold standard treatment for advanced-stage classical Hodgkin lymphoma. —Joseph M. Connors, MD

“Pulmonary toxicity was reversible in most patients, but one should never take the chance of it occurring,” Dr. Connors emphasized.

Updated Survival Data In the current analysis, the combination of AVD and brentuximab vedotin led to complete responses in 96% of 50 patients, a 3-year failure-free survival rate of 92%, and a 3-year overall survival rate of 100%. Responses to AVD (or ABVD) were durable. At a median follow-up of 40 months, the longest time to relapse was 22 months; 96% of patients have been followed longer than 22 months. “No deaths from Hodgkin lymphoma have occurred,” Dr. Connors noted. “All five patients who relapsed after primary treatment have undergone autologous stem cell transplantation, and only one has subsequently relapsed.”

These updated outcomes “strongly support” the current international front-line phase III ECHELON-1 trial comparing AVD and brentuximab vedotin with standard ABVD, he said. The target enrollment is 1,040 patients. “We hope with this trial to definitively establish brentuximab vedotin [plus AVD] front line as a new, less toxic gold standard treatment for advanced-stage classical Hodgkin lymphoma,” Dr. Connors concluded.

Front-Line Brentuximab Alone and With Dacarbazine Another multicenter phase II study evaluated brentuximab vedotin as monotherapy and in combination with dacarbazine as front-line treatment of Hodgkin lymphoma in patients aged 60 and older. The interim results were continued on page 4

EXPERT POINT OF VIEW

s session moderator, Fredrick Hagemeister, MD, Professor of Medicine, University of Texas MD Anderson Cancer Center, Houston, com-

rating them off-label in the clinic. “When our new biologic agents become available, it’s necessary to do carefully designed trials of combina-

We would never have known about the pulmonary toxicity with bleomycin and brentuximab vedotin without this particular trial. —Fredrick Hagemeister, MD

mented during the discussion of Dr. Connors’ study. He first emphasized the need to establish the safety of new drugs in clinical trials before incorpo-

tions. We would never have known about the pulmonary toxicity with bleomycin and brentuximab vedotin without this particular trial,” he said.

He also questioned whether, in light of the positive data for the combination of AVD and brentuximab vedotin, patients will elect to enroll in ECHELON-1 and accept treatment with ABVD alone. Dr. Connors responded: “The question is, is there equipoise, and I think there is. But these are preliminary results in a small number of patients selected for enrollment in a phase II trial. They should never be taken as evidence that this regimen should be incorporated into standard practice yet.” “The state of the art continues to rely on ABVD as the best balance of effectiveness and toxicity for advancedstage Hodgkin lymphoma. Only through trials such as ECHELON-1 can we take a step forward,” he said. Dr. Hagemeister told The ASCO

Post that he hopes the trial will fully accrue. “We do need this confirmatory trial, though personally, I think there may be evidence that for high-risk patients who don’t want to go onto this trial, one could give them the option of receiving brentuximab vedotin plus AVD, and that has to be carefully considered. It’s a personal opinion, not everyone’s.” Commenting on Dr. ForeroTorres’ study, Dr. Hagemeister said, “We now have an idea of what brentuximab vedotin does in untreated patients. It doesn’t look like it holds up to what many had hoped. You can give the drug and get away with it, but the median progression-free survival is short.” n Disclosure: Dr. Hagemeister reported no potential conflicts of interest.

The ASCO Post | JANUARY 25, 2015

PAGE 4

ASH Annual Meeting Hematology

Brentuximab Vedotin continued from page 3

reported by Andres Forero-Torres, MD, of the University of Alabama at Birmingham.2 “Older patients have poorer outcomes, including lower survival rates and more treatment-related toxicities. Comorbidities may limit the administration of standard-intensity regimens,” Dr. Forero-Torres noted. The study assigned patients to single-agent brentuximab vedotin (1.8 mg/kg; n = 27; median age, 78 years) or brentuximab vedotin plus dacarbazine (375 mg/m2, every 3 weeks; n = 18; median age, 72 years). Brentuximab vedotin as a single agent in-

duced responses in 93%, including 16 complete and 6 partial responses. The median progression-free survival was 10.5 months. In 14 evaluable patients, brentuximab vedotin plus dacarbazine led to a 93% response rate, with data not yet available for progression-free survival. The regimens were well tolerated, though one-third of patients had grade 1/2 neuropathy and gastrointestinal side effects; 83% of patients remain on the brentuximab vedotin plus dacarbazine regimen. Although high single-agent activity was noted, Dr. Forero-Torres said it was not long-lasting. “That’s why we went to the combination, to see whether adding

Clinical Trials Update on Brentuximab Vedotin in Hodgkin Lymphoma ■■ Several studies presented at the 2014 ASH Annual Meeting evaluated the role of brentuximab vedotin in Hodgkin lymphoma. ■■ In a phase I dose-escalation study, the addition of brentuximab vedotin to AVD (without bleomycin) induced complete responses in 92% of patients, with a 3-year overall survival of 100%. ■■ The study also showed that brentuximab vedotin should not be combined with bleomycin, to avoid the risk of pulmonary toxicity. ■■ In another phase I/II study, brentuximab vedotin plus bendamustine in relapsed/refractory patients induced responses in 96%, including complete responses in 83%. ■■ In older patients, single-agent brentuximab vedotin had high activity, but responses were not durable; brentuximab vedotin combined with dacarbazine appeared more promising.

icity—and it had no adverse impact on stem cell mobilization or engraftment. “This combination represents a promising salvage regimen for patients with Hodgkin lymphoma who have relapsed/refractory disease after frontline therapy,” she said. Response durability continues to be assessed. n

Andres Forero-Torres, MD

a chemotherapy agent would continue giving efficacy but with less toxicity and could keep those responses going for awhile.” “Results from this trial will be used to identify an optimal regimen for this patient population,” he said.

Brentuximab Vedotin Plus Bendamustine in Patients With Refractory Disease Another phase I/II study presented at the 2014 ASH Annual Meeting by Ann LaCasce, MD, of Dana-Farber Cancer Institute, Boston, found that an outpatient regimen of brentuximab vedotin (1.8 mg/kg) plus bendamustine (90 mg/m2) induced responses in 96% of 54 relapsed/refractory Hodgkin lymphoma patients, including complete responses in 83%.3 The median progression-free survival was not reached. “This compared favorably to historical data,” she noted. The combination had a manageable safety profile with premedication for infusion-related reactions—the main tox-

Disclosure: Dr. Connors has received research funding from Seattle Genetics. Dr. Forero-Torres has received research funding from and has served on the speakers bureau of Seattle Genetics. Dr. LaCasce has received research funding from Seattle Genetics.

References 1. Connors JM, Ansell S, Park SI, et al: Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed advanced stage Hodgkin lymphoma: Long-term outcomes. 2014 ASH Annual Meeting. Abstract 292. Presented December 8, 2014. 2. Forero-Torres A, Holkova B, Sharman JP, et al: Brentuximab vedotin monotherapy and in combination with dacarbazine in frontline treatment of Hodgkin lymphoma in patients aged 60 years and above: Interim results of a phase 2 study. 2014 ASH Annual Meeting. Abstract 294. Presented December 8, 2014. 3. LaCasce A, Bociek RG, Matous J, et al: Brentuximab vedotin in combination with bendamustine for patients with Hodgkin lymphoma who are relapsed or refractory after frontline therapy. 2014 ASH Annual Meeting. Abstract 293. Presented December 8, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Roy S. Herbst, MD, PhD, on Immunotherapy in Lung Cancer Treatment see page 44

Caroline Robert, MD, PhD, and Axel Hauschild, MD, PhD, on Treatment Paradigm in Advanced Melanoma see page 56

Andrea McKee, MD, on Overdiagnosis in Lung Cancer see page 46

John L. Marshall, MD, on Colorectal Cancer see page 51

Ruth O’Regan, MD, on Targeting HER2 in Estrogen Receptor-Positive Breast Cancers see page 106

Jacek Jassem, MD, PhD, and Rafal Dziadziuszko, MD, PhD, on Crizotinib and ROS1-Positive NSCLC see page 100

See pages 50 and 147 for more important reports in this issue.

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | JANUARY 25, 2015

PAGE 5

ASH Annual Meeting Hematology

Post-Transplant Brentuximab Vedotin Improved Progression-Free Survival in Hodgkin Lymphoma Patients By Alice Goodman

n patients with Hodgkin lymphoma who are at risk for disease progression following autologous stem cell transplantation, early consolidation with brentuximab vedotin (Adcetris) post-transplant significantly improved progression-free survival compared with placebo in the phase III AETHERA trial.1 The median progression-free survival was 43 months for the brentuximab-treated group vs 24 months for the placebo group, representing a significant 43% reduction in the risk of disease progression (P = .001).

decades, no autologous stem cell transplantation regimens for aggressive lymphoma have improved outcomes further. About 50% of patients will relapse after autologous stem cell transplantation, reflecting the need for better treatments. Brentuximab vedotin is an antibody drug conjugate directed to CD30, which is expressed almost universally on Reed-Sternberg cells malignant cell in Hodgkin lymphoma. The drug is approved by the U.S. Food & Drug Administration for relapsed/refractory

A 20% difference in progression-free survival has never been seen in this patient population. —Craig Moskowitz, MD

“In my opinion, once this study is published, brentuximab should be the standard of care for patients with the characteristics in this trial: that is, remission duration less than 1 year, extranodal disease, B symptoms, two or more prior salvage therapies, and primary refractory disease,” said lead author Craig Moskowitz, MD, Clinical Director of the Division of Hematologic Oncology at Memorial Sloan Kettering Cancer Center, New York. Dr. Moskowitz explained that autologous stem cell transplantation may achieve cure in approximately 50% of patients with relapsed/refractory Hodgkin lymphoma. Over the past 2

Hodgkin lymphoma and for systemic anaplastic large cell lymphoma but not as post-transplant consolidation. “AETHERA is the only placebocontrolled randomized study ever done in Hodgkin lymphoma and it compares brentuximab vs placebo in patients at risk for disease progression after autologous stem cell transplantation,” he said.

Study Details The multicenter AETHERA trial was conducted at 78 sites in the United States and Europe. A total of 329 Hodgkin lymphoma patients who had not received brentuximab and who had at least one risk factor for relapse were randomized

Post-Transplant Brentuximab Vedotin in Hodgkin Lymphoma ■■ AETHERA is the first trial to show improved progression-free survival following autologous stem cell transplantation with any regimen. ■■ Immediate post-transplant consolidation with the antibody-drug conjugate brentuximab vedotin extended progression-free survival by 20% vs placebo. ■■ Brentuximab vedotin post-transplant is poised to become the standard of care for patients at risk of disease progression following transplantation.

EXPERT POINT OF VIEW

“A

ETHERA is the first study to show a significant effect of a posttransplant strategy in patients at high risk of relapse after transplant,” said Brad S. Kahl, MD, Associate Professor at the University of Wisconsin School of Medicine and Public Health, Madison.

AETHERA is the first study to show a significant effect of a post-transplant strategy in patients at high risk of relapse after transplant. —Brad S. Kahl, MD

“The question remains whether brentuximab is delaying inevitable relapse or taking patients who are destined to relapse to a cure. We don’t have the answer to that question. It will take longer follow-up,” Dr. Kahl said. n Disclosure: Dr. Kahl has received consulting fees from Seattle Genetics.

to receive 16 cycles of treatment with brentuximab vedotin or placebo. Risk factors for relapse included a history of refractory Hodgkin lymphoma, relapse within 1 year of front-line chemotherapy, and extranodal disease at the time of pre-autologous stem cell transplantation relapse. Nearly 50% of patients had three risk factors for relapse. Patients who relapsed on placebo were allowed to cross over to the brentuximab vedotin arm, and 85% did so.

Survival Results and Toxicity As assessed by investigators, the 2-year progression-free survival was 65% vs 45%, respectively. This finding represented a 50% reduction in the risk of disease progression at 2 years (hazard ratio = 0.50, 95% confidence interval = 0.36–0.70). “A 20% difference in progression-free survival has never been seen in this patient population,” Dr. Moskowitz said. The progression-free survival benefit was consistent across all prespecified subgroups, including primary refractory patients who relapsed within 12 months of front-line therapy and patients who relapsed after 12 months with extranodal disease.

At the interim analysis, overall survival was similar in both groups at 2 years. Dr. Moskowitz attributed this finding to the large percentage of patients who crossed over to active treatment from the placebo arm (85%). Currently, overall survival is 88%. The final overall survival analysis is expected in 2016. In the brentuximab vedotin arm, peripheral sensory neuropathy was the most common adverse event (56%), followed by neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%). With dose reductions, peripheral sensory neuropathy resolved in 85% of patients on the brentuximab vedotin arm. n

Disclosure: Dr. Moskowitz has received research funding from Genentech, Merck, and Seattle Genetics and also has served as a consultant for Seattle Genetics.

Reference 1. Moskowitz CH, Nadamanee A, Masszi T, et al: The AETHERA trial: Results of a randomized, double-blind, placebo-controlled phase 3 study of brentuximab vedotin in the treatment of patients at risk of progression following autologous stem cell transplant for Hodgkin lymphoma. 2014 ASH Annual Meeting. Abstract 673. Presented December 8, 2014.

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Please see additional Important Safety Information on adjacent page.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO® (nivolumab) treatment. Across the clinical trial experience in 574 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.9% (5/574) of patients receiving OPDIVO; no cases occurred in Trial 1. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immunemediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2. Immune-Mediated Colitis In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO. Immune-Mediated Hepatitis In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immunemediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis. Immune-Mediated Nephritis and Renal Dysfunction In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Other Immune-Mediated Adverse Reactions In Trial 1, the following clinically significant, immunemediated adverse reactions occurred in less than 1% of OPDIVO-treated patients: pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillian-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Embryofetal Toxicity Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO. Lactation It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment. Serious Adverse Reactions Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. Common Adverse Reactions The most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). Please see brief summary of Full Prescribing Information on the following pages. Reference: 1 OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2014.

OPDIVO® (nivolumab) injection, for intravenous use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE OPDIVO® (nivolumab) is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor [see Clinical Studies (14) in full Prescribing Information]. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 574 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.9% (5/574) of patients receiving OPDIVO. No cases of fatal pneumonitis occurred in Trial 1; all five fatal cases occurred in a dose-finding study with OPDIVO doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving OPDIVO: one with Grade 3 and five with Grade 2 pneumonitis. The median time to onset for the six cases was 2.2 months (range: 25 days-3.5 months). In two patients, pneumonitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 pneumonitis led to interruption or permanent discontinuation of OPDIVO in the remaining four patients. All six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day); immune-mediated pneumonitis improved to Grade 0 or 1 with corticosteroids in all six patients. There were two patients with Grade 2 pneumonitis that completely resolved (defined as improved to Grade 0 with completion of corticosteroids) and OPDIVO was restarted without recurrence of pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration (2.2) in full Prescribing Information]. Immune-Mediated Colitis In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving OPDIVO: five patients with Grade 3 and one patient with Grade 2 colitis. The median time to onset of immunemediated colitis from initiation of OPDIVO was 2.5 months (range: 1-6 months). In three patients, colitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 or 3 colitis led to interruption or permanent discontinuation of OPDIVO in the remaining three patients. Five of these six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 1.4 months (range: 3 days-2.4 months) preceding corticosteroid taper. The sixth patient continued on low-dose corticosteroids started for another immune-mediated adverse reaction. Immune-mediated colitis improved to Grade 0 with corticosteroids in five patients, including one patient with Grade 3 colitis retreated after complete resolution (defined as improved to Grade 0 with completion of corticosteroids) without additional events of colitis. Grade 2 colitis was ongoing in one patient. Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold OPDIVO for Grade 2 or 3 immune-mediated colitis. Permanently discontinue OPDIVO for Grade 4 colitis or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.2) in full Prescribing Information].

Immune-Mediated Hepatitis In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO (nivolumab)-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs. 12%), alkaline phosphatase (22% vs. 13%), ALT (16% vs. 5%), and total bilirubin (9% vs. 0). Immune-mediated hepatitis, defined as requirement for corticosteroids and no clear alternate etiology, occurred in 1.1% (3/268) of patients receiving OPDIVO: two patients with Grade 3 and one patient with Grade 2 hepatitis. The time to onset was 97, 113, and 86 days after initiation of OPDIVO. In one patient, hepatitis was diagnosed after discontinuation of OPDIVO for other reasons. In two patients, OPDIVO was withheld. All three patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Liver tests improved to Grade 1 within 4-15 days of initiation of corticosteroids. Immune-mediated hepatitis resolved and did not recur with continuation of corticosteroids in two patients; the third patient died of disease progression with persistent hepatitis. The two patients with Grade 3 hepatitis that resolved restarted OPDIVO and, in one patient, Grade 3 immunemediated hepatitis recurred resulting in permanent discontinuation of OPDIVO. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Nephritis and Renal Dysfunction In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVOtreated group as compared to the chemotherapy-treated group (13% vs. 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction (defined as ≥ Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology) occurred in 0.7% (2/268) of patients at 3.5 and 6 months after OPDIVO initiation, respectively. OPDIVO was permanently discontinued in both patients; both received high-dose corticosteroids (at least 40 mg prednisone equivalents). Immune-mediated nephritis resolved and did not recur with continuation of corticosteroids in one patient. Renal dysfunction was ongoing in one patient. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently discontinue OPDIVO. For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, withhold OPDIVO and administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue OPDIVO [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 1, where patients were evaluated at baseline and during the trial for thyroid function, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. The median time to onset was 2.5 months (range: 24 days-11.7 months). Seventeen of the 21 patients with hypothyroidism received levothyroxine. Fifteen of 17 patients received subsequent OPDIVO dosing while continuing to receive levothyroxine. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. The median time to onset in OPDIVO-treated patients was 1.6 months (range: 0-3.3 months). Four of five patients with Grade 1 hyperthyroidism and two of three patients with Grade 2 hyperthyroidism had documented resolution of hyperthyroidism; all three patients received medical management for Grade 2 hyperthyroidism. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of OPDIVO for hypothyroidism or hyperthyroidism. Other Immune-Mediated Adverse Reactions Other clinically significant immune-mediated adverse reactions can occur. Immunemediated adverse reactions may occur after discontinuation of OPDIVO therapy. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of OPDIVO-treated patients in Trial 1: pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis. Across clinical trials of OPDIVO administered at doses of 3 mg/kg and 10 mg/kg the following additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome.

For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, withhold OPDIVO (nivolumab), administer high-dose corticosteroids, and if appropriate, initiate hormonereplacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting OPDIVO after completion of corticosteroid taper based on the severity of the event [see Dosage and Administration (2.2) in full Prescribing Information]. Embryofetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-Mediated Pneumonitis [see Warnings and Precautions] • Immune-Mediated Colitis [see Warnings and Precautions] • Immune-Mediated Hepatitis [see Warnings and Precautions] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions] • Immune-Mediated Hypothyroidism and Hyperthyroidism [see Warnings and Precautions] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described in the WARNINGS and PRECAUTIONS section and below reflect exposure to OPDIVO in Trial 1, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received OPDIVO 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks [see Clinical Studies (14) in full Prescribing Information]. The median duration of exposure was 5.3 months (range: 1 day-13.8+ months) with a median of eight doses (range: 1 to 31) in OPDIVO-treated patients and was 2 months (range: 1 day-9.6+ months) in chemotherapy treated patients. In this ongoing trial, 24% of patients received OPDIVO for greater than 6 months and 3% of patients received OPDIVO for greater than 1 year. Clinically significant adverse reactions were also evaluated in 574 patients with solid tumors enrolled in two clinical trials receiving OPDIVO at doses of 0.1 to 10 mg/kg every 2 weeks, supplemented by immune-mediated adverse reaction reports across ongoing clinical trials [see Warnings and Precautions]. In Trial 1, patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumabrelated Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. The study population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% white, baseline ECOG performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated LDH at baseline (51% vs. 38%). OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. Table 1 summarizes the adverse reactions that occurred in at least 10% of OPDIVO-treated patients. The most common adverse reaction (reported in at least 20% of patients) was rash.

Table 1:

Selected Adverse Reactions Occurring in ≥10% of OPDIVO (nivolumab)-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 1) OPDIVO (n=268) All Grades

All Grades

Grades 3-4

Percentage (%) of Patients

Adverse Reaction Skin and Subcutaneous Tissue Disorders Rasha Pruritus Respiratory, Thoracic, and Mediastinal Disorders Cough Infections and Infestations Upper respiratory tract infectionb General Disorders and Administration Site Conditions Peripheral edema a

Grades 3-4

Chemotherapy (n=102)

21 19

0.4 0

7 3.9

0 0

2.0

Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash macular, rash papular, rash pustular, rash vesicular, and dermatitis acneiform. b Upper respiratory tract infection is a composite term which includes rhinitis, pharyngitis, and nasopharyngitis.

Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO were: Cardiac Disorders: ventricular arrhythmia Eye Disorders: iridocyclitis General Disorders and Administration Site Conditions: infusion-related reactions Investigations: increased amylase, increased lipase Nervous System Disorders: dizziness, peripheral and sensory neuropathy Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis. Table 2:

Selected Laboratory Abnormalities Increased from Baseline Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 1) Percentage of Patients with Worsening Laboratory Test from Baselinea OPDIVO

Test Increased AST Increased alkaline phosphatase Hyponatremia Increased ALT Hyperkalemia a

Chemotherapy

All Grades

Grades 3-4

All Grades

Grades 3-4

28 22

2.4 2.4

12 13

1.0 1.1

25 16 15

5 1.6 2.0

18 5 6

1.1 0 0

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range 252 to 256 patients) and chemotherapy group (range 94 to 96 patients).

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Of 281 patients who were treated with OPDIVO 3 mg/kg every 2 weeks and evaluable for the presence of anti-product antibodies, 24 patients (8.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in two patients (0.7%). There was no evidence of altered pharmacokinetic profile or toxicity profile with anti-product binding antibody development based on the population pharmacokinetic and exposure-response analyses.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to OPDIVO (nivolumab) with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) in full Prescribing Information] and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in full Prescribing Information]. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Data Animal Data A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). Nivolumab administration resulted in a non-doserelated increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Lactation Risk Summary It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment with OPDIVO. Females and Males of Reproductive Potential Contraception Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO. Pediatric Use The safety and effectiveness of OPDIVO have not been established in pediatric patients. Geriatric Use Clinical studies of OPDIVO did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 272 patients randomized to OPDIVO in Trial 1, 35% of patients were 65 years or older and 15% were 75 years or older.

Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. OPDIVO (nivolumab) has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There is no information on overdosage with OPDIVO. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of OPDIVO, including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions]. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions]. • Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions]. • Hypothyroidism and Hyperthyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism and hyperthyroidism [see Warnings and Precautions]. Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions]. Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions, Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO [see Use in Specific Populations]. Advise women not to breastfeed while taking OPDIVO [see Use in Specific Populations]. Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321663A0

Issued December 2014 1506US14BR02624-01-01

ASCOPost.com | JANUARY 25, 2015

PAGE 11

ASH Annual Meeting Hematology

Nilotinib With Low-Intensity Chemotherapy Useful in Elderly Patients With Philadelphia Chromosome–Positive ALL By Alice Goodman

he addition of the tyrosine kinase inhibitor nilotinib (Tasigna) to standard low-intensity chemotherapy improved outcomes in elderly patients with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) and may represent a new approach to this group of patients, who are known to have a poor prognosis. “Our study showed that nilotinib combined with age-adapted, low-intensity chemotherapy is highly effective for elderly [Philadelphia chromosome–

The combination of chemotherapy and tyrosine kinase inhibition is now the gold standard for treatment of Philadelphia chromosome–positive ALL. However, despite the use of a tyrosine kinase inhibitor, elderly patients not eligible for transplant still have a poor outcome.

Study Details The European Working Group in ALL (EWALL) developed an age-adapted, low-intensity chemotherapy backbone for Philadelphia chromosome–positive

Our study strongly supports adding nilotinib to standard chemotherapy to help elderly ALL patients achieve remission without significant toxicity. We hope that further study will confirm this drug’s positive effect in elderly Philadelphia chromosome–positive ALL and lead to its approval in this setting. —Oliver G. Ottmann, MD

positive] ALL patients. At 2 years, overall survival was 72.7% without stem cell transplant. A high rate of molecular response was achieved, and this increased over time,” said study author Oliver G. Ottmann, MD, of Johann Wolfgang Goethe University, Frankfurt, Germany. “Our study strongly supports adding nilotinib to standard chemotherapy to help elderly ALL patients achieve remission without significant toxicity. We hope that further study will confirm this drug’s positive effect in elderly [Philadelphia chromosome–positive] ALL and lead to its eventual approval in this setting,” Dr. Ottmann stated.

ALL patients aged 55 and older. At the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, Dr. Ottmann reported results of a phase II trial designed to evaluate the secondgeneration tyrosine kinase inhibitor nilotinib in combination with the EWALL low-intensity chemotherapy backbone.1 “We had little prior experience with nilotinib in these patients,” Dr. Ottmann said. The low-intensity chemotherapy regimen follows: patients were pretreated with dexamethasone and optional cyclophosphamide, and nilotinib was given with induction therapy and

EXPERT POINT OF VIEW

“P

atients with Philadelphia chromosome– positive ALL have traditionally done poorly with conventional chemotherapy, but outcomes are improving in the era of tyrosine kinase inhibitors. This study reports the safety and efficacy with a combination of a targeted approach and lowintensity chemotherapy,” said David Steensma, MD, of Dana-Farber Cancer Institute, Boston. David Steensma, MD “Several studies have already been presented combining dasatinib [Sprycel] with chemotherapy in Philadelphia chromosome–positive ALL, and this has become routine clinical practice, especially in older patients ineligible for transplant. This study uses nilotinib (Tasigna) instead of dasatinib, which has different side effects. We can now comfortably use nilotinib in elderly patients with Philadelphia chromosome–positive ALL,” he concluded. n Disclosure: Dr. Steensma reported no potential conflicts of interest.

continued thereafter. During induction therapy, nilotinib was combined with weekly vincristine. Consolidation therapy consisted of nilotinib, methotrexate, and asparaginase (Elspar) for cycles 1, 3, and 5 and cytarabine for cycles 2, 4, and 6. Maintenance therapy consisted of continued nilotinib, mercaptopurine daily, and methotrexate weekly over 1 month every other month and dexamethasone with vincristine given in 2-month intervals for up to 24 months of treatment. The study enrolled 56 newly diag-

nosed patients, with a median age of 65 years (range, 55–85 years); 12 of these patients were aged 70 or older. None had central nervous system involvement.

Interim Analysis In an interim analysis of 47 patients evaluable for efficacy, complete hematologic response was achieved in 41 (87%). There was a low incidence of failure (two patients, 4%). Three patients were excluded from the analysis continued on page 12

Treating Philadelphia Chromosome–Positive ALL ■■ Elderly patients with Philadelphia chromosome–positive acute lymphoblastic leukemia have had a poor prognosis. ■■ A phase II study showed that nilotinib was safe and effective when combined with age-adjusted, low-intensity chemotherapy. ■■ Nilotinib has fewer side effects than dasatinib (also used with chemotherapy in this setting), and the combination regimen may improve outcomes.

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PAGE 12

ASH Annual Meeting Relapsed Myeloma continued from page 1

achieved with bortezomib (Velcade) plus lenalidomide/dexamethasone. Speaking of KRd, he said, “We have never seen this duration of remission with this side-effect profile.” The objective response rate was also significantly higher for the triplet, 87% vs 67%. “Even more impressively,” he added, “the rate of complete responses was more than three times higher for the three drugs, 32% vs 9% (P < .0001).” Median duration of response was 28.6 and 21.2 months.

Improved Survival Trend At the time of this interim analysis, median overall survival was not reached in either group, but there was a trend toward longer survival in the carfilzomib arm (HR = 0.79; P = .018). “We didn’t

Nilotinib in ALL continued from page 11

due to early treatment discontinuation. The median time to response was 6 weeks. At a median follow-up of 8.5 months, which Dr. Ottmann noted was short, the regimen was highly effective, with few relapses. In patients who did not go on to stem cell transplant, the median overall survival at 2 years was 72.7%; in all patients, the median overall survival at 2 years was 67.1%. The investigators looked at minimal residual disease after induction therapy. Major molecular response was 45.5% after induction therapy and 79% during consolidation therapy. The minimal residual disease–negative status increased over time. After induction therapy, only 1.4% tested negative for minimal residual disease; during consolidation therapy, 26% tested negative for minimal residual disease. In the study, 20% of patients underwent stem cell transplant. “This is evolving as a therapeutic option, even among elderly patients with [Philadelphia chromosome–positive] ALL,” Dr. Ottmann said. n Disclosure: Dr. Ottmann has received honoraria as well as research funding from and has served as a consultant for Novartis.

Reference 1. Ottmann OG, Pfeifer H, Cayuela J-M, et al: Nilotinib (Tasigna®) and chemotherapy for first-line treatment in elderly patients with de novo Philadelphia chromosome/ BCR-ABL1 positive acute lymphoblastic leukemia: A trial of the European Working Group for Adult ALL (EWALL-PH-02). 2014 ASH Annual Meeting. Abstract 798. Presented December 9, 2014.

cross the prespecified stopping boundary [P = .005]. There is still some instability in the curves, and the difference is not yet statistically significant,” he noted. At 24 months, survival rates were 73.3% for KRd vs 65.0% for Rd (P = .0046). Dr. Stewart explained that an overall survival benefit could be difficult to show, since “survival in multiple myeloma has be-

come much longer, as we have very effective treatments for when patients relapse.” He added, “If we don’t see an overall survival advantage, it doesn’t change the overall benefit we saw with this regimen. This regimen is also being studied in newly diagnosed patients and will probably be the most effective one ever applied.”

Safety of Carfilzomib Despite the addition of carfilzomib, and the fact that patients stayed on treatment much longer (88 vs 57 weeks), toxicity was not significantly increased in the KRd arm. Patients receiving the triplet actually had higher health-related quality-of-life scores, he reported. Treatment discontinuations due to

BLEED TRIM:

LIVE: 1

ASCOPost.com | JANUARY 25, 2015

PAGE 13

ASH Annual Meeting

D: 15.4” 15.15”

14.15”

Brad Kahl, MD

study drug were similar between the arms: approximately 16%. Rates of peripheral neuropathy were also the same (17%), “confirming the lack of this toxicity with carfilzomib,” he said, but hypertension was more common (14% vs 7%). Cardiac and renal events, which have been reported in some previous studies

of heavily pretreated patients, were “marginally higher” in the three-drug regimen but overall consistent or even lower than those previously reported. “We saw a slight increase in all grades of cardiac failure—6% vs 4% in the control arm—and for grade 3 and higher, it was 3% vs 2%, but there were more deaths from cardiac failure in the control arm,” he said.

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“To some degree this puts to rest the concerns that have been raised anecdotally about carfilzomib,” Dr. Stewart maintained. Based on these findings, he said, “It’s fair to say that KRd could represent a new standard of care in relapsed myeloma.” Press briefing moderator Brad Kahl, MD, the Skoronski Chair of Lymphoma Research and Associate Professor of Medicine at the University of Wisconsin School of Medicine and Public Health, Madison, agreed. “Dr. Stewart’s study will establish a new standard of care in this patient population,” he said. n Disclosure: Dr. Stewart has been a consultant for Novartis, Array BioPharma, BMS, and Celgene and has received research funding from Millennium. Dr. Kahl reported no potential conflicts of interest.

Reference 1. Stewart KA, Rajkumar SV, Dimopoulos MA, et al: Carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients with relapsed multiple myeloma: Interim results from ASPIRE, a randomized, open-label, multicenter phase 3 study. ASH Annual Meeting. Abstract 79. Presented December 7, 2014.

EXPERT POINT OF VIEW

BLEED: 10.825”

LIVE: 9.575”

Making the human connection

TRIM: 10.575”

Introducing

avid H. Vesole, MD, PhD, FACP, Co-Division Chief and Director of Research for the Multiple Myeloma Division at the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey, commented after the presentation of the ASPIRE trial data that the findings were “impressive.” “It’s not overly surprising to most of us that three drugs have superiority over two drugs. The outcome that is most impressive is the safety signal. It assures us the drug is safe,” Dr. Vesole said. “There have been such concerns about using single-agent carfilzomib (Kyprolis), with the potential for cardiac and pulmonary toxicity. This study of nearly 800 patients shows that the drug can be safely administered with a toxicity profile virtually identical to the lenalidomide (Revlimid) and dexamethasone control arm. I am pleased to see this kind of data.” n Disclosure: Dr. Vesole reported no potential conflicts of interest.

The ASCO Post | JANUARY 25, 2015

PAGE 14

San Antonio Breast Cancer Symposium SOFT Trial Results continued from page 1

Tamoxifen has been the standard of care for adjuvant therapy in premenopausal women with hormone receptor– positive early-stage breast cancer. Studies of ovarian function suppression have been equivocal in younger patients. The SOFT study was designed to address this issue by including only patients who retained or regained a premenopausal estradiol level after chemotherapy. “I believe this trial is practice-changing. If I see a woman under age 35 with hormone receptor–positive breast cancer, I will know how to advise her. I also feel more comfortable with tamoxifen alone in an older premenopausal woman with a small, low-risk breast cancer,” stated lead author Prudence Francis, MD, Head of Breast Medical Oncology at Peter MacCallum Cancer Centre, Melbourne, Australia. She presented these results at the 2014 San Antonio Breast Cancer Symposium.1

Closer Look at the SOFT Trial The SOFT trial was designed to assess the value of ovarian function suppression in 3,047 premenopausal women with hormone receptor–positive breast cancer treated for 5 years with tamoxifen plus ovarian function suppression vs tamoxifen alone or exemestane plus ovarian function suppression. Women randomly assigned

of 5.6 years, there was no overall benefit for the addition of ovarian function suppression to tamoxifen; 5-year event-free survival was 84.7% with tamoxifen alone vs 86.6% for tamoxifen plus ovarian function suppression (P = NS). However, in the cohort that remained premenopausal after chemotherapy (median age, 40 years), ovarian function suppression added to tamoxifen achieved a 22% reduction in the relative risk of tumor recurrence vs tamoxifen alone. A secondary analysis showed that the combination of exemestane plus ovarian function suppression was even better in the premenopausal prior chemotherapy cohort, with a 35% relative risk reduction for tumor recurrence vs tamoxifen alone. In the cohort of women who remained premenopausal after chemotherapy, the 5-year breast cancer–free interval was 78.0% for tamoxifen alone, 82.5% for tamoxifen plus ovarian function suppression, and 85.7% for exemestane plus ovarian function suppression. “In women under age 35, approximately one in three women assigned tamoxifen alone had a tumor recurrence within 5 years compared with one in six for exemestane plus ovarian function suppression,” Dr. Francis stated. The cohort of women who did not receive chemotherapy (median age, 46 years) did well in all three study arms.

Ovarian Function Suppression in Premenopausal Breast Cancer ■■ Ovarian function suppression reduced the risk of breast cancer recurrence when added to adjuvant tamoxifen in women with hormone receptor– positive breast cancer who remained premenopausal after chemotherapy. ■■ In women who did not receive chemotherapy, 5 years of tamoxifen was sufficient to reduce the risk of tumor recurrence, and ovarian function suppression is not advised in this low-risk group.

to ovarian function suppression had the choice of 5 years of monthly injections of triptorelin (Trelstar), surgical removal of the ovaries, or radiation therapy to ovaries. These treatments were compared in two different groups of women: women who had received prior adjuvant chemotherapy (53%) and women who did not receive chemotherapy (47%). The women who received chemotherapy were on average younger with higher-risk larger tumors that were more likely to be node-positive; the women who did not receive chemotherapy had low-risk tumors. Women who had chemotherapy entered the trial up to 8 months postchemotherapy, whereas those who had no chemotherapy entered the trial within 12 weeks after surgery. The primary analysis was between tamoxifen vs tamoxifen plus ovarian function suppression. At a median follow-up

The 5-year breast cancer–free interval was 95.8% with tamoxifen alone, 95.1% with tamoxifen plus ovarian function suppression, and 97.1% with exemestane plus ovarian function suppression. “In this older group of women who did not have chemotherapy, there is no reason to add ovarian function suppression. Their average age is 46 years, and some of these women will naturally go into menopause soon,” Dr. Francis said.

three treatment arms. For the primary comparison, endocrine symptoms were initially worse with the combination of tamoxifen and ovarian function suppression compared with tamoxifen alone.

Karin Ribi, PhD

Sexual function was impacted in all three treatment arms. This parameter was worse in the tamoxifen plus ovarian function suppression arm compared with tamoxifen alone, as measured by patientreported interest in sex, and was the worst in the exemestane plus ovarian function suppression arm, Dr. Ribi noted. When these symptoms were analyzed according to whether patients received chemotherapy, treatment differences for endocrine symptoms and sexual function were less pronounced in those who previously had chemotherapy. “Our hypothesis is that women treated with chemotherapy already had experienced side effects, and when they move to hormonal therapy, they already know they have a worse risk profile, so they may be more willing to accept these side effects,” Dr. Ribi suggested in an interview with The ASCO Post.

‘Convincing Data’ Commenting on the SOFT study, Carlos L. Arteaga, MD, Director of the Breast Cancer Program at VanderbiltIngram Cancer Center in Nashville and President of the American Association for Cancer Research, said that he found these data convincing. “This was a solid presentation. I am persuaded by the findings in women under 35, and I was impressed by the clear separation between the curves. Perhaps the most important aspect of this study is that the researchers included only women who were premenopausal at the start of the study, whereas this was not true of other studies of ovarian function suppression,” he said.

Questions Remain The formal discussant of this trial, Hope S. Rugo, MD, of the University of California, San Francisco, said that the biggest question for treatment of premenopausal hormone-sensitive breast cancer is “how much [ovarian suppression] is enough.” “If we use ovarian function suppression should we use tamoxifen or an aromatase inhibitor? In whom should we avoid chemotherapy? We don’t have a randomized trial and have to use inferential data,” she noted. “The take-home points of this trial are that it is a successful international collaboration with a rigorous definition of menopausal status. However, follow-up is still too short to determine the effects of ovarian function suppression on distant tumor recurrence and overall survival,” she said. “Attention has to be paid to management of toxicity with ovarian function suppression, including endocrine symptoms, hypertension, bone health, and depression,” Dr. Rugo continued. She said that treatment of premenopausal early-stage breast cancer needs to be individualized, and she proposed the fol-

Hope S. Rugo, MD

lowing algorithm: In women with low-risk, node-negative tumors, tamoxifen should be given for at least 5 years. For high-risk patients under the age of 35, ovarian function suppression should be considered due to the marked reduction in breast cancer recurrence. “It is an individualized decision whether we use exemestane or tamoxifen with ovarian function suppression in this group, based on toxicity,” she said. “For intermediate-risk women, ovarian function suppression and endocrine therapy would be reasonable.” n

Quality of Life

Disclosure: Drs. Francis and Ribi reported no potential conflicts of interest. Dr. Arteaga reported research support from Novartis, AstraZeneca, Puma Biotechnology, U3-Daiichi, and OSIAstellas. Dr. Rugo reported research support to the Regents of the University of California from Novartis, Pfizer, Merck, and Lilly.

Karin Ribi, PhD, a psychologist with the IBCSG, presented a separate analysis of patient-reported changes from baseline in endocrine symptoms, sexual function, and quality of life in SOFT participants.2 Mood and well-being did not differ between the three treatment arms. Endocrine symptoms were present in all

References 1. Francis PA, et al: 2014 San Antonio Breast Cancer Symposium. Abstract S3-08. Presented December 12, 2014. 2. Ribi K, et al: 2014 San Antonio Breast Cancer Symposium. Abstract S3-09. Presented December 12, 2014.

Carlos L. Arteaga, MD

THERE’S A

NATURAL KILLER INSIDE EVERYONE WITH THE POTENTIAL TO TAKE ON

MULTIPLE MYELOMA

NATURAL KILLER CELLS A first line of defense against cancer1

In multiple myeloma, Natural Killer Cells scan the body in search of myeloma cells and once recognized, may become activated to exert cytotoxicity against these cells while sparing normal cells.2-6 However, as a consequence of multiple myeloma, immune function declines significantly over time and mechanisms of immune evasion and immunosuppression impair Natural Killer Cell activity.2,5,7-14 Directly enhancing Natural Killer Cell activity is a fundamentally different approach under investigation for multiple myeloma. SLAMF7, along with KIR and CD137, are among cell surface proteins that have been implicated in regulating Natural Killer Cell activity.15-17

A CLOSER LOOK AT NATURAL KILLER CELL-MEDIATED CYTOTOXICITY: Once a malignant cell is recognized, Natural Killer Cells can release cytotoxic granules, among other mechanisms, to elicit targeted cell death18-20 Natural Killer Cell Natural Killer Cell cytotoxic granules

Myeloma cell Cytotoxic Granule Release19

Myeloma cell Targeted Cell Death19

Can the bodyâ&#x20AC;&#x2122;s own Natural Killer Cells be activated to target myeloma cells? Exploring the potential of the SLAMF7, KIR, and CD137 pathways

SLAMF7 Natural Killer Cell SLAMF7

SLAMF7

Myeloma cell

Signaling Lymphocytic Activation Molecule Family member 7 is a cell surface protein that is highly expressed on the surface of myeloma cells across disease stages and cytogenetic subtypes.21 SLAMF7 is also expressed on Natural Killer Cells, plasma cells, and other immune cells.21 The potential of the SLAMF7 pathway to regulate Natural Killer Cell cytotoxicity in multiple myeloma is currently under investigation.

KIR Natural Killer Cell KIR

Myeloma cell

Ligand

Killer cell Immunoglobulin-like Receptors are expressed on the surface of various immune cells, including Natural Killer Cells, and are key regulators of their activation.16 Myeloma cells are able to evade Natural Killer Cell-mediated recognition and cytotoxicity by upregulating the ligand for inhibitory KIRs.5 The potential of the KIR pathway to regulate Natural Killer Cell activation in multiple myeloma is currently being studied.

CD137 Natural Killer Cell CD137

CD137 is a cell surface protein that can be upregulated on the surface of Natural Killer Cells, T cells and other immune cells, and its ligand is highly expressed on myeloma cells.17,22 The potential of the CD137 pathway to regulate Natural Killer Cell cytotoxicity in multiple myeloma is also being explored.

Myeloma cell

Ligand

Despite recent advances, multiple myeloma remains a largely incurable disease, with fewer than half of patients surviving five years after diagnosis.23

We need a new approach. Bristol-Myers Squibb is deeply committed to furthering the science behind immuno-oncology. Leading the way in immuno-oncology research, Bristol-Myers Squibb is investigating the potential of the SLAMF7, KIR, and CD137 pathways to activate the body’s own Natural Killer Cells to target myeloma cells. www.naturalkillercellinside.com REFERENCES: 1. Cheng M et al. NK cell-based immunotherapy for malignant disease. Cell Molec Immunol. 2013;10:230-252. 2. Jurisic V et al. Med Oncol. 2007;24:312-317. 3. Marcus A et al. Adv Immunol. 2014;122:91-128. 4. Vivier E et al. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol. 2012;12:239-252. 5. Carbone E et al. Blood. 2005;105:251-258. 6. Frohn C et al. Br J Haematol. 2002;119:660-664. 7. Teh BW et al. Changing treatment paradigms for patients with plasma cell myeloma: Impact upon immune determinants of infection. Blood Rev. 2014;28:75-86. 8. Bernal M et al. Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma : Implications for tumor evasion of T and NK cells. Human Immunol. 2009;70:854-857. 9. Jinushi M et al. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA. 2008;105:1285-1290. 10. von Lilienfeld-Toal M et al. Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked. Cancer Immunol Immunother. 2010;59:829-839. 11. Cook G et al. Transforming growth factor ß from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes. J Leukoc Biol. 1999;66:981-988. 12. Yu J et al. Pro- and anti-inflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity. 2006;24:575-590. 13. Nielsen H et al. Immune dysfunction in multiple myeloma. Reduced natural killer cell activity and increased levels of soluble interleukin-2 receptors. APMIS. 1991;99:340-346. 14. Tinhofer I et al. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood. 2000;95:610-618. 15. Cruz-Munoz ME et al. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nat Immunol. 2009;10:297-305. 16. Campbell KS and Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology. 2011;132:312-325. 17. Murillo O et al. Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma. Clin Cancer Res. 2008;14:68956906. 18. Caligiuri MA. Blood. 2008;112:461-469. 19. Mace EM et al. Immunol Cell Biol. 2014;92:245-255. 20. Krzewski H and Coligan JE. Front Immunol. 2012;3:335. 21. Bae J, Prabhala RH, Munshi NC. Dendritic cells and peptide-based vaccine in multiple myeloma. In: Munshi NC, Anderson KC, eds. Advances in Biology and Therapy of Multiple Myeloma, Volume 2: Translational and Clinical Research. New York, NY: Springer; 2013:131-150. 22. Gullo C et al. PLoS One. 2010;5:e10845. 23. SEER Stat Fact Sheets: Myeloma, 2004-2010. http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed September 4, 2014.

ASCOPost.com | JANUARY 25, 2015

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San Antonio Breast Cancer Symposium Breast Cancer

Neoadjuvant Therapy in Triple-Negative Breast Cancer: Impact of Subtype By Caroline Helwick

mong women with triple-negative breast cancer, overall, basal-like and non–basal-like tumors were equally likely to demonstrate a pathologic complete response to neoadjuvant chemotherapy, but they responded differently to the addition of carboplatin and bevacizumab (Avastin) to a standard chemotherapy regimen, according to an analysis of CALGB/ Alliance 40603 presented at the 2014 San Antonio Breast Cancer Symposium.1 “The magnitude of pathologic complete response benefit with carboplatin was consistent across subtypes, while a basal-like pattern was predictive of a greater pathologic complete response increment with bevacizumab,” said William Sikov, MD, of Women and Infants Hospital and the Alpert Medical School of Brown University, Providence, Rhode Island. Although carboplatin increased pathologic complete response rates equally for women with basal-like and non–basal-like tumors, the addition of bevacizumab contributed benefit only among women with basal-like tumors, and the drug actually diminished pathologic complete responses in women with non–basal-like cancers, he said.

CALGB 40603 Details The randomized phase II trial included 443 patients with stage II-III triplenegative breast cancer who underwent neoadjuvant chemotherapy. The study evaluated the benefit of adding carboplatin (AUC [area under the curve] 6) or bevacizumab (10 mg/kg) to a standard neoadjuvant regimen of paclitaxel (80 mg/m2

360 tumor samples by intrinsic subtype. They classified the tumors as basal-like (n = 314)—which accounted for 87% of the samples and tends to carry a worse prognosis—or non–basal-like (n = 46). Non–basal-like tumors were a mix of subtypes, including HER2-enriched, normal-like, claudin-low, and luminal A. The overall pathologic complete response rate in these subtyped samples

The magnitude of pathologic complete response benefit with carboplatin was consistent across subtypes, while a basallike pattern predicted a greater pathologic complete response increment with bevacizumab. —William Sikov, MD

did not differ between basal-like (54%) and non–basal-like (52%) tumors, but some treatment interactions were noted. In patients in the basal-like cohort randomized to receive carboplatin or no carboplatin, pathologic complete response in the breast was achieved by 61% of the carboplatin arm vs 47% in the standard chemotherapy arm (odds ratio = 1.76, P = .014). The findings were similar for non–basal-like tumors, where pathologic complete responses were achieved by 58% and 45%, respectively (odds ratio = 1.67, P = .55). “The interesting thing was that, for the addition of carboplatin, the benefit was equivalent in basal-like and non–

Update on CALGB 40603 in Triple-Negative Breast Cancer ■■ Tumors from patients with triple-negative breast cancers in the CALGB/ Alliance 40603 trial were analyzed by intrinsic subtype and assessed for the effect of carboplatin or bevacizumab added to neoadjuvant chemotherapy. ■■ Pathologic complete responses were observed in 54% of basal-like tumors and 52% of non–basal-like tumors. ■■ Carboplatin increased the rate of pathologic complete response in both basal-like and non–basal-like subtypes; bevacizumab increased pathologic complete response rates only in the basal-like subtype.

weekly) followed by dose-dense doxorubicin and cyclophosphamide. At the 2013 San Antonio Breast Cancer Symposium, Dr. Sikov and colleagues reported that either agent increased pathologic complete response rates.2 In this analysis, the investigators drilled deeper for a closer examination of

horts. The benefit with bevacizumab was significantly greater in the basal-like subtype, more than doubling the odds of achieving a pathologic complete response. In basal-like patients, pathologic complete response rates were 64% with bevacizumab and 45% without (odds ratio = 2.15, P = .0009), but for the other subtypes, the rates were 43% and 60%, respectively (odds ratio = 0.50, P = .25),

basal-like cancers. This doesn’t mean that carboplatin was of no benefit in the basal-like subtype, only that there was no amplification of benefit vs the non– basal-like subtype,” he explained. In contrast, subtype was important for the achievement of pathologic complete response in the bevacizumab co-

indicating a trend toward worse responses when bevacizumab was added. CALGB 40603 also showed that higher levels of expression of any of five immune signatures, reflecting an increase in tumor-infiltrating lymphocytes, were associated with higher pathologic complete response rates. Expression of high proliferation, low estrogen expression, or high TP53-mutation signatures, in particular, was predictive of higher pathologic complete response rates overall and greater pathologic complete response benefit from the addition of bevacizumab, Dr. Sikov also reported. “None of these signatures was predictive of greater pathologic complete response benefit for carboplatin in all patients or in the basal-like subset,” he added.

Not Likely to Change Practice “Although these are interesting observations, I don’t think our data will change clinical practice,” Dr. Sikov acknowledged. Interest in using bevacizumab in earlystage triple-negative disease has diminished following disappointing results from several phase III studies, he said. Regarding the role of carboplatin in the neoadjuvant setting for triple-negative disease, he said, “The jury is still out.” Dr. Sikov said that these data will probably reinforce the way clinicians already view the use of carboplatin in early-stage triple-negative disease. Some clinicians feel that the 14% absolute increase in pathologic complete response rates with the addition of carboplatin is encouraging and could benefit their high-risk triple-

negative patients, especially since its use is associated with relatively modest increases in hematologic toxicities, and the drug is familiar and inexpensive. Other clinicians may think the absolute increase in the pathologic complete response rate is not high enough to convince them of the benefit of adding carboplatin, will point to the increase of toxicity and the lack of long-term outcomes, and will conclude that the available data does not support the use of carboplatin outside of a clinical trial, he said. “A risk/benefit assessment must be done with the patient and clinician together,” he concluded. In an interview, John Cole, MD, Head of Medical Oncology at the Ochsner Clinic Foundation in New Orleans, commented that he does not yet use carboplatin in the neoadjuvant treatment of triple-negative cancers, and before he does, he would like to see a subset of patients likely to benefit. “There are no clear, compelling data yet on the use of carboplatin at this point. We are trying to find a way to enrich the population of patients who might benefit from this (and bevacizumab),” he said. He was curious about the high rate (87%) of cancers that were subtyped as basal-like, since this is much higher than observed in other studies. “It makes you

John Cole, MD

wonder a bit about patient selection,” Dr. Cole continued. He said he would also like to know what percentage were BRCA mutation–positive and what their outcomes were. “This is an important question, because this might be the group getting the most bang, while others are not,” he said. n

Disclosure: Drs. Sikov and Cole reported no potential conflicts of interest.

References 1. Sikov WM, et al: 2014 San Antonio Breast Cancer Symposium. Abstract S4-05. Presented December 11, 2014. 2. Sikov WM, et al: 2013 San Antonio Breast Cancer Symposium. Abstract S5-01. Presented December 13, 2013.

The ASCO Post | JANUARY 25, 2015

PAGE 20

San Antonio Breast Cancer Symposium Breast Cancer

Pembrolizumab Holds Promise in Breast Cancer, Early Studies Suggest By Caroline Helwick

ingle-agent treatment with the immunotherapy drug pembrolizumab produced a “signal of activity” and led to some durable responses in patients with metastatic triple-negative breast cancer, Rita Nanda, MD, of the University of Chicago, reported at the 2014 San Antonio Breast Cancer Symposium.1

Pembrolizumab is a humanized monoclonal antibody that targets the programmed cell death protein 1 (PD-1). This releases the PD-1 pathway–mediated inhibition of the immune response, in effect “taking the brakes off” the immune system to allow it to attack the tumor. Pembrolizumab is already ap-

There is excitement about immunotherapy in breast cancer, and this study shows that, as in other tumor types, a small proportion of patients may respond, and those who do respond tend to be long-term responders. —Rita Nanda, MD

“There is excitement about immunotherapy for the treatment of triple-negative breast cancer. What this study shows, as is the case for other tumor types, is that a proportion of patients appear to respond to therapy. And those who do respond tend to be long-term responders,” Dr. Nanda indicated at a press briefing.

proved for the treatment of advanced melanoma.

KEYNOTE-012 Details The phase Ib KEYNOTE-012 trial recruited 32 patients with metastatic triple-negative breast cancer, most of whom had received at least three prior

Pembrolizumab Findings Spark Interest ■■ The anti–PD-1 agent pembrolizumab produced an 18.5% response rate in patients with metastatic triple-negative breast cancer. ■■ For responders, median duration of response has not been reached; 6-month progression-free survival was 23.3%.

chemotherapies for advanced disease. Patients were only eligible if their tumors were positive for PD-L1 expression. Patients received pembrolizumab at 10 mg/kg every 2 weeks until progression of disease or unacceptable toxicity. Among 27 patients with measurable disease (by RECIST 1.1 criteria), the overall response rate was 18.5%, including one (3.7%) complete response and four (14.8%) partial responses. In addition, seven patients (25.9%) had stable disease, and 15 (55.6%) had progressive disease. “The current standard of care for this heavily pretreated triple-negative breast cancer population is chemotherapy, and in comparison to chemotherapy, an 18% response rate is of interest,” Dr. Nanda suggested. “Furthermore, those patients who did experience a response had responses that lasted 40 weeks or more, which is

very exciting when you think about how well tolerated this drug appears to be.” Adverse events of any grade were observed in 56% of patients; grade 3 events were observed in 12.5% and grade 4 in 3.1%. Three patients (9.4%) had a serious adverse event. “Pembrolizumab showed an acceptable safety and tolerability profile in patients with heavily pretreated, PDL1–positive, advanced triple-negative breast cancer,” Dr. Nanda concluded. “Responses were durable, and three of five responders have been on treatment for at least 11 months.” n

Disclosure: Dr. Nanda reported no potential conflicts of interest.

Reference 1. Nanda R, et al: San Antonio Breast Cancer Symposium. Abstract S1-09. Presented December 10, 2014.

EXPERT POINT OF VIEW

tudy discussant Mary L. Disis, MD, Professor of Medicine and Associate Dean of Translational Science at the University of Washington, Seattle, com-

tions, so we can drive these response rates up,” Dr. Disis said. “Let’s not wait. Let’s move on these findings so that we can benefit our other breast cancer patients.”

I say onward to the rational combinations, so we can drive these response rates up…. Let’s move on these findings so that we can benefit our other breast cancer patients. —Mary L. Disis, MD

mented that the response rate, approaching 20%, is “in the ballpark” of those observed in melanoma, lung cancer, and renal cancer. She pointed out that when anti–PD-1 agents are combined with other active agents—especially MEK inhibitors, as is done in melanoma—response rates can exceed 50%. “We are seeing the biology, response rates, and toxicity that we see in other diseases,” she pointed out. “I say onward to the rational combina-

Good Target for Immunotherapy The ASCO Post also spoke with Lajos Pusztai, MD, DPhil, Professor of Medicine, Chief of Breast Medical Oncology and Co-Director of Cancer Genetics Research Program at Yale Cancer Center, New Haven, Connecticut. He agreed that the overall response rate of 18% to the single agent is almost as high as that seen in other malignancies where

anti–PD-1 agents are being studied. “Remember, the single-agent activity of trastuzumab [Herceptin] in HER2-

Lajos Pusztai, MD, DPhil

positive patients was 20%,” he added. “We will learn how to leverage the single-agent activity of these drugs.” This will most likely be achieved by giving these drugs in combination with other immunotherapies, as is being studied in melanoma right now, he predicted. To Dr. Pusztai, the findings are particularly “exciting” because triple-negative breast cancer has been completely lacking in new, effective treatments. Meeting this unmet need is partly driving the interest in anti–PD-1 agents in triple-negative cancer, but so

is the biology of this subtype: triplenegative tumors are a good target for immunotherapy, he pointed out. “Based on indirect data, the most dramatic prognostic effect of an immune presence is in triple-negative breast cancer. This is the breast cancer with the highest degree of immune infiltration,” he noted. “This is very exciting. For a long time we have known that patients with a lot of tumor-infiltrating lymphocytes do better, but we haven’t known if this was cause or association. Now we have drugs with which to test this prospectively.” Dr. Pusztai is involved in the development of an adjuvant study of pembrolizumab in triple-negative breast cancer. He indicated that several companies are in a race to develop these drugs, “which will probably change practice…. We are in a new era of cancer therapies.” n Disclosure: Dr. Disis received grant funding from Seattle Genetics, VentiRx, and EMD Serono and has stock in VentiRx and Epithany. Dr. Pusztai reported no potential conflicts of interest.

ASCOPost.com | JANUARY 25, 2015

PAGE 21

San Antonio Breast Cancer Symposium Breast Cancer

BOLERO-1: Everolimus Plus Trastuzumab/Paclitaxel Misses the Mark in First-Line HER2-Positive Advanced Breast Cancer By Caroline Helwick

he addition of everolimus (Afinitor) to weekly trastuzumab (Herceptin) plus paclitaxel in the first-line metastatic breast cancer setting did not improve outcomes in the phase III BOLERO-1/ TRIO-019 but did provide a “signal” in the hormone receptor–negative subset. The study was reported at the 2014 San Antonio Breast Cancer Symposium by Sara A. Hurvitz, MD, of the University of California, Los Angeles.1 “The study did not meet its objective in the full population,” Dr. Hurvitz reported,

primary endpoint was investigator-assessed progression-free survival in the whole population and in the hormone receptor–negative subpopulation. Overall survival was a secondary endpoint. In the full study population, progression-free survival was comparable between the arms: 14.95 months with the addition of everolimus and 14.49 months with placebo (hazard ratio [HR] = 0.89, P = .1166). In the hormone receptor–negative subpopulation, however, everolimus-treated

Safety was consistent with the known safety profile from BOLERO-3, but the increased rate of adverse events on treatment underscores the need for proactive, aggressive management of adverse events when combining everolimus with chemotherapy. —Sara A. Hurvitz, MD

but it did show an “interesting” benefit in hormone receptor–negative patients. The data validate preliminary observations from other studies that the treatment effect of everolimus differs based on hormone receptor expression in patients with HER2-positive advanced breast cancer in the absence of hormonal therapy, she said. BOLERO-1 was based on the concept of countering treatment resistance by inhibiting the mTOR pathway in early metastatic disease. In the previously reported BOLERO-3 trial, everolimus added to trastuzumab and vinorelbine significantly improved progression-free survival for patients with trastuzumabresistant previously treated cancer.2 “We were interested in evaluating whether inhibiting mTOR early in metastatic disease will help delay the development of resistance to HER2-targeted therapy,” she said.

BOLERO-1/TRIO-019 Study The study enrolled 719 patients with locally advanced or metastatic HER2positive breast cancer and no prior treatment in this setting. They were randomly assigned 2:1 to everolimus (10 mg/d) plus paclitaxel and trastzumab or paclitaxel/trastuzumab alone, until disease progression or intolerable toxicity. The

patients achieved a median progression-free survival of 20.27 months, vs 13.08 months with placebo (HR = 0.66, P = .0049), Dr. Hurvitz reported. “We saw a 7-month improvement favoring the everolimus arm, and while this was intriguing, it did not meet the prespecified level of significance (P < .0044),” she reported.

Everolimus-Related Toxicities Adverse events were similar to those seen in BOLERO-3. Patients treated with everolimus had more stomatitis (67% vs 32%) and diarrhea (56% vs 47%), which were the most common adverse events in this arm, along with alopecia (47% vs 53%). Suspected drug-related serious adverse events were reported for 22% of the everoli-

mus arm vs 8% of the control arm. There were also several adverse event–related, on-treatment deaths in the everolimus arm (3.6%), due to pneumonitis, pulmonary embolism, respiratory failure, pulmonary edema, pneumonia, and cardiorespiratory arrest, and none in the control arm. Only one of these occurred, however, after clinicians undertook more proactive management of toxicities. “The deaths may be associated with a lack of experience in managing adverse events related to everolimus when combined with chemotherapy, as there was a higher rate of on-treatment deaths in regions with limited experience with the drug. In some cases, protocol-defined adverse event management guidelines were not followed,” Dr. Hurvitz indicated. “Safety was consistent with the known safety profile from BOLERO-3, but the increased rate of adverse event– related on-treatment deaths underscores the need for proactive, aggressive management of adverse events when combining everolimus with chemotherapy,” she emphasized.

tion so we would not miss a signal,” she explained. “We are all thinking about this now and asking whether future studies should be planned in the [hormone receptor]-negative subset.” Additional discussion about the BOLERO-1 design revolved around the lack of an endocrine therapy arm for the HER2-positive patients. The design was predicated on previous studies showing that progression-free survival and response rates associated with the combination of endocrine and anti-HER2 agents are “relatively low,” and therefore, “we felt it was ethical to use chemotherapy with trastuzumab and everolimus,” she said.

‘Escape Mechanism’ C. Kent Osborne, MD, Director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, elaborated on this point. “Based on studies done with tamoxifen 20 years ago, we learned it’s not good to give tamoxifen with chemotherapy, and we extrapolated that to all endocrine therapies—that we should not give them at the same time as chemotherapy. I suspect that’s wrong,

Retrospective Considerations The benefit in the previous BOLERO-3 trial was also predominantly observed in the hormone receptor–negative subset. “Had we known about this [hormone receptor]-negative signal from the start, we might have done this trial in a [hormone receptor]-negative population or enrolled more [hormone receptor]negative patients,” she said. This could have given BOLERO-1 more power to show a benefit, at least in a certain subpopulation of HER2-positive patients. “We came so close to meeting the prespecified level of significance. We set the bar high for the [hormone receptor]-negative subset because we wanted to heavily favor the full popula-

Role of Everolimus in HER2-Positive Breast Cancer ■■ In the phase III BOLERO-1/TRIO-019 trial of patients with previously untreated advanced/metastatic HER2-positive breast cancer, the addition of everolimus to trastuzumab/paclitaxel did not improve outcomes in the overall population. ■■ In the hormone receptor–negative subset, however, progression-free survival was improved by 7 months; due to a stringent P value, this difference just missed being statistically significant. ■■ Toxicities were greater in the everolimus arm, including several treatmentrelated deaths.

C. Kent Osborne, MD

since other endocrine therapies work by different mechanisms, and trials are now looking at adding other endocrine therapies like an aromatase inhibitor with chemotherapy,” he said. “This is important because the estrogen receptor (ER) provides an escape mechanism that can cause resistance to HER2-targeted therapy. If you don’t block ER in an ER/HER2-positive tumor, the estrogen receptor can provide alternative signals for the cells to survive,” he explained. The latest studies are examining different combinations in HER2-positive, ER-positive advanced breast cancer. NCT02152943 is evaluating everolimus, letrozole, and trastuzumab, and NCT01791478 is testing a PI3K inhibitor (BYL719) plus letrozole and trastucontinued on page 22

The ASCO Post | JANUARY 25, 2015

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San Antonio Breast Cancer Symposium BOLERO-1 Trial continued from page 21

zumab. NSABP B52 is testing whether letrozole can be added to chemotherapy and dual HER2-targeted therapy in HER2-positive breast cancer. Dr. Osborne also suggested that the effect of everolimus might have been obscured by the use of paclitaxel, which in-

hibits tumors with PI3K alterations. He suggested it would be interesting to study trastuzumab plus everolimus without chemotherapy, “to get a better indication of whether you are reversing a component of HER2 therapy resistance.” n Disclosure: Dr. Hurvitz has received research funding from Novartis, Genentech, and Roche (paid to UCLA) and travel reimbursement from

Novartis and Genetech. Dr. Osborne has served on advisory boards for AstraZeneca, Pfizer, and NanoString in the past year.

References 1. Hurvitz SA, Andre F, Jiang Z, et al: Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and

paclitaxel as first-line therapy in women with HER2+ advanced breast cancer. San Antonio Breast Cancer Symposium. Abstract S6-01. Presented December 12, 2014. 2. André F, O’Regan R, Ozguroglu M, et al: Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3). Lancet Oncol 15:580-591, 2014.

FOR THEIR TREATMENT JOURNEY TO CONTINUE,

WHEN IS IT TIME TO ACT? Consider using STIVARGA® (regorafenib) as early as 3rd-line in metastatic colorectal cancer (mCRC)

For patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy.

In the phase 3 CORRECT trial: • 23% reduction in the risk of death1 – Median overall survival (OS): 6.4 months (95% CI, 5.8-7.3) with STIVARGA vs 5.0 months (95% CI, 4.4-5.8) with placebo; hazard ratio (HR): 0.77 (95% CI, 0.64-0.94; P=0.0102)1 • 51% reduction in the risk of disease progression1 – Median progression-free survival (PFS): 2.0 months (95% CI, 1.9-2.3) with STIVARGA vs 1.7 months (95% CI, 1.7-1.8) with placebo; HR: 0.49 (95% CI, 0.42-0.58; P<0.0001)1 • 26.7% and 24.7% of patients received fewer than 3 prior lines of therapy in the STIVARGA and placebo arms, respectively 2 – 73.3% and 75.3% of patients received at least 3 prior lines of therapy in the STIVARGA and placebo arms, respectively2 Evaluate patients early and often to monitor for adverse events (AEs)

Indication STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy. Important Safety Information WARNING: HEPATOTOXICITY • Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. • Monitor hepatic function prior to and during treatment. • Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence. Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in 0.3% of 1200 STIVARGA-treated patients across all clinical trials. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver.

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FDA Update

FDA Approves Nivolumab for Advanced Melanoma

he U.S. Food and Drug Administration (FDA) has granted accelerated approval to nivolumab (Opdivo) for patients with unresectable or metastatic melanoma who no longer respond to other drugs. Nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, is

intended for patients who have been previously treated with ipilimumab ( Yervoy) and, for melanoma patients whose tumors express the BRAF V600 mutation, for use after treatment with ipilimumab and a BRAF inhibitor. “[Nivolumab] is the seventh new mel-

anoma drug approved by the FDA since 2011,” said Richard Pazdur, MD, Di-

rector of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The continued development and approval of novel therapies based on our increasing understanding of tumor immunology continued on page 24

Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% with STIVARGA compared to 8% with placebo in mCRC. Fatal hemorrhage occurred in 4 of 632 (0.6%) STIVARGA-treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin. Please see additional Important Safety Information on the following page, and brief summary of full Prescribing Information, including the Boxed Warning.

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Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.

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FDA Update Nivolumab continued from page 23

and molecular pathways are changing the treatment paradigm for serious and life-threatening diseases.”

Clinical Trial Nivolumab’s efficacy was demonstrated in 120 clinical trial participants

with unresectable or metastatic melanoma. The drug demonstrated an objective response rate of 32%, and this effect lasted for more than 6 months in approximately one-third of the participants who experienced tumor shrinkage. Nivolumab’s safety was evaluated in the overall trial population of 268 participants treated with nivolumab and 102

participants treated with chemotherapy. The most common side effects of the drug were rash, itching, cough, upper respiratory tract infections, and edema. The most serious side effects are severe immunemediated side effects involving healthy organs, including the lungs, colon, liver, kidneys, and hormone-producing glands. Nivolumab is being approved more

than 3 months ahead of the prescription drug user fee goal date of March 30, 2015. The FDA granted nivolumab Breakthrough Therapy designation, priority review, and Orphan Product designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies. n

$0CO-PAY CO-PAYPROGRAM PROGRAM $0 ® ® • Available eligible patients through REACH and a select network SPPs* • Available forfor eligible patients through REACH and a select network ofof SPPs* • Only patients not currently enrolled the REACH Co-pay Assistance Program are eligible • Only patients not currently enrolled inin the REACH Co-pay Assistance Program are eligible –Current participants may enroll upon their annual renewal date –Current participants may enroll upon their annual renewal date

• Contact REACH 1-866-639-2827 visit www.STIVARGA-US.com/hcp/ more information • Contact REACH atat 1-866-639-2827 oror visit www.STIVARGA-US.com/hcp/ forfor more information *Patients enrolled in any of government insurance or reimbursement programs eligible. a condition precedent of the co-payment support provided under *Patients whowho areare enrolled in any typetype of government insurance or reimbursement programs areare notnot eligible. As As a condition precedent of the co-payment support provided under program, co-pay refunds, participating patients pharmacies obligated to inform insurance companies third-party payors of any beneﬁ ts they receive thisthis program, e.g.,e.g., co-pay refunds, participating patients andand pharmacies areare obligated to inform insurance companies andand third-party payors of any beneﬁ ts they receive andand value of this program, as required by contract or otherwise. where prohibited by law, taxed, or restricted. Patients enrolled in Bayer’s Patient Assistance Program thethe value of this program, as required by contract or otherwise. VoidVoid where prohibited by law, taxed, or restricted. Patients enrolled in Bayer’s Patient Assistance Program eligible. Bayer determine eligibility, monitor participation, equitably distribute product modify or discontinue aspect of the REACH program at any time, areare notnot eligible. Bayer maymay determine eligibility, monitor participation, equitably distribute product andand modify or discontinue anyany aspect of the REACH program at any time, including limited to this commercial co-pay assistance program. including butbut notnot limited to this commercial co-pay assistance program.

Important Safety Information (continued) Important Safety Information (continued) ® ® caused an increased Dermatological Toxicity: STIVARGA Dermatological Toxicity: STIVARGA caused an increased incidence hand-foot skin reaction (HFSR) (also known incidence of of hand-foot skin reaction (HFSR) (also known asas palmar-plantar erythrodysesthesia [PPE]) and severe rash, palmar-plantar erythrodysesthesia [PPE]) and severe rash, frequently requiring dose modification. The overall incidence frequently requiring dose modification. The overall incidence HFSR was increased with STIVARGA compared placebo of of HFSR was increased with STIVARGA compared to to placebo in in mCRC (45% 7%). The incidence Grade 3 HFSR (17% 0%), mCRC (45% vs vs 7%). The incidence of of Grade 3 HFSR (17% vs vs 0%), Grade 3 rash (6% <1%), serious adverse reactions erythema Grade 3 rash (6% vs vs <1%), serious adverse reactions of of erythema multiforme (0.2% 0%), and Stevens-Johnson syndrome (0.2% multiforme (0.2% vs vs 0%), and Stevens-Johnson syndrome (0.2% 0%) was higher STIVARGA-treated patients. Toxic epidermal vs vs 0%) was higher in in STIVARGA-treated patients. Toxic epidermal necrolysis occurred 0.17% 1200 STIVARGA-treated patients necrolysis occurred in in 0.17% of of 1200 STIVARGA-treated patients across clinical trials. Withhold STIVARGA, reduce dose, across allall clinical trials. Withhold STIVARGA, reduce thethe dose, permanently discontinue depending severity and or or permanently discontinue depending onon thethe severity and persistence dermatologic toxicity. persistence of of dermatologic toxicity.

Gastrointestinal Perforation Fistula: Gastrointestinal Gastrointestinal Perforation oror Fistula: Gastrointestinal perforation fistula occurred 0.6% 1200 patients treated perforation or or fistula occurred in in 0.6% of of 1200 patients treated with STIVARGA across clinical trials; this included 4 fatal with STIVARGA across allall clinical trials; this included 4 fatal events. Permanently discontinue STIVARGA patients who events. Permanently discontinue STIVARGA in in patients who develop gastrointestinal perforation fistula. develop gastrointestinal perforation or or fistula. Wound Healing Complications: Treatment with STIVARGA Wound Healing Complications: Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. should be stopped at least 2 weeks prior to scheduled surgery. Resuming treatment after surgery should be based on clinical Resuming treatment after surgery should be based on clinical judgment adequate wound healing. STIVARGA should judgment of of adequate wound healing. STIVARGA should bebe discontinued in patients with wound dehiscence. discontinued in patients with wound dehiscence.

Embryo-Fetal Toxicity: STIVARGA cause fetal harm when Embryo-Fetal Toxicity: STIVARGA cancan cause fetal harm when administered a pregnant woman. Use effective contraception administered to to a pregnant woman. Use effective contraception during treatment and 2 months after completion therapy. during treatment and upup to to 2 months after completion of of therapy. If this drug used during pregnancy, if the patient becomes If this drug is is used during pregnancy, or or if the patient becomes Hypertension: STIVARGA caused increased incidence Hypertension: STIVARGA caused anan increased incidence of of pregnant while taking this drug, patient should apprised pregnant while taking this drug, thethe patient should bebe apprised hypertension (30% with STIVARGA with placebo mCRC). of of hypertension (30% with STIVARGA vs vs 8%8% with placebo in in mCRC). potential hazard fetus. thethe potential hazard to to thethe fetus. Hypertensive crisis occurred 0.25% 1200 STIVARGA-treated Hypertensive crisis occurred in in 0.25% of of 1200 STIVARGA-treated patients across clinical trials. initiate STIVARGA until patients across allall clinical trials. DoDo notnot initiate STIVARGA until Nursing Mothers: Because many drugs excreted human Nursing Mothers: Because many drugs areare excreted in in human blood pressure adequately controlled. Monitor blood pressure blood pressure is is adequately controlled. Monitor blood pressure milk and because potential serious adverse reactions milk and because of of thethe potential forfor serious adverse reactions weekly first 6 weeks treatment and then every cycle, weekly forfor thethe first 6 weeks of of treatment and then every cycle, or or in in nursing infants from STIVARGA, a decision should made nursing infants from STIVARGA, a decision should bebe made more frequently, clinically indicated. Temporarily permanently whether more frequently, asas clinically indicated. Temporarily or or permanently whether discontinue nursing discontinue drug, taking to to discontinue nursing or or discontinue thethe drug, taking withhold STIVARGA severe uncontrolled hypertension. withhold STIVARGA forfor severe or or uncontrolled hypertension. into account importance drug mother. into account thethe importance of of thethe drug to to thethe mother. Cardiac Ischemia and Infarction: STIVARGA increased Cardiac Ischemia and Infarction: STIVARGA increased thethe incidence myocardial ischemia and infarction (1.2% with incidence of of myocardial ischemia and infarction (1.2% with STIVARGA 0.4% with placebo). Withhold STIVARGA STIVARGA vs vs 0.4% with placebo). Withhold STIVARGA in in patients who develop new acute cardiac ischemia patients who develop new or or acute cardiac ischemia or or infarction, and resume only after resolution acute cardiac infarction, and resume only after resolution of of acute cardiac ischemic events if the potential benefits outweigh risks ischemic events if the potential benefits outweigh thethe risks further cardiac ischemia. of of further cardiac ischemia. Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred 1 of 1200 STIVARGA-treated patients (RPLS): RPLS occurred in in 1 of 1200 STIVARGA-treated patients across clinical trials. Perform evaluation RPLS across allall clinical trials. Perform anan evaluation forfor RPLS in in anyany patient presenting with seizures, headache, visual disturbances, patient presenting with seizures, headache, visual disturbances, confusion, altered mental function. Confirm diagnosis confusion, or or altered mental function. Confirm thethe diagnosis RPLS with MRI and discontinue STIVARGA patients who of of RPLS with MRI and discontinue STIVARGA in in patients who develop RPLS. develop RPLS.

Bayer Boulevard, Whippany, 07981-0915 100100 Bayer Boulevard, PO PO BoxBox 915,915, Whippany, NJ NJ 07981-0915 USAUSA © 2014 Bayer HealthCare Pharmaceuticals Whippany, © 2014 Bayer HealthCare Pharmaceuticals Inc.,Inc., Whippany, NJ NJ ® ® ® ® ® ® ® ® , REACH , Bayer , and Bayer Crossareare registered trademarks of Bayer. STIVARGA , REACH , Bayer , and thethe Bayer Cross registered trademarks of Bayer. STIVARGA PP-900-US-1354 12/14 Printed in USA PP-900-US-1354 12/14 Printed in USA

Most Frequently Observed Adverse Drug Reactions Most Frequently Observed Adverse Drug Reactions in in mCRC (≥30%): The most frequently observed adverse drug mCRC (≥30%): The most frequently observed adverse drug reactions (≥30%) STIVARGA-treated patients placebo-treated reactions (≥30%) in in STIVARGA-treated patients vs vs placebo-treated patients mCRC, respectively, were: asthenia/fatigue (64% patients in in mCRC, respectively, were: asthenia/fatigue (64% vs vs 46%), decreased appetite and food intake (47% 28%), HFSR/ 46%), decreased appetite and food intake (47% vs vs 28%), HFSR/ PPE (45% 7%), diarrhea (43% 17%), mucositis (33% 5%), PPE (45% vs vs 7%), diarrhea (43% vs vs 17%), mucositis (33% vs vs 5%), weight loss (32% 10%), infection (31% 17%), hypertension weight loss (32% vs vs 10%), infection (31% vs vs 17%), hypertension (30% 8%), and dysphonia (30% 6%). (30% vs vs 8%), and dysphonia (30% vs vs 6%). References: 1. STIVARGA Prescribing Information. Whippany, Bayer HealthCare References: 1. STIVARGA Prescribing Information. Whippany, NJ:NJ: Bayer HealthCare Pharmaceuticals 2014. 2. Data le, Bayer HealthCare Pharmaceuticals Pharmaceuticals Inc;Inc; 2014. 2. Data on ﬁonle,ﬁBayer HealthCare Pharmaceuticals Inc.Inc.

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FDA Update

FDA Approves Ramucirumab Combination for Non–Small Cell Lung Cancer

he U.S. Food and Drug Administration (FDA) has approved ramucirumab (Cyramza) for use in combination with docetaxel for the treatment of patients with metastatic non–small cell lung cancer (NSCLC) with disease progression on or after platinum-based che-

motherapy. Patients with EGFR or ALK mutations should have experienced disease progression on FDA-approved therapy for these mutations prior to receiving ramucirumab. This is the third indication that ramucirumab has received in 2014.

® ® (regorafenib) tablets, for oral use STIVARGA STIVARGA (regorafenib) tablets, for oral use Initial U.S. Approval: 2012 Initial U.S. Approval: 2012 BRIEF SUMMARY PRESCRIBING INFORMATION BRIEF SUMMARY OFOF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

WARNING: HEPATOTOXICITY WARNING: HEPATOTOXICITY • Severeandandsometimes sometimesfatal fatalhepatotoxicity hepatotoxicityhashasbeen beenobserved observedin in • Severe clinical trials [see Warnings Precautions (5.1)]. clinical trials [see Warnings andand Precautions (5.1)]. • Monitor hepatic function prior during treatment [see Warnings • Monitor hepatic function prior to to andand during treatment [see Warnings Precautions (5.1)]. andand Precautions (5.1)]. • Interrupt then reduce discontinue Stivarga hepatotoxicity • Interrupt andand then reduce or or discontinue Stivarga forfor hepatotoxicity manifestedby byelevated elevatedliver liverfunction functiontests testsor orhepatocellular hepatocellular as asmanifested necrosis, depending upon severity persistence [see Dosage necrosis, depending upon severity andand persistence [see Dosage andand Administration (2.2)]. Administration (2.2)].

Ramucirumab was previously approved as a single agent and for use in combination with paclitaxel for the treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma after disease progression on first-line therapy.

Clinical Study Details The approval of ramucirumab in combination with docetaxel in NSCLC was based on the demonstration of improved overall survival in a multicenter, double-blind, placebo-controlled study continued on page 26

Monitor blood pressure weekly first 6 weeks treatment then Monitor blood pressure weekly forfor thethe first 6 weeks of of treatment andand then everycycle, cycle,or ormore morefrequently, frequently,as asclinically clinicallyindicated. indicated.Temporarily Temporarilyor or every permanently withhold Stivarga severe uncontrolled hypertension [see permanently withhold Stivarga forfor severe or or uncontrolled hypertension [see Dosage Administration (2.2)]. Dosage andand Administration (2.2)]. Cardiac Ischemia Infarction 5.55.5 Cardiac Ischemia andand Infarction Stivarga increased incidence myocardial ischemia infarction Stivarga increased thethe incidence of of myocardial ischemia andand infarction in in Study 1 (1.2% versus 0.4%) [see Adverse Reactions (6.1)]. Withhold Stivarga Study 1 (1.2% versus 0.4%) [see Adverse Reactions (6.1)]. Withhold Stivarga patients who develop new acute onset cardiac ischemia infarction. in in patients who develop new or or acute onset cardiac ischemia or or infarction. Resume Stivarga only after resolution acute cardiac ischemic events, if the Resume Stivarga only after resolution of of acute cardiac ischemic events, if the potential benefits outweigh risks of further cardiac ischemia. potential benefits outweigh thethe risks of further cardiac ischemia.

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Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 5.65.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome subcortical vasogenic edema diagnosed characteristic finding MRI, of of subcortical vasogenic edema diagnosed by by characteristic finding onon MRI, occurred 1200 Stivarga-treated patients across clinical trials. occurred in in oneone of of 1200 Stivarga-treated patients across all all clinical trials. Perform evaluation RPLS patient presenting with seizures, Perform an an evaluation forfor RPLS in in anyany patient presenting with seizures, INDICATIONS AND USAGE 1 1 INDICATIONS AND USAGE headache,visual visualdisturbances, disturbances,confusion confusionor oraltered alteredmental mentalfunction. function. headache, Colorectal Cancer 1.11.1 Colorectal Cancer ® ® Discontinue Stivarga in patients who develop RPLS. Stivarga in patients who develop RPLS. is indicated treatment patients with metastatic colorectal Discontinue Stivargais indicated forfor thethe treatment of of patients with metastatic colorectal Stivarga cancer(CRC) (CRC)who whohave havebeen beenpreviously previouslytreated treatedwith withfluoropyrimidine-, fluoropyrimidine-, 5.75.7 Gastrointestinal cancer Gastrointestinal Perforation Fistula Perforation or or Fistula oxaliplatinirinotecan-based chemotherapy, anti-VEGF therapy, and, oxaliplatinandand irinotecan-based chemotherapy, an an anti-VEGF therapy, and, if if Gastrointestinal Gastrointestinal perforation fistula occurred 0.6% 1200 patients perforation or or fistula occurred in in 0.6% of of 1200 patients KRAS wild type, anti-EGFR therapy. KRAS wild type, an an anti-EGFR therapy. treated with Stivarga across clinical trials; included four fatal events. treated with Stivarga across all all clinical trials; thisthis included four fatal events. Gastrointestinal Stromal Tumors In Study 2, 2.1% (4/188) of Stivarga-treated patients who were treated during 1.21.2 Gastrointestinal Stromal Tumors In Study 2, 2.1% (4/188) of Stivarga-treated patients who were treated during Stivargais isindicated indicatedforforthethetreatment treatmentof ofpatients patientswith withlocally locallyadvanced, advanced, thethe blinded open-label portion study developed gastrointestinal Stivarga blinded or or open-label portion of of thethe study developed gastrointestinal unresectable metastatic gastrointestinal stromal tumor (GIST) who have fistula fistula perforation; these, cases gastrointestinal perforation unresectable or or metastatic gastrointestinal stromal tumor (GIST) who have or or perforation; of of these, twotwo cases of of gastrointestinal perforation been previously treated with imatinib mesylate sunitinib malate. werefatal. fatal.Permanently Permanentlydiscontinue discontinueStivarga Stivargain inpatients patientswho whodevelop develop been previously treated with imatinib mesylate andand sunitinib malate. were gastrointestinal perforation fistula. gastrointestinal perforation or or fistula. CONTRAINDICATIONS 4 4 CONTRAINDICATIONS None None Wound Healing Complications 5.85.8 Wound Healing Complications formal studies effect regorafenib wound healing have been NoNo formal studies of of thethe effect of of regorafenib onon wound healing have been WARNINGS AND PRECAUTIONS 5 5 WARNINGS AND PRECAUTIONS conducted.Since Sincevascular vascularendothelial endothelialgrowth growthfactor factorreceptor receptor(VEGFR) (VEGFR) conducted. Hepatotoxicity 5.15.1 Hepatotoxicity inhibitorssuch suchas asregorafenib regorafenibcancanimpair impairwound woundhealing, healing,treatment treatmentwith with Severe drug induced liver injury with fatal outcome occurred in 0.3% 1200 inhibitors Severe drug induced liver injury with fatal outcome occurred in 0.3% of of 1200 regorafenib should stopped least 2 weeks prior scheduled surgery. should be be stopped at at least 2 weeks prior to to scheduled surgery. Stivarga-treated patients across clinical trials. Liver biopsy results, when regorafenib Stivarga-treated patients across all all clinical trials. Liver biopsy results, when decision resume regorafenib after surgery should based clinical decision to to resume regorafenib after surgery should be be based onon clinical available, showed hepatocyte necrosis with lymphocyte infiltration. Study TheThe available, showed hepatocyte necrosis with lymphocyte infiltration. In In Study judgment adequate wound healing. Regorafenib should discontinued of of adequate wound healing. Regorafenib should be be discontinued in in 1, fatal hepatic failure occurred in 1.6% patients in the regorafenib arm 1, fatal hepatic failure occurred in 1.6% of of patients in the regorafenib arm andand judgment patients with wound dehiscence. with wound dehiscence. in 0.4% patients in the placebo arm; patients with hepatic failure in 0.4% of of patients in the placebo arm; all all thethe patients with hepatic failure hadhad patients metastatic disease in the liver. In Study 2, fatal hepatic failure occurred in 0.8% 5.95.9 Embryo-Fetal metastatic disease in the liver. In Study 2, fatal hepatic failure occurred in 0.8% Embryo-Fetal Toxicity Toxicity of patients in the regorafenib arm [see Adverse Reactions (6.1)]. of patients in the regorafenib arm [see Adverse Reactions (6.1)]. Stivarga cause fetal harm when administered a pregnant woman. Stivarga cancan cause fetal harm when administered to to a pregnant woman. Obtain liver function tests (ALT, AST and bilirubin) before initiation of Stivarga Obtain liver function tests (ALT, AST and bilirubin) before initiation of Stivarga Regorafenib was embryolethal teratogenic in rats rabbits at exposures Regorafenib was embryolethal andand teratogenic in rats andand rabbits at exposures and monitor at least every two weeks during the first 2 months of treatment. and monitor at least every two weeks during the first 2 months of treatment. lower lowerthan thanhuman humanexposures exposuresat atthetherecommended recommendeddose, dose,with withincreased increased Thereafter, monitor monthly more frequently clinically indicated. Monitor incidences Thereafter, monitor monthly or or more frequently as as clinically indicated. Monitor incidences cardiovascular, genitourinary, skeletal malformations. If this of of cardiovascular, genitourinary, andand skeletal malformations. If this liver function tests weekly in patients experiencing elevated liver function tests drug liver function tests weekly in patients experiencing elevated liver function tests drug is used during pregnancy, if the patient becomes pregnant while taking is used during pregnancy, or or if the patient becomes pregnant while taking until improvement to less than 3 times ULN baseline. until improvement to less than 3 times thethe ULN or or baseline. drug, patient should apprised potential hazard a fetus [see thisthis drug, thethe patient should be be apprised of of thethe potential hazard to to a fetus [see Temporarilyhold holdandandthen thenreduce reduceor orpermanently permanentlydiscontinue discontinueStivarga Stivarga UseUse in Specific Populations (8.1)]. Temporarily in Specific Populations (8.1)]. depending severity persistence hepatotoxicity manifested depending onon thethe severity andand persistence of of hepatotoxicity as as manifested ADVERSE REACTIONS REACTIONS elevated liver function tests hepatocellular necrosis [see Dosage by by elevated liver function tests or or hepatocellular necrosis [see Dosage andand 6 6 ADVERSE following serious adverse reactions discussed elsewhere in the labeling: TheThe following serious adverse reactions areare discussed elsewhere in the labeling: Administration (2.2)]. Administration (2.2)]. • Hepatotoxicity [See Warnings Precautions (5.1)] • Hepatotoxicity [See Warnings andand Precautions (5.1)] Hemorrhage 5.25.2 Hemorrhage • Hemorrhage [See Warnings Precautions (5.2)] • Hemorrhage [See Warnings andand Precautions (5.2)] Stivarga caused increased incidence hemorrhage. overall incidence Stivarga caused an an increased incidence of of hemorrhage. TheThe overall incidence • Dermatological Toxicity [See Warnings Precautions (5.3)] • Dermatological Toxicity [See Warnings andand Precautions (5.3)] (Grades 1-5) was 21% and 11% in Stivarga-treated patients compared to (Grades 1-5) was 21% and 11% in Stivarga-treated patients compared to • Hypertension [See Warnings and Precautions (5.4)] • Hypertension [See Warnings and Precautions (5.4)] placebo-treated patients Studies 1 and Fatal hemorrhage 8%8% andand 3%3% in in placebo-treated patients in in Studies 1 and 2. 2. Fatal hemorrhage • Cardiac Ischemia Infarction [See Warnings Precautions (5.5)] Ischemia andand Infarction [See Warnings andand Precautions (5.5)] occurred of 632 (0.6%) of Stivarga-treated patients in Studies 1 and 2 and • Cardiac occurred in 4inof4 632 (0.6%) of Stivarga-treated patients in Studies 1 and 2 and Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings • Reversible involved respiratory, gastrointestinal, genitourinary tracts. involved thethe respiratory, gastrointestinal, or or genitourinary tracts. Precautions (5.6)] andand Precautions (5.6)] Permanently discontinue Stivarga patients with severe life-threatening Permanently discontinue Stivarga in in patients with severe or or life-threatening • Gastrointestinal Perforation Fistula [See Warnings Precautions (5.7)] Perforation or or Fistula [See Warnings andand Precautions (5.7)] hemorrhage. Monitor levels more frequently in patients receiving warfarin • Gastrointestinal hemorrhage. Monitor INRINR levels more frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)]. [see Clinical Pharmacology (12.3)]. Because clinical trials conducted under widely varying conditions, adverse Because clinical trials areare conducted under widely varying conditions, adverse reaction rates observed clinical trials a drug cannot directly reaction rates observed in in thethe clinical trials of of a drug cannot be be directly Dermatological Toxicity 5.35.3 Dermatological Toxicity compared rates in the clinical trials another drug may reflect to to rates in the clinical trials of of another drug andand may notnot reflect thethe Stivarga caused increased incidences adverse reactions involving skin compared Stivarga caused increased incidences of of adverse reactions involving thethe skin observed in practice. observed in practice. subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% raterate andand subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% most frequently observed adverse drug reactions (≥20%) patients most frequently observed adverse drug reactions (≥20%) in in patients Study including hand-foot skin reaction (HFSR) also known palmar- TheThe in in Study 2),2), including hand-foot skin reaction (HFSR) also known as as palmarreceiving Stivarga asthenia/fatigue, HFSR, diarrhea, decreased appetite/ Stivarga areare asthenia/fatigue, HFSR, diarrhea, decreased appetite/ plantar erythrodysesthesia (PPE), severe rash requiring dose modification. receiving plantar erythrodysesthesia (PPE), andand severe rash requiring dose modification. food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise overall incidence HFSR was higher Stivarga-treated patients, (45% food TheThe overall incidence of of HFSR was higher in in Stivarga-treated patients, (45% specified), decreased weight, gastrointestinal abdominal pain, rash, fever, decreased weight, gastrointestinal andand abdominal pain, rash, fever, versus in Study 1 and 67% versus 12% in Study than in the placebo- specified), versus 7%7% in Study 1 and 67% versus 12% in Study 2),2), than in the placebonausea. nausea. treated patients. Most cases HFSR Stivarga-treated patients appeared andand treated patients. Most cases of of HFSR in in Stivarga-treated patients appeared most serious adverse drug reactions patients receiving Stivarga most serious adverse drug reactions in in patients receiving Stivarga areare during first cycle treatment (69% 71% patients who developed TheThe during thethe first cycle of of treatment (69% andand 71% of of patients who developed hepatotoxicity, hemorrhage, gastrointestinal perforation. hemorrhage, andand gastrointestinal perforation. HFSR Study 1 and Study respectively). incidence Grade 3 HFSR hepatotoxicity, HFSR in in Study 1 and Study 2, 2, respectively). TheThe incidence of of Grade 3 HFSR (17% versus Study 1 and 22% versus Study Grade 3 rash 6.16.1 Clinical (17% versus 0%0% in in Study 1 and 22% versus 0%0% in in Study 2),2), Grade 3 rash Clinical Trials Experience Trials Experience (6% versus <1% Study 1 and versus Study serious adverse (6% versus <1% in in Study 1 and 7%7% versus 0%0% in in Study 2),2), serious adverse Colorectal Cancer Colorectal Cancer reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens safety data described below, except where noted, derived from safety data described below, except where noted, areare derived from a a Johnson Syndrome (0.2% Study was higher Stivarga-treated TheThe Johnson Syndrome (0.2% vs.vs. 0%0% in in Study 1) 1) was higher in in Stivarga-treated randomized (2:1), double-blind, placebo-controlled (Study which randomized (2:1), double-blind, placebo-controlled trialtrial (Study 1) 1) in in which patients [see Adverse Reactions (6.1)]. patients [see Adverse Reactions (6.1)]. 500 patients (median age 61 years; 61% men) with previously-treated Toxic epidermal necrolysis occurred in 0.17% of 1200 Stivarga-treated patients 500 patients (median age 61 years; 61% men) with previously-treated Toxic epidermal necrolysis occurred in 0.17% of 1200 Stivarga-treated patients metastatic colorectal cancer received Stivarga a single agent dose metastatic colorectal cancer received Stivarga as as a single agent at at thethe dose across clinical trials. across all all clinical trials. daily first 3 weeks each 4 week treatment cycle of of 160160 mgmg daily forfor thethe first 3 weeks of of each 4 week treatment cycle andand WithholdStivarga, Stivarga,reduce reducethethedose, dose,or orpermanently permanentlydiscontinue discontinueStivarga Stivarga 253253 Withhold patients (median years; 60% men) received placebo. median patients (median ageage 6161 years; 60% men) received placebo. TheThe median depending severity persistence of dermatologic toxicity [see Dosage duration depending onon thethe severity andand persistence of dermatologic toxicity [see Dosage duration therapy was (range 47.0) weeks patients receiving of of therapy was 7.37.3 (range 0.3,0.3, 47.0) weeks forfor patients receiving and Administration (2.2)]. Institute supportive measures for symptomatic relief. and Administration (2.2)]. Institute supportive measures for symptomatic relief. Stivarga. Stivarga. Due adverse reactions, 61% patients receiving Stivarga Due to to adverse reactions, 61% of of thethe patients receiving Stivarga required a dose interruption 38% patients their dose reduced. required a dose interruption andand 38% of of thethe patients hadhad their dose reduced. Hypertension 5.45.4 Hypertension Drug-related adverse reactions resulted treatment discontinuation adverse reactions thatthat resulted in in treatment discontinuation Stivarga caused increased incidence hypertension (30% versus Stivarga caused an an increased incidence of of hypertension (30% versus 8%8% in in Drug-related were reported 8.2% Stivarga-treated patients compared 1.2% reported in in 8.2% of of Stivarga-treated patients compared to to 1.2% of of Study 1 and 59% versus 27% Study [see Adverse Reactions (6.1)]. were Study 1 and 59% versus 27% in in Study 2) 2) [see Adverse Reactions (6.1)]. patients who received placebo. Hand-foot skin reaction (HFSR) rash were who received placebo. Hand-foot skin reaction (HFSR) andand rash were Hypertensive crisis occurred 0.25% 1200 Stivarga-treated patients patients Hypertensive crisis occurred in in 0.25% of of 1200 Stivarga-treated patients most common reasons permanent discontinuation Stivarga. most common reasons forfor permanent discontinuation of of Stivarga. across clinical trials. onset hypertension occurred during first thethe across all all clinical trials. TheThe onset of of hypertension occurred during thethe first cycle treatment most patients who developed hypertension (72% cycle of of treatment in in most patients who developed hypertension (72% in in Table Table 1 compares incidence adverse reactions (≥10%) patients 1 compares thethe incidence of of adverse reactions (≥10%) in in patients Study 1 and Study Study 1 and Study 2).2). receiving Stivarga reported more commonly than patients receiving receiving Stivarga andand reported more commonly than in in patients receiving initiateStivarga Stivargaunless unlessblood bloodpressure pressureis isadequately adequatelycontrolled. controlled. placebo placebo (Study DoDonotnotinitiate (Study 1).1).

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FDA Update Ramucirumab continued from page 25

(I4T-MC-JVBA) that enrolled 1,253 patients with previously treated metastatic NSCLC. Patients were randomly assigned to receive either ramucirumab (10 mg/kg every 3 weeks) in combination with docetaxel (75 mg/m2 every 3 weeks) on day 1 of a 21-day cycle (n =

628) or matching placebo plus docetaxel (n = 625). A statistically significant prolongation of overall survival was demonstrated (hazard ratio [HR] = 0.86, 95% confidence interval = 0.75–0.98, P = .024); median overall survival was 10.5 months in the ramucirumabplus-docetaxel arm and 9.1 months in

the placebo-plus-docetaxel arm. Progression-free survival was also significantly longer for patients receiving ramucirumab plus docetaxel (HR = 0.76, 95% CI = 0.68–0.86, P < .001). Safety data were evaluated in 1,245 patients who received at least one dose of study drug. The most frequently reported adverse reactions

Table 1 Adverse drug reactions (≥10%) reported in patients treated with Stivarga in Study 1 and reported more commonly than in patients receiving placebo Stivarga Placebo (N=500) (N=253) Grade Grade Adverse Reactions All ≥ 3 All ≥ 3 % % % % General disorders and administration site conditions Asthenia/fatigue 64 15 46 9 Pain 29 3 21 2 Fever 28 2 15 0 Metabolism and nutrition disorders Decreased appetite and food intake 47 5 28 4 Skin and subcutaneous tissue disorders 45 17 7 0 HFSR/PPE 26 6 4 <1 Rash a Gastrointestinal disorders Diarrhea 43 8 17 2 Mucositis 33 4 5 0 Investigations Weight loss 32 <1 10 0 Infections and infestations Infection 31 9 17 6 Vascular disorders 30 8 8 <1 Hypertension 21 2 8 <1 Hemorrhage b Respiratory, thoracic and mediastinal disorders Dysphonia 30 0 6 0 Nervous system disorders Headache 10 <1 7 0 a The term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash. b Fatal outcomes observed. Laboratory Abnormalities Laboratory abnormalities observed in Study 1 are shown in Table 2. Table 2 Laboratory test abnormalities reported in Study 1 Placebo Stivarga (N=253 a) (N=500 a) Grade b Grade b Laboratory Parameter All 3 4 All 3 4 % % % % % % Blood and lymphatic system disorders Anemia 79 5 1 66 3 0 Thrombocytopenia 41 2 <1 17 <1 0 Neutropenia 3 1 0 0 0 0 Lymphopenia 54 9 0 34 3 0 Metabolism and nutrition disorders Hypocalcemia 59 1 <1 18 1 0 Hypokalemia 26 4 0 8 <1 0 Hyponatremia 30 7 1 22 4 0 Hypophosphatemia 57 31 1 11 4 0 Hepatobiliary disorders Hyperbilirubinemia 45 10 3 17 5 3 Increased AST 65 5 1 46 4 1 Increased ALT 45 5 1 30 3 <1 Renal and urinary disorders Proteinuria 60 <1 0 34 <1 0 Investigations c 24 4 N/A 17 2 N/A Increased INR Increased Lipase 46 9 2 19 3 2 Increased Amylase 26 2 <1 17 2 <1 a % based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo). b Common Terminology Criteria for Adverse Events (CTCAE), v3.0. c International normalized ratio: No Grade 4 denoted in CTCAE, v3.0. Gastrointestinal Stromal Tumors The safety data described below are derived from a randomized (2:1), doubleblind, placebo-controlled trial (Study 2) in which 132 patients (median age 60 years; 64% men) with previously-treated GIST received Stivarga as a single agent at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64% men) received placebo. The median duration of therapy was 22.9 (range 0.1, 50.9) weeks for patients receiving Stivarga. Dose interruptions for adverse events were required in 58% of patients receiving Stivarga and 50% of patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 2.3% of Stivarga-treated patients compared to 1.5% of patients who received placebo. Table 3 compares the incidence of adverse reactions (≥10%) in GIST patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 2).

with ramucirumab plus docetaxel (incidence greater than or equal to 30%) were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. The most common serious adverse reactions with ramucirumab plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). n

Table 3 Adverse reactions (≥10%) reported in patients treated with Stivarga in Study 2 and reported more commonly than in patients receiving placebo Stivarga Placebo (N=132) (N=66) Adverse Reactions Grade Grade All ≥ 3 All ≥ 3 % % % % Skin and subcutaneous tissue disorders 67 22 15 2 HFSR/PPE 30 Rash a 7 3 0 Alopecia 24 2 2 0 General disorders and administration site conditions Asthenia/Fatigue 52 4 39 2 Fever 21 0 11 2 Vascular disorders 59 28 27 5 Hypertension Hemorrhage 11 4 3 0 Gastrointestinal disorders Diarrhea 47 8 9 0 Mucositis 40 2 8 2 Nausea 20 2 12 2 Vomiting 17 <1 8 0 Respiratory, thoracic and mediastinal disorders Dysphonia 39 0 9 0 Infections and infestations Infection 32 5 5 0 Metabolism and nutrition disorders 31 <1 21 3 Decreased appetite and food intake 18 0 6 0 Hypothyroidism b Nervous system disorders Headache 16 0 9 0 Investigations Weight loss 14 0 8 0 Musculoskeletal and connective tissue disorders Musculoskeletal stiffness 14 0 3 0 a The term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic rash. b Hypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline. Laboratory Abnormalities Laboratory abnormalities observed in Study 2 are shown in Table 4. Table 4 Laboratory test abnormalities reported in Study 2 Placebo Stivarga (N=66 a) (N=132 a) Grade b Laboratory Parameter Grade b All 3 4 All 3 4 % % % % % % Blood and lymphatic system disorders Thrombocytopenia 13 1 0 2 0 2 Neutropenia 16 2 0 12 3 0 Lymphopenia 30 8 0 24 3 0 Metabolism and nutrition disorders Hypocalcemia 17 2 0 5 0 0 Hypokalemia 21 3 0 3 0 0 Hypophosphatemia 55 20 2 3 2 0 Hepatobiliary disorders Hyperbilirubinemia 33 3 1 12 2 0 Increased AST 58 3 1 47 3 0 Increased ALT 39 4 1 39 2 0 Renal and urinary disorders 30 3 -c Proteinuria 33 3 -c Investigations Increased Lipase 14 0 1 5 0 0 a % based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo). b CTCAE, v4.0. c No Grade 4 denoted in CTCAE, v4.0. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inducers on Regorafenib Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of Stivarga with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) [see Clinical Pharmacology (12.3)]. 7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant

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FDA Update

FDA Approves Olaparib to Treat BRCA-Mutated Advanced Ovarian Cancer

he U.S. Food and Drug Administration (FDA) has granted accelerated approval to olaparib (Lynparza) for women with advanced ovarian cancer with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer, as detected by an FDA-approved test, who

have been treated with three or more prior lines of chemotherapy. The FDA concurrently approved a companion diagnostic, BRACAnalysis CDx, for the qualitative detection and classification of variants in the BRCA1 and BRCA2 genes. Olaparib is a poly ADP-ribose poly-

use of Stivarga with strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)].

8.8 Females and Males of Reproductive Potential Contraception Use effective contraception during treatment and up to 2 months after completion of therapy. Infertility There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology (13.1)]. 10 OVERDOSAGE The highest dose of Stivarga studied clinically is 220 mg per day. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells. Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans. 13.2 Animal Toxicology and/or Pharmacology In a chronic 26-week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals.

Distributed and marketed by:

6708302BS2

Olaparib’s efficacy was examined in a study of 137 participants with germline BRCA mutation–associated advanced ovarian cancer. The study was designed to measure objective response rate, and results showed that 34% of participants

experienced an objective response for an average of 7.9 months. Common side effects of olaparib included nausea, fatigue, vomiting, diarrhea, distorted taste, indigestion, headache, decreased appetite, nasopharyngitis, cough, joint pain, musculoskeletal pain, muscle pain, back pain, rash, and abdominal pain. Serious side effects included the development of myelodysplastic syndrome, acute myeloid leukemia, and lung inflammation. The most common laboratory abnormalities were increased creatinine levels, increased average volume of red blood cells, decreased hemoglobin, decreased lymphocytes and neutrophils, and decreased platelet levels. T:10.75”

Manufactured in Germany

Clinical Trial

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17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). Inform your patients of the following: • Stivarga may cause severe or life-threatening liver damage. Inform patients that they will need to undergo monitoring for liver damage and to immediately report any signs or symptoms of severe liver damage to their health care provider. • Stivarga can cause severe bleeding. Advise patients to contact their health care provider for any episode of bleeding. • Stivarga can cause hand-foot skin reactions or rash elsewhere. Advise patients to contact their health care provider if they experience skin changes associated with redness, pain, blisters, bleeding, or swelling. • Stivarga can cause or exacerbate existing hypertension. Advise patients they will need to undergo blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • Stivarga increased the risk for myocardial ischemia and infarction. Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, or feel dizzy or like passing out. • Contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, severe diarrhea (frequent or loose bowel movements), or dehydration. • Stivarga may complicate wound healing. Advise patients to inform their health care provider if they plan to undergo a surgical procedure or had recent surgery. • Inform patients that regorafenib can cause fetal harm. Advise women of reproductive potential and men of the need for effective contraception during Stivarga treatment and for up to 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her health care provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with Stivarga. • Advise nursing mothers that it is not known whether regorafenib is present in breast milk and discuss whether to discontinue nursing or to discontinue regorafenib. • Inform patients to take any missed dose on the same day, as soon as they remember, and that they must not take two doses on the same day to make up for a dose missed on the previous day. • Inform patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Any remaining tablets should be discarded 7 weeks after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle.

ter for Drug Evaluation and Research. “Olaparib is approved for patients with specific abnormalities in the BRCA gene and is an example of how a greater understanding of the underlying mechanisms of disease can lead to targeted, more personalized treatment.”

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8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)] Risk Summary Based on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Stivarga in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC). In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. In a repeat dose study with daily administration of regorafenib to pregnant rats during organogenesis, findings included delayed ossification in fetuses at doses ≥ 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) with dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/ kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis. In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies. 8.3 Nursing Mothers It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established. In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate. 8.5 Geriatric Use Of the 632 Stivarga-treated patients enrolled in Studies 1 and 2, 37% were 65 years of age and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients. 8.6 Hepatic Impairment No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions (5.1)]. Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C), as it has not been studied in this population. 8.7 Renal Impairment No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease.

merase (PARP) inhibitor that blocks enzymes involved in repairing DNA. “[This] approval constitutes the first of a new class of drugs for treating ovarian cancer,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Cen-

Approval Process In June, olaparib was reviewed by the FDA’s Oncologic Drugs Advisory Committee for potential use as maintenance therapy. The committee advised the agency in a vote of 11 to 2 that the data did not support olaparib’s accelerated approval for this use. The company then submitted additional information supporting olaparib’s use for a different indication: in patients with germline BRCA mutation–associated ovarian cancer who have received three or more chemotherapy treatments. The FDA is approving olaparib under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. n See page 101 for more FDA Update, including news on the companion diagnostic approved for use in identifying candidates for olaparib therapy.

The ASCO Post | JANUARY 25, 2015

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San Antonio Breast Cancer Symposium Breast Cancer

Tamoxifen Prevention of Breast Cancer Extends More Than 16 Years By Alice Goodman

he benefits of tamoxifen as primary prevention of breast cancer are well established. The good news is that the benefits live on, with a protective effect that extends up to 22 years. At a median follow-up of 16 years, women treated with 5 years of tamoxifen enjoyed a 29% reduction in the risk of developing any type of breast cancer

“Tamoxifen is a well-established and effective treatment for certain breast cancers, but now we have evidence of its very long-term preventive benefits in women at risk for breast cancer. The preventive effect of tamoxifen is highly significant, with a reduction in breast cancer rates of around one-third, and this impact has remained strong and unabat-

Long-Term Prevention of Breast Cancer With Tamoxifen ■■ The IBIS-I trial once again confirmed the risk reduction for breast cancer in women at high risk. ■■ Long-term follow-up showed that 5 years of tamoxifen protects against developing breast cancer for a mean of 16 years and up to 22 years. ■■ The greatest risk reduction was for invasive estrogen receptor–positive breast cancers. ■■ The risk of all-cause mortality was not reduced by tamoxifen.

For most premenopausal high-risk women, tamoxifen remains the only choice for breast cancer prevention, and it is a good one—as shown by the IBIS-I evidence. —Jack Cuzick, PhD

and a 35% reduction in the risk of developing estrogen receptor–positive breast cancer compared with placebo-treated controls. These positive results of the large International Breast Cancer Intervention Study (IBIS-I) were presented at the 2014 San Antonio Breast Cancer Symposium and published online simultaneously in Lancet Oncology.1,2

ed for 20 years. We hope these results will stimulate more women, particularly younger women, to consider treatment options for breast cancer prevention if they have a family history of the disease or other risk factors,” stated lead author Jack Cuzick, PhD, of Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University

London, United Kingdom. Even though these long-term results are so striking, Dr. Cuzick acknowledged that we still have a lot to do to convince women at risk who are otherwise healthy to take the drug. “This has been a major issue. Cardiologists are more effective at primary prevention of cardiovascular disease. We have to find a way to make it very clear that women at high risk of breast cancer should be offered prevention. There is a misunderstanding about the side effects of tamoxifen. If a woman develops side effects, she can always stop the drug,” he said.

Closer Look at IBIS-I IBIS-I enrolled 7,154 high-risk

EXPERT POINT OF VIEW

“T

hese data do not change what we already know: Chemoprevention is slam-dunk, hands-down effective in preventing breast cancer. The effects of 5 years of chemoprevention persist for 20 years. This is great because it [could potentially] reduce the

I don’t think it will change women’s minds. Many women at high risk don’t want to take a medication once they hear about the side effects. We need better ways to identify [women who truly are at high risk] and inform women about their real risk. Then they

These data do not change what we already know: Chemoprevention is slam-dunk, hands-down effective in preventing breast cancer. The effects of 5 years of chemoprevention persist for 20 years. —Erin Hofstatter, MD

numbers of women we need to treat,” said Erin Hofstatter, MD, Assistant Professor and Co-Director of the Cancer Genetics and Prevention Program at Yale University School of Medicine. “Will these results impact care and improve the uptake of chemoprevention among high-risk women? Sadly,

might decide to take chemoprevention,” she continued. In her practice, Dr. Hofstatter counsels women to try chemoprevention and says that they can stop it if they have unacceptable side effects. “I [also] think we need to study approaches outside of tamoxifen and aromatase

inhibitors. Some people are studying the effects of natural substances, such as omega 3 fatty acids. That would be acceptable to most women, [and could have a real effect on breast cancer incidence if taken by a large population of women],” she said. Dr. Hofstatter also offers postmenopausal women raloxifene, which has a better side-effect profile than tamoxifen and aromatase inhibitors and also protects their bones. “I’ve had much better [uptake rates] with raloxifene,” she said. She noted that tamoxifen also protects bones and said that if it were marketed that way, uptake might be better. “Cardiologists do a much better job of primary prevention than breast oncologists. Just look at the uptake of [atorvastatin (Lipitor)], and that drug has side effects. The number needed to treat with [atorvastatin] to avoid one heart attack is in the 60s, which is much higher than the number needed to treat with tamoxifen,” she said. n Disclosure: Dr. Hofstatter reported no potential conflicts of interest.

premenopausal and postmenopausal women from genetics clinics and breast care clinics in 8 different countries and randomized them 1:1 to receive 5 years of tamoxifen or placebo. Most of these women were deemed at high risk due to a family history of breast cancer. The median age at study initiation was 50.8 years; during the trial, about 50% of women in the placebo group used hormone replacement therapy, compared with 41% of women in the tamoxifen group. About 35% of both groups had previous hysterectomy. At a median follow-up of 16 years (maximum follow-up, 22 years), breast cancers were reported in 251 patients (7%) in the tamoxifen group vs 350 (9.8%) in the placebo group, a highly significant 29% reduction in risk favoring tamoxifen (P < .0001). The greatest risk reduction was observed for invasive estrogen receptor–positive breast cancer, a highly significant 34% reduction (P < .0001) and ductal carcinoma in situ (35% risk reduction, P = .05). The effect on ductal carcinoma in situ was predominantly seen during the first 10 years of follow-up. However, tamoxifen did not protect against invasive estrogen receptor–negative breast cancer. At 10 years, previous results of the trial showed that the number needed to treat with tamoxifen to prevent one case of breast cancer was 59; at 20 years, the number needed to treat to prevent one case of breast cancer was reduced to 22. The number needed to treat to prevent one case of invasive estrogen receptor– positive breast cancer was 29. The benefits of tamoxifen were significantly greater for women who did not take hormone replacement therapy during the trial: a 38% reduction in the risk of breast cancer vs a 12% reduction in the risk for women taking hormone replacement therapy during the trial (P = .04) and a 45% risk reduction for estrogen receptor–positive breast cancers in noncurrent users of hormone replace-

ASCOPost.com | JANUARY 25, 2015

PAGE 29

San Antonio Breast Cancer Symposium ment therapy vs 13% in current users of hormone replacement therapy (P = .03). “This indicates the clear loss of efficacy of tamoxifen when menopausal hormone therapy is used concomitantly, and this effect needs to be studied further,” Dr. Cuzick said. No significant difference in breast cancer prevention related to age younger or older than 50 years was observed.

including the aromatase inhibitors anastrozole and exemestane in clinical guidelines for breast cancer prevention in postmenopausal women. “For most premenopausal high-risk women, tamoxifen remains the only choice for breast cancer prevention, and it is a good one—as shown by the IBISI evidence,” he concluded. n

Disclosure: Dr. Cuzick is on the speakers bureau for AstraZeneca.

References 1. Cuzick J, Sestak I, Cawthorn S, et al: 16 BLEED:8.375” year long-term follow-up of the IBIS-I breast TRIM:7.875” cancer prevention trial. 2014 San Antonio SAFETY:7” Breast Cancer Symposium. Abstract S3-07. Presented December 11, 2014. 2. Cuzick J, Sestak I, Cawthorn S, et al:

Tamoxifen for prevention of breast cancer. Lancet Oncol. December 10, 2014 (early release online). 3. Cuzick J, Sestak I, Forbes JF, et al: Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBISII): An international, double-blind, randomised placebo-controlled trial. Lancet 383:1041-1048, 2014.

Other Cancers

Now enrolling for alectinib

NCT 02075840 BO28984

A Randomized, Phase III Study Comparing Alectinib With Crizotinib in Treatment-Naïve Anaplastic Lymphoma Kinase (ALK)-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

Randomize 1:1

Over follow-up, 666 other cancers were reported: 351 (9%) in the tamoxifen group compared with 315 (8%) in the placebo group. There was a trend toward more endometrial cancers in the tamoxifen group over extended followup, with a total of 29 vs 20 in the placebo group; most of the endometrial cancers in the tamoxifen group occurred over the first 5 years, when patients were on active treatment. Nonmelanoma skin cancers were also increased in the tamoxifen group: 116 compared with 84 in the placebo group (P = .022). Gastrointestinal cancers were decreased in the tamoxifen group: 42 compared with 63 in the placebo group.

Patients (N=286) • Advanced, recurrent, or metastatic ALK-positive NSCLC

Alectinib1

Crizotinib

Causes for Concern The reduction in the incidence of breast cancer with tamoxifen did not translate into a mortality reduction or a reduction in breast cancer mortality at 20 years. A nonsignificant numerical incidence in endometrial cancer deaths was reported in the tamoxifen group: 5 vs 0. “Clearly, the lack of a mortality benefit and the slight increase in endometrial deaths are concerns,” Dr. Cuzick said. “The number of deaths is still small compared with the number of breast cancer cases, which is 10 times higher. We will continue to monitor these women for another decade to gain a better understanding of the impact of tamoxifen on death rates. Some of the side effects of tamoxifen are also cause for concern and require continued monitoring, specifically endometrial cancer.”

Primary Endpoint:

Secondary Endpoints:

• Progression-free survival (PFS), investigator-assessed,

• Objective response rate, investigator-assessed,

by RECIST 1.1

using RECIST 1.1 • Time to CNS progression, IRC-assessed, using

RECIST 1.1 • PFS, IRC-assessed, using RECIST 1.1 • Duration of response • Overall survival • Safety: incidence of adverse events • AUC of alectinib • Patient-reported outcomes

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Advanced, recurrent, or metastatic ALK-positive NSCLC

• Prior malignancy in past 3 years

• Life expectancy ≥12 weeks

• Any ≥ grade 3 toxicity (NCI CTCAE 4.0) from

• ECOG performance status of 0-2 • No prior systemic therapy for advanced, recurrent, or

metastatic disease • Measurable disease by RECIST 1.1

A Glimpse at IBIS-II Results IBIS-II trial results, presented in 2013 and published in 2014,3 showed that 5 years of anastrozole reduced the risk of developing breast cancer in at-risk postmenopausal women by 53%, a greater magnitude of benefit than is seen with tamoxifen. Dr. Cuzick said that an aromatase inhibitor such as anastrozole or exemestane should be the drug of choice in postmenopausal women and that the National Institute for Health and Care Excellence was currently considering

a prior therapy

• Baseline QTc >470 ms or symptomatic

bradycardia <45 beats per minute • Concomitant strong cytochrome P4503A

inhibitors/inducers or QT-prolonging medications

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com. 1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for the use of any product for unapproved purposes. 2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

The ASCO Post | JANUARY 25, 2015

PAGE 30

San Antonio Breast Cancer Symposium Breast Cancer

Fulvestrant Surpasses Anastrozole in First-Line Treatment of Metastatic Breast Cancer By Alice Goodman

ulvestrant (Faslodex) at a 500-mg dose was superior to anastrozole as first-line therapy for advanced hormone receptor–positive breast cancer in the phase II FIRST study.1 Overall survival and time to disease progression were significantly better with fulvestrant than with the current standard of care, anastrozole. “This is an exciting and promising finding. Together with results from an earlier phase III trial in the second-line setting called CONFIRM, fulvestrant has now shown an advantage in the firstand second-line settings. I don’t know any other endocrine therapy where there is a time to disease progression and overall survival advantage in both the second- and first-line settings,” said lead author John Robertson, MD, of Graduate Entry Medicine and Health School, University of Nottingham, Royal Derby Hospital, United Kingdom. Fulvestrant, a selective estrogen– receptor downregulator, is given via intramuscular injection once a month. The drug is approved for use in the second-line setting for metastatic hormone receptor–positive breast cancer that has progressed on first-line hormonal therapy. It is not approved as adjuvant therapy, even though it is considered the most potent antiendocrine therapy available, Dr. Robertson noted.

At a press conference during the 2014 San Antonio Breast Cancer Symposium, Dr. Robertson explained that fulvestrant was developed at a dose of 250 mg, and at that dose, it was found to be equivalent to anastrozole and similar to tamoxifen. “Then it was decided that the dose of fulvestrant could be doubled in the

as reflected by disease control at the end of 6 months of treatment; this endpoint was achieved in 72.5% of the fulvestrant group vs 67% of the anastrozole group, demonstrating that fulvestrant at the 500-mg dose was at least as effective as anastrozole on this measure. Fulvestrant achieved significantly

Fulvestrant has now shown an advantage in the first- and secondline settings. I don’t know any other endocrine therapy where there is a time to disease progression and overall survival advantage in both the secondand first-line settings. —John Robertson, MD

second-line setting. The CONFIRM study showed that the higher dose significantly improved the time to disease progression and overall survival,” he continued.

Prolonged Control of Disease In the FIRST trial, fulvestrant (500-mg dose) was compared with anastrozole in the first-line setting in 205 patients with advanced or metastatic breast cancer. The primary endpoint was clinical benefit rate,

Fulvestrant in First-Line Treatment of Metastatic Breast Cancer ■■ Fulvestrant significantly improved time to disease progression and overall survival vs anastrozole as first-line therapy in hormone receptor–positive metastatic breast cancer. ■■ Together with the findings from the CONFIRM trial, these results demonstrate the superiority of fulvestrant over anastrozole in both the firstand second-line settings for metastatic breast cancer. ■■ If the results of an ongoing phase III trial are positive, fulvestrant may be approved as first-line treatment in the metastatic setting. ■■ Although these data suggest that fulvestrant could be superior to anastrozole as adjuvant treatment, such a trial is unlikely to be done.

prolonged control of disease. At 13 months, the median time to disease progression was 23.4 months with fulvestrant vs 13 months with anastrozole, which represented a highly significant 34% reduction in the risk of disease progression (P = .01). Overall survival was not defined as an endpoint until the protocol was amended in 2011. At a median followup of 49.6 months for fulvestrant and 42.5 months for anastrozole, 23 patients (22.5%) were alive in the fulvestrant group, and 10 patients (9.7%) were alive in the anastrozole group. The median overall survival was 54.1 months for fulvestrant vs 48.4 months for anastrozole (P = .041), an absolute increase of 5.7 months. In addition, the overall survival benefit was consistent across all subgroups. “To put these results in context, 30 years ago, the average survival in hormone receptor–positive metastatic breast cancer was 24 months. We have improved survival step by step,” Dr. Robertson stated.

No new safety concerns for either drug emerged during the trial.

‘Could Be Practice-Changing’ Dr. Robertson said the FALCON phase III study was initiated to support the regulatory approval of fulvestrant as first-line therapy in advanced breast cancer. If it is positive for fulvestrant, “this study could be practice-changing,” he noted. Dr. Robertson said, “The data cry out for an adjuvant study. But this is a commercial issue, and adjuvant studies take many years to do. The drug is going to go off patent soon. It is unlikely that the company will do an adjuvant trial.” Press conference moderator C. Kent Osborne, MD, Director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, noted, “Because fulvestrant was not better than tamoxifen in a study of first-line treatment of metastatic disease (albeit with the lower 250-mg dose), it was not taken into an adjuvant therapy trial. Now that the higher dose has shown to be better than the aromatase inhibitor anastrozole, an adjuvant trial is reasonable.” n

Disclosure: Dr. Robertson reported receiving consulting fees for advisory boards organized by AstraZeneca; honoraria for speaking at non–Accreditation Council for Continuing Medical Education events; and serving as an investigator in trials sponsored by AstraZeneca. In addition, all funding related to these research studies has been paid to his academic institution, and Dr. Robertson received travel expenses to make a presentation on the FALCON study at the 2013 San Antonio Breast Cancer Symposium.

Reference 1. Robertson JFR, Llombart-Cussac A, Felti D, et al: Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: Overall survival from the phase II ‘FIRST’ study. 2014 San Antonio Breast Cancer Symposium. Abstract S604. Presented December 12, 2014.

Visit The ASCO Post website at ASCOPost.com

FOR OVERALL SURVIVAL LOOK TO ZELBORAF Significant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma1*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There was a 53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (hazard ratio [HR]=0.47; 95% confidence interval [CI], 0.35-0.62; P<0.0001). There were 78 deaths and 122 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1-3

EXTEND SURVIVAL WITH ZELBORAF Significant improvement in OS in a randomized, open-label Phase III trial1* OS at FDA approval (August 2011)† 100

HR=0.47 (95% CI, 0.35-0.62), P<0.0001

Percentage surviving

80 60 40 20 0

7 8 OS (months)

ZELBORAF (n=337)

Dacarbazine (n=338)

53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (HR=0.47; 95% CI, 0.35-0.62; P<0.0001) —78 (23%) deaths and 122 (36%) deaths in the ZELBORAF and dacarbazine arms, respectively In an updated analysis, median OS was reached at 13.6 months with ZELBORAF: 3.3-month improvement over median OS of 10.3 months with dacarbazine (95% CI, 12.0-15.3 months vs 9.1-12.8 months) —Updated based on 478 deaths (ZELBORAF median follow-up 13.4 months)

Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT substudy in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated. Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.

Significant improvement in PFS1 ≈4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine first line1,3 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients4

Baseline assessment

1 month

First postbaseline assessment

Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). Hepatotoxicity Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-finding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid). Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modifications for intolerable grade 2 or greater photosensitivity. Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis. Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm. Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. ZELBORAF Prescribing Information. Genentech, Inc. November 2014. 2. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutationpositive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/ drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed August 26, 2013. 3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 4. Data on file. Genentech, Inc.

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | JANUARY 25, 2015

PAGE 34

Journal Spotlight Gastrointestinal Oncology

Vitamin D Protects Against Colorectal Cancer by Boosting the Immune System

study by investigators at DanaFarber Cancer Institute has demonstrated that vitamin D can protect some people with colorectal cancer by heightening the immune system’s vigilance against tumor cells. The research, released earlier this

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2. Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF* Trial 1: Treatment Naïve Patients

ADRs

Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

ZELBORAF n= 336 Grade All Grades 3a (%) (%)

Trial 2: Patients with Failure of at Least One Prior Systemic Therapy Dacarbazine ZELBORAF n= 287 n= 132 Grade Grade All All Grades 3a Grades 3 (%) (%) (%) (%)

37 33 45 23 24 9 8 19 5 14

8 3 <1 1 1 2 0 0 <1 0

2 4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, panniculitis, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

0 * For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)].

D in their bloodstream have a lower overall risk of developing colorectal cancer,” said Shuji Ogino, MD, PhD, of Dana-Farber, Harvard School of Public Health, and Brigham and Women’s Hospital, one of the study’s senior authors. “Laboratory research suggests

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)]. Blood and lymphatic systems disorder: Neutropenia 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. 7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment. 8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see Dosage and Administration (2.1)]. • ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin [see Warnings and Precautions (5.1)]. • Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Advise patients to stop taking ZELBORAF and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and Precautions (5.3)]. • Severe dermatologic reactions can occur in patients receiving ZELBORAF. Advise patients to stop taking ZELBORAF and to contact their health care provider for severe dermatologic reactions [see Warnings and Precautions (5.4)]. • ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see Warnings and Precautions (5.5)]. • Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF. Advise patients of the importance of laboratory monitoring of their liver during ZELBORAF treatment and to contact their health care provider for relevant symptoms [see Warnings and Precautions (5.6)]. • ZELBORAF can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see Warnings and Precautions (5.7)]. • Ophthalmologic reactions can occur in patients treated with ZELBORAF. Advise patients to contact their health care provider immediately for ophthalmologic symptoms [see Warnings and Precautions (5.8)]. • ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. Advise patients to contact their health care provider immediately if they become pregnant [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

that vitamin D boosts immune system function by activating T cells that recognize and attack cancer cells. In this study, we wanted to determine if these two phenomena are related: Does vitamin D’s role in the immune system account for the lower rates of colorectal cancer in people with high circulating levels of the vitamin?”

Study Details Dr. Ogino and his colleagues theorized that if the two phenomena were connected, then people with high levels of vitamin D would be less likely to develop colorectal tumors that are permeated with large numbers of immune system cells. Colorectal tumors that do develop in these individuals would, by the same logic, be more resistant to the immune response. To determine if this is indeed the case, the research team drew on data from 170,000 participants in the Nurses’ Health Study and Health Professionals Follow-up Study, two long-term health-tracking research projects. Within this population, researchers compared carefully selected groups of 318 colorectal cancer patients and 624 individuals who were free of cancer. All 942 of them had blood samples drawn in the 1990s, before any developed cancer. The investigators tested these samples for 25-hydroxyvitamin D. They found that patients with high amounts of 25-hydroxyvitamin D indeed had a lower-than-average risk of developing colorectal tumors that were enriched with immune system cells. “This is the first study to show evidence of the effect of vitamin D on anticancer immune function in actual patients and vindicates basic laboratory discoveries that vitamin D can interact with the immune system to raise the body’s defenses against cancer,” Dr. Ogino said. “In the future, we may be able to predict how increasing an individual’s vitamin D intake and immune function can reduce his or her risk of colorectal cancer.” n

Safety:10"

ZELBORAF ® (vemurafenib) tablet for oral use Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1)]. 5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)]. 5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). 5.6 Hepatotoxicity Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

month by the journal Gut, shows a link between vitamin D and the immune response to cancer in a large human population.1 The finding adds to a growing body of research showing that vitamin D plays a keySafety:7" role in cancer prevention. “People with high levels of vitamin

Disclosure: Funding for the study was provided by the National Institutes of Health, the Friends of Dana-Farber Cancer Institute, the Bennett Family Fund, the Entertainment Industry Foundation, and the Paula and Russell Agrusa Fund for Colorectal Cancer Research. For full disclosures of all study authors, visit gut. bmj.com.

Reference 1. Song MY, Hong CP, Park SJ, et al: Protective effects of Fc-fused PD-L1 on two different animal models of colitis. Gut 64:260-271, 2015.

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American College of Surgeons Clinical Congress Breast Cancer

Contralateral Prophylactic Mastectomy: Know the Data When Discussing the Option With Patients By Caroline Helwick

ncologists need a better understanding of why women choose contralateral prophylactic mastectomies without indication, and they need data to counter their patients’ misperceptions about this treatment choice. “Many women who choose [contralateral prophylactic mastectomy] are not at increased risk of a contralateral breast cancer,” said Tari A. King, MD, FACS, Deputy Chief and Director of Research, Breast Surgery Service, Me-

lege of Surgeons Clinical Congress in San Francisco.

Surgeon’s Opinion Critical Perhaps nothing is more influential to the patient contemplating contralateral mastectomy than their surgeon, but surgeons say they feel ineffectual. A patient who wants a contralateral mastectomy merely goes where she can get one, the speakers agreed. Data from the Young Women’s Breast Cancer Study (YWS) reflect

[Contralateral prophylactic mastectomy] is not a quick fix. A woman can be trading one problem for another. We need to get the patient to focus on the net benefit, not the total threat. —Tari A. King, MD, FACS

morial Sloan Kettering Cancer Center, New York. “There is a frequent disconnect in the decision-making process that is likely fueled by fear and anxiety.” On the other hand, a minority of patients, in particular young women with early-stage estrogen receptor (ER)-negative breast cancer may derive a small disease-free survival benefit from contralateral prophylactic mastectomy. “To simply say there’s no benefit to these younger women—and it’s a very small population—is an oversimplification. While level I evidence would be ideal to confirm these retrospective population based observations, such evidence is not likely to ever be had. Therefore, we need use the emerging data to appropriately counsel our patients,” according to Isabelle Bedrosian, MD, FACS, Associate Professor in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston. In general, 3% to 5% of early breast cancer patients will develop contralateral breast cancer over 10 years’ time, but patients estimate this risk at greater than 30%. Clinicians and patients alike need data to make informed decisions, said Drs. King and Bedrosian, speaking at the 2014 American Col-

the importance of the surgeon in discussing all the risks and benefits of the procedure. Among 132 women under the age of 40, 80% aid their physicians discussed reasons to have a contralateral prophylactic mastectomy, whereas only 51% said their physicians discussed reasons not to have the procedure. Further, when asked about their reasons for choosing contralateral prophylactic mastectomy, “to improve survival” and “to prevent metastatic disease” was rated as extremely important or very important by 94% and 85% of patients, respectively, reflecting a real disconnect between the data and the decision-making process.1 “Surgeons can play a major role in the decision-making process,” said Dr. King, who added that despite the evidence, physicians need to remain sensitive to their patients’ needs, and this is challenging. “We are trying to practice evidence-based medicine, but we are also trying to do so in the era of patient-centered care—defined by the Institute of Medicine as care that is respective of and responsive to individual patient preferences, needs, and values,” she added. “This does not mean giving patients what they want,” she emphasized. “Rather, patients want guidance

from their care providers, and they expect that guidance to be provided in the context of full and unbiased information about options, benefits, and risks.”

Trend in Younger Patients The rise in contralateral mastectomy has been widely documented. In one study involving 189,734 patients, bilateral mastectomy rates increased from 2.0% in 1998 to 12.3% in 2011, an annual increase of 14.3%; among women younger than 40 years, the rate increased from 3.6% to 33%.2 “Very recent data show the trend is occurring across all age groups, but especially in younger patients,” Dr. King said. Contralateral prophylactic mastectomy rates are 40% for women under 40, dropping to 20% among women aged 40 to 50 and to 10% among those 50 to 60. Only 5% of the oldest patients undergo contralateral mastectomy. “In concert, the rate of unilateral mastectomy is decreasing. Women are choosing between the most minimal

“Surgeons need to come to a consensus on what is a negative margin so that we avoid unnecessary reoperations,” she offered. This, and routine MRI, are factors that surgeons can potentially impact.

Operating on Anxiety? “We know there are some patients who may benefit from [contralateral prophylactic mastectomy],” Dr. King acknowledged. They include patients at high risk (eg, those with BRCA mutations), those for whom surveillance is difficult (eg, extremely dense breasts, diffuse indeterminate calcifications, or who are difficult to examine); and those with significant reconstructive issues (eg, to improve symmetry). “But an increasing number of women choosing [contralateral mastectomy] are not necessarily falling into these groups,” she pointed out. “Instead, surgeons appear to be operating on anxiety.” In the YWS, 95% listed “peace of mind” as extremely important or very important in the decision for contralateral prophylactic mastectomy. While

In the majority of patients, we can find no association between a survival benefit and [contralateral prophylactic mastectomy]. —Isabelle Bedrosian, MD, FACS

surgery [ie, lumpectomy] and the maximum,” she said.

Things the Surgeon Can Control Multiple studies have demonstrated that preoperative magnetic resonance imaging (MRI) is a trigger for contralateral prophylactic mastectomy. In fact, a Memorial Sloan Kettering study of 2,965 women found MRI at diagnosis to be the strongest predictor (odds ratio = 3.2) for having a contralateral prophylactic mastectomy.3 Prior attempt at breastconserving surgery is another trigger. Rather than undergo reexcision per the surgeon’s desire for a negative margin of a certain distance, many patients opt for contralateral mastectomy.

undergoing prophylactic mastectomy may calm some of these fears, “We have all seen failed reconstructions and women who are still worried after the operation,” Dr. King noted. Outcomes do not always meet expectations. “[Contralateral prophylactic mastectomy] is not a quick fix. A woman can be trading one problem for another,” she said. “We need to encourage patients to focus on the net benefit, not the total threat.”

What Is the Actual Risk? While women vastly overestimate their risk of contralateral cancer, the fact is that for women initially diagnosed with an ER-positive breast cancer, the continued on page 36

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American College of Surgeons Clinical Congress Contralateral Prophylactic Mastectomy continued from page 35

rate of contralateral cancer is only 0.4% per year in the youngest patients, and 0.2% in women over 60, largely because adjuvant hormone therapy reduces risk by 50%. The rate of contralateral breast cancer among women treated for ERnegative breast cancer is 1% per year in the youngest patients. For those treated for HER2 amplified breast cancer, antiHER2 therapy is also protective. Risks of contralateral breast cancer associated with family history are also overestimated. Women with a family history of breast cancer, who are younger than age 55 at first diagnosis and not BRCA mutation carriers have less than a 10% risk of contralateral cancer at 10 years. The risk exceeds 10% only when a first-degree relative had a bilateral breast cancer or if the patient is a BRCA mutation carrier.4

Challenges in Estimating Risk of Contralateral Breast Cancer When predicting the impact of contralateral prophylactic mastectomy on contralateral breast cancer risk, Dr. Bedrosian indicated that “different patients have different degrees of benefit.” While, in general, contralateral prophylactic mastectomy conveys a 90% relative reduction in risk of contralateral breast cancer events, patients with the highest baseline risk of contralateral breast cancer will derive far greater absolute benefit than patients with lower risk. When determining the risk of contralateral breast cancer for any given individual, it is hard to give a straightforward number, since there are dynamic interactions among factors that influence risk: BRCA status, age at diagnosis, and ER status of the index cancer, as well as family history (number of relatives and relatedness). “Combinations of these are much more informative than any one alone,” Dr. Bedrosian noted. Even BRCA status is more heterogeneous than first believed, with first diagnosis before age 40 carrying a twofold greater risk of developing a contralateral breast cancer at 10 years compared to first diagnosis after age 50. The analysis of survival benefit in BRCA mutation carriers is also com-

plicated by prophylactic oophorectomy and by the preventive effect of endocrine therapy.

What Is the Actual Survival Benefit? The determination of survival benefit is also challenging because of the retrospective nature of studies and the bias inherent in statistical modeling. For example, women choosing contralateral prophylactic mastectomy tend to be healthier; hence, they live longer and can undergo more aggressive systemic cancer treatment, which alters outcomes, she pointed out. Dr. Bedrosian and her colleagues evaluated the Surveillance, Epidemiology, and End Results (SEER) database, stratifying by age (a surrogate for comorbidity), stage of index tumor, and ER status, and concluded that for young women (< age 50) with stage I/ II ER-negative breast cancer, contralat-

and improved disease-free survival, she explained. “But this perfect storm scenario is not common. We saw this in only 6% of women in our series,” Dr. Bedrosian emphasized. “In the majority of patients, we can find no association between a disease-free survival benefit and [contralateral prophylactic mastectomy].” This was confirmed in her matched propensity analysis of patients at MD Anderson,7 which observed a benefit in the subset of ER-negative matched patients only (HR = 0.48, P = .05) and not in ER-positive pairs (HR = 0.73, P = .19).6 A recent, unrelated study, using a Markov analysis to estimate the effect of contralateral prophylactic mastectomy on survival outcomes, confirms a modest disease-free survival benefit across younger ages and earlier stages of index disease, but the overall survival benefit is less than 1% across all patient groups.7

Advising Patients on Contralateral Mastectomy ■■ Rates of contralateral prophylactic mastectomy continue to increase, especially among women aged 40 and younger—a group in which onethird are choosing this surgery. ■■ Women greatly overestimate their risk of contralateral cancer. The actual risk is generally 3% to 5% over 10 years, but some women are at higher risk. ■■ More than 95% of say they choose contralateral prophylactic mastectomy for “peace of mind.” ■■ Some ER-negative patients will derive a 5% disease-free survival benefit. These tend to be patients with high contralateral risk, low risk of death from the index tumor, and low risk of a non–cancer-related death. ■■ This population with a benefit comprises only about 6% of women with breast cancer. In the vast majority, there is no disease-free or overall survival benefit from contralateral prophylactic mastectomy.

eral prophylactic mastectomy conveyed approximately a 5% disease-free survival benefit; this was not true for young women with early-stage, ER-positive patients.5 “There is not a straightforward relationship between [contralateral prophylactic mastectomy] and survival,” she emphasized. The model must include a woman’s estimated risk of dying from the index tumor and from a noncancer cause. For women with a relatively high risk for a contralateral breast cancer event, a relatively low risk of death from the index tumor, and low risk of death from something other than cancer, the data suggests an association between contralateral prophylactic mastectomy

“Looked at another way, the additional life expectancy gained from [contralateral prophylactic mastectomy] could be measured at best in a matter of months,” Dr. Bedrosian concluded. “For the majority of breast cancer patients, there are no compelling data to show an improvement in either disease-free or overall survival,” Dr. Bedrosian emphasized. “In a very small subset, [contralateral prophylactic mastectomy] is associated with improved disease-free survival, but if you believe that overall survival is the endpoint of interest, the data are less compelling.” She said she tells young women who are part of that small minority who may

benefit, “Yes, there’s a suggestion that [contralateral prophylactic mastectomy] will improve your disease-free survival, but if you do develop a contralateral breast cancer, there’s a very good chance it will be cured, so your overall life expectancy is not affected. These are hard concepts to communicate to patients.” “Our challenge,” she emphasized, “is presenting information to patients so that they choose approaches other than [contralateral prophylactic mastectomy], and that if they do end up choosing contralateral prophylactic mastectomy, it is an informed decision.” n

Disclosure: Drs. King and Bedrosian reported no potential conflicts of interest.

References 1. Rosenberg SM, Tracy MS, Meyer ME, et al: Perceptions, knowledge, and satisfaction with contralateral prophylactic mastectomy among young women with breast cancer: A cross-sectional survey. Ann Intern Med 159:373-381, 2013. 2. Kurian AW, Lichtensztain DY, Keegan THM, et al: Use of and mortality after bilateral mastectomy compared with other surgical treatments for breast cancer in California, 1998-2011. JAMA 312:902914, 2013. 3. King TA, Sakr R, Patil S, et al: Clinical management factors contribute to the decision for contralateral prophylactic mastectomy. J Clin Oncol 29:2158-2164, 2011. 4. Reiner AS, John EM, Brooks JD, et al: Risk of asynchronous contralateral breast cancer in noncarriers of BRCA1 and BRCA2 mutations with a family history of breast cancer: A report from the Women’s Environmental Cancer and Radiation Epidemiology Study. J Clin Oncol 31:433439, 2013. 5. Bedrosian I, Hu CY, Chang GJ: Population-based study of contralateral prophylactic mastectomy and survival outcomes of breast cancer patients. J Natl Cancer Inst 102:401-409, 2010. 6. Brewster AM, Bedrosian I, Parker PA, et al: Association between contralateral prophylactic mastectomy and breast cancer outcomes by hormone receptor status. Cancer 118:5637-5643, 2012. 7. Portschy PR, Kuntz KM, Tuttle TM, et al: Survival outcomes after contralateral prophylactic mastectomy: A decision analysis. J Natl Cancer Inst 106(8):dju160, 2014.

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Chicago Multidisciplinary Symposium in Thoracic Oncology Thoracic Oncology

Significant Improvement in Progression-Free Survival Using Sunitinib as Switch Maintenance in Advanced NSCLC By Charlotte Bath

rogression-free survival was significantly improved among patients with advanced non–small cell lung cancer (NSCLC) receiving sunitinib (Sutent) as switch maintenance compared to placebo, according to results of an Alliance phase III trial (Cancer and Leukemia Group B [CALGB] 3067). The effect of sunitinib as switch maintenance on progression-free survival was seen independent of histology, the trials lead investigator, Mark A. Socinski, MD, reported at the Plenary Session of the 2014 Chicago Multidisciplinary

doublet,” Dr. Socinski said. Patients with nonprogressive disease were randomly assigned to sunitinib at 37.5 mg daily (106 patients) or placebo (104 patients) until disease progression. Bevacizumab (Avastin) “was allowed during first-line treatment but the treating physician had to be willing to discontinue it after the fourth cycle,” Dr. Socinski noted. Stratification factors included stage of disease (IIIB vs IV), performance status (0 and 1 vs 2), prior use of bevacizumab (yes or no), and gender. Fewer than half the patients were female in the

This is the first trial evaluating an antiangiogenic agent as maintenance therapy in advanced NSCLC. —Mark A. Socinski, MD

Symposium in Thoracic Oncology. No effect was seen on overall survival. Dr. Socinski is Director, Lung Cancer Section, Division of Hematology Oncology, at the University of Pittsburgh Cancer Institute. Sunitinib, an oral tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor and other kinases, “has shown single-agent activity in advanced NSCLC,” Dr. Socinski noted, and an acceptable toxicity profile. “This is the first trial evaluating an antiangiogenic agent as maintenance therapy in advanced NSCLC,” he added.

First-Line Platinum-Based Doublet In CALGB 3067, “similar to all the maintenance trials, patients received four cycles of a first-line platinum-based

sunitinib group (46.2%) and the placebo group (42.3%). The average age was 65 in the sunitinib group and 67 in the placebo group. Patients could have no cavitary lesions or symptomatic or untreated brain metastases. “The dominant histology was adenocarcinoma,” Dr. Socinski reported. “Squamous cell carcinoma was second.” Most patients were past smokers, and about 25% were current smokers.

P = .0005). The secondary endpoint of overall survival was not met, being 11.7 months in both groups. “The toxicity was different, as one would expect,” Dr. Socinski noted, consistent with known sunitinib side effects and with no new toxicity signals identified. There were increases in all grades of neutropenia, thrombocytopenia, and anemia, which occurred in 1% of placebo recipients but 12%, 18%, and 14%, respectively, of sunitinib recipients. Most of the differences in nonhematologic toxicities occurred in all grades, but patients receiving sunitinib were more likely to have grade 3/4 mucositis, rash, hypertension, and fatigue.

Results in Context In addition to achieving its goal of increasing progression-free survival, “the overall response rate was actually numerically better for sunitinib than placebo, 11.3% vs 5%, noted Plenary Session discussant Vassiliki A. Papadimitrakopoulou, MD, Jay and Lori Eisenberg Endowed Professor of Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Primary Endpoint Met The study “met its primary endpoint, showing a significant improvement in [progression-free survival] for sunitinib as switch maintenance in advanced NSCLC,” Dr. Socinski observed. Median progression-free survival was 4.3 months with sunitinib vs 2.6 months with placebo (hazard ratio [HR] = 0.61,

Vassiliki A. Papadimitrakopoulou, MD

“To put this in context,” Dr. Papadimitrakopoulou presented data from other maintenance trials. Those data showed median a progression-free survival of 3.9 and 4 months from mainte-

nance trials with pemetrexed (Alimta), comparable to the 4.3 months in the sunitinib trial results presented by Dr. Socinski. “This is a little better than we have seen with erlotinib,” she added, with median progression-free survival of 2.9 month, and “inferior to what we have seen with the combination of therapy with bevacizumab and erlotinib,” with median progression-free survival of 4.8 months. While the effect of sunitinib was seen independent of histology, Dr. Papadimitrakopoulou cautioned that this was “at the expense of toxicity, with myelosuppression, mucositis, hypertension, fatigue, and rash. There were three deaths on study and no improvement in overall survival.” Dr. Papadimitrakopoulou added, “bevacizumab remains a standard practice option for patients with nonsquamous NSCLC,” but noted that predictive biomarkers and selection strategies are still unavailable for both bevacizumab and sunitinib. n

Disclosure: Dr. Socinski’s institution receives research funding from Pfizer. Dr. Papadimitrakopoulou is a consultant for Merck, Biothera, Genentech, ACEA Biosciences, Clovis, Janssen, Gensignia Life Sciences, AstraZeneca, and Lilly, and has received research support from Merck, Medimmune, BMS, AstraZeneca, Janssen, Clovis, Novartis, Astellas, and Celgene.

References 1. Socinski MA, Wang X, Baggstrom M, et al: Sunitinib (S) switch maintenance in advanced non-small cell lung cancer (NSCLC): An Alliance (CALGB 30607), randomized, placebo-controlled phase III trial. Chicago Multidisciplinary Symposium in Thoracic Oncology. Abstract 1. Presented October 31, 2014. 2. Papadimitrakopoulou V: What is new in NSCLC in 2014. Chicago Multidisciplinary Symposium in Thoracic Oncology. Presented October 31, 2014.

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For patients with bone metastases from solid tumors

Prevent bone complications longer In a prespecified integrated analysis of 3 pivotal trials (N = 5,723),

8.2

XGEVA® was proven to delay the median time to first bone complication by

months longer vs zoledronic acid1

XGEVA® is a convenient 120 mg subcutaneous injection administered once every 4 weeks.2

Bone complications, or skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.2,3 Median Time to First Bone Complication1 27.7

months

Data from a prespecified integrated analysis of three international, phase 3, double-blind, double-dummy, active-controlled trials comparing XGEVA® with zoledronic acid for the prevention of bone complications in patients with bone metastases from solid tumors or multiple myeloma.1

XGEVA VA® 120 mg Q4W (n = 2,862) VA

19.5

months

zoledronic acid 4 mg Q4W (n = 2,861) 1 YEAR

HR* = 0.83 (95% CI: 0.76-0.90)

2 YEARS

P < 0.001

†

IMPORTANT SAFETY INFORMATION Hypocalcemia • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®. XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. • An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake. Hypersensitivity • XGEVA® is contraindicated in patients with known clinically significant hypersensitivity to XGEVA®, including anaphylaxis that has been reported with use of XGEVA®. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA® therapy permanently.

*Hazard ratio (HR) is defined as the increase or decrease in likelihood of an event of interest (in this case a bone complication) for one group relative to that in a comparator group. P value for superiority.

†

Drug Products with Same Active Ingredient • Patients receiving XGEVA® should not take Prolia® (denosumab). Osteonecrosis of the Jaw • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure. • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. • Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Atypical Subtrochanteric and Diaphyseal Femoral Fracture • Atypical femoral fracture has been reported with XGEVA®. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. • RANK Ligand (RANKL) is produced by bone cells in the skeleton and is a key mediator of bone resorption4 • RANKL production is increased at sites of bone metastases, and stimulates osteoclasts to destroy bone4 • XGEVA® acts precisely to bind RANKL and inhibits osteoclast formation, function, and survival2 • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®2

Learn more at XGEVA.com

• Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA® treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA® therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Embryo-Fetal Toxicity • XGEVA® can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA® is expected to result in adverse reproductive effects.

• Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA®. Apprise the patient of the potential hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. Please see brief summary of Prescribing Information on the following page. REFERENCES: 1. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48:3082-3092. 2. XGEVA® (denosumab) prescribing information, Amgen. 3. Brodowicz T, O’Byrne K, Manegold C. Bone matters in lung cancer. Ann Oncol. 2012;23:2215-2222. 4. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.

www.XGEVA.com

S:9.5”

Brief Summary: Consult package insert for complete Prescribing Information

DOUS14CDNY4736_XGEVA_Tabloid_BS_V10_8pt_r13.indd 1

Body System GASTROINTESTINAL Nausea Diarrhea GENERAL Fatigue/ Asthenia IN VESTIGATIONS Hypocalcemiab Hypophosphatemiab NEUROLOGICAL Headache RESPIRATORY Dyspnea Cough

Xgeva n = 2841 %

Zoledronic Acid n = 2836 %

31 20

32 19

18 32

9 20

21 15

18 15

Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] Severe Mineral/Electrolyte Abnormalities • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes. • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid. Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1 – 40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 – 53). Atypical Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva. Postmarketing Experience. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. • Hypersensitivity, including anaphylactic reactions. • Musculoskeletal pain, including severe musculoskeletal pain. Positive rechallenge has been reported. Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy. USE IN SPECIFIC POPULATIONS: Pregnancy: Category D. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva. a

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation. Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated. Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth. Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Renal Impairment. Two clinical trials were conducted in patients without cancer and with varying degrees of renal function. In one study, patients (N=55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a second study, patients (N=32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/no calcium supplementation. Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium levels and, calcium and vitamin D intake. Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk. OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a singleuse vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of a hypersensitivity reaction, including rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension and respiratory tract edema • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth • Persistent pain or slow healing of the mouth or jaw after dental surgery • Symptoms of atypical femoral fracture, including new or unusual thigh, hip, or groin pain • Pregnancy or nursing Advise patients of the need for: • Avoiding therapy with Xgeva if a serious allergic reaction occurred with prior Xgeva or Prolia therapy • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ©2010-2014 Amgen Inc. All rights reserved. Printed in USA. 8/11/14 11:56 AM

S:13”

INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia. Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way. Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva. Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva. WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia. Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently. Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake. Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions). Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis. EMBRYO-FETAL TOXICITY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth, and decreased neonatal growth (see Use in Specific Populations). Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time. ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia • Osteonecrosis of the Jaw The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the

jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/ oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy. Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)

ASCOPost.com | JANUARY 25, 2015

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Chicago Multidisciplinary Symposium in Thoracic Oncology Thoracic Oncology

‘Clinically Meaningful Improvements’ in Survival for Patients With NSCLC When Veliparib Is Added to Carboplatin and Paclitaxel By Charlotte Bath

dding veliparib to carboplatin and paclitaxel resulted in “clinically meaningful improvements” in progression-free survival and overall survival among patients with previously untreated metastatic or advanced non–small cell lung cancer (NSCLC), particularly those with squamous histology. The results of the phase II M10-898 trial were presented by Suresh Ramalingam, MD, at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology.1 Dr. Ramalingam is Chief of Thoracic Oncology and Director of Medical Oncology at Winship Cancer Institute of Emory University, Atlanta. Veliparib (ABT-888) is a potent, orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor that enhances the efficacy of platinum drugs, the current standard of care for metastatic NSCLC. PARP inhibitors, Dr. Ramalingam explained, interfere with the repair of DNA damage and sensitize tumors to chemotherapy and radiation therapy. A previously reported phase I trial combining veliparib with full-dose carboplatin and paclitaxel showed “safety and signs of efficacy in patients with advancedstage NSCLC,” Dr. Ramalingam reported. “And that formed the basis for this randomized phase II clinical trial.”

Almost Half Had Squamous Histology The study randomly assigned patients 2:1 to receive carboplatin and paclitaxel plus either veliparib at 120 mg twice daily or placebo, given on days 1 to 7 of each 21-day cycle. Chemotherapy was administered on day 3 of each cycle. Patients could receive a maximum of six cycles of chemotherapy.

Patients were stratified by histology (squamous vs nonsquamous, with 49% squamous) and smoking history (current, past, or never, with 60% having smoked within 1 year of study entry). The average age of patients was 62 years in the placebo group and 63 years in the veliparib group. Patients were predominantly male, more so in the veliparib group—75 of 105 patients (71%) vs 32 of 53 patients (60%) in the placebo group. All but four patients were Caucasian. Most patients had stage IV disease.

No Increase in Toxicity “Overall, the treatment was tolerated well,” Dr. Ramalingam reported. “More than 90% of the patients were able to receive the planned dose of veliparib without dose reduction.” Adverse events were similar between the two study arms, “suggesting there was no increase in toxicity with the addition of veliparib to chemotherapy,” Dr. Ramalingam noted. Adverse events of any grade occurred in 89% of the placebo group and 96% of the veliparib group, and grade 3 or higher events were reported in 58% and 67% of the respective groups. The most common adverse events were alopecia (42% in the placebo group and 39% in the veliparib group), anemia (42% vs 31%), and neutropenia (29% vs 36%). The one area of imbalance was in leukopenia, affecting 11% of patients in the veliparib group but 0% of the placebo group.

Deeper Responses With Veliparib “The overall response rate was very similar between the two arms of the trial, 28% for placebo and 31% for veliparib. However, the duration of the response

was significantly higher for patients treated with veliparib with chemotherapy, 6.9 months vs 3.3 months, with a hazard ratio of 0.11,” Dr. Ramalingam reported. The median progression-free survival was 4.2 months for those receiv-

Based on the results in patients with squamous cell NSCLC, a phase III pivotal trial (M11-089)2 has been initiated for patients with squamous histology. Additional studies are being conducted with tumor specimens

Overall, the treatment was tolerated well. More than 90% of the patients were able to receive the planned dose of veliparib without dose reduction. —Suresh Ramalingam, MD

ing placebo and 5.8 months for those receiving veliparib. “The hazard ratio was 0.74. The P value did not reach significance (P = .193),” Dr. Ramalingam noted. “Similarly, with overall survival, we saw 9.1 months for the control arm and 11.7 months for the combination, with a hazard ratio of 0.77, with a P value that was not significant (P = .205). ” For patients with squamous cell histology, “there was an improvement in median progression-free survival from 4.1 months to 6.1 months, with a hazard ratio of 0.50,” Dr. Ramalingam stated. “The median overall survival was also increased, from 8.4 months in the control arm to 10.3 months with the combination of veliparib and chemotherapy, with a hazard ratio of 0.71. The P value was .217,” Dr. Ramalingam summarized. “In the patients with nonsquamous disease, there was no difference in progression-free survival or overall survival between the two arms of the trial.”

from patients in the phase II study “to try to identify specific markers that might predict benefit,” Dr. Ramalingam added. n Disclosure: Dr. Ramalingam reported no potential conflicts of interest.

References 1. Ramalingam S, Blais N, Mazieres J, et al: A randomized, double-blind, phase 2 trial of veliparib (ABT-88) with carboplatin and paclitaxel in previously untreated metastatic or advanced non-small cell lung cancer. Chicago Multidisciplinary Symposium in Thoracic Oncology. Abstract 8. Presented October 30, 2014. 2. U.S. National Institutes of Health: Randomized, double-blind, multicenter, study comparing veliparib plus carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel in previously untreated advanced or metastatic squamous non-small cell lung cancer. Available at http://clinicaltrials.gov/ct2/show/NCT02106546. Accessed December 12, 2014.

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The ASCO Post | JANUARY 25, 2015

PAGE 42

News

More Than 1.5 Million Cancer Deaths Averted During 2 Decades of Dropping Mortality

he American Cancer Society’s annual cancer statistics report found that a 22% drop in cancer mortality over 2 decades led to the avoidance of more than 1.5 million cancer deaths that would have occurred if peak rates had persisted. And while cancer death rates have declined in every state, the report found substantial variation in the magnitude of these declines, generally with the states in the South showing the smallest decline and in the Northeast the largest decline.

women) are down more than one-third (35%) from peak rates, while prostate and colorectal cancer death rates are each down by nearly half (47%). The magnitude of the decline in

overall cancer mortality between 1991 and 2011 varied by state. The smallest declines were generally in the South, where drops were about 15%. They were largest in the Northeast, where

there were declines of 25% to 30% in Maryland, New Jersey, Massachusetts, New York, and Delaware. As a result, a total of 29,000 cancer deaths were averted in 2011 in these states.

ADVERTORIAL

The continuing drops we’re seeing in cancer mortality are reason to celebrate, but not to stop [research]. —John R. Seffrin, PhD

Each year, the American Cancer Society compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute and the Centers for Disease Control and Prevention and mortality data from the National Center for Health Statistics. The data will be disseminated in two reports: Cancer Statistics 2015, to be published in CA: A Cancer Journal for Clinicians,1 and Cancer Facts & Figures 2015.2 The reports also estimate the number of new cancer cases and deaths expected in the United States in the current year. Largely driven by rapid increases in lung cancer deaths among men as a consequence of the tobacco epidemic, the overall cancer death rate rose during most of the 20th century, peaking in 1991. The subsequent, steady decline in the cancer death rate is the result of fewer Americans smoking, as well as advances in cancer prevention, early detection, and treatment.

Mortality During the most recent 5 years for which data are available (2007–2011), the average annual decline in cancer mortality was slightly larger among men (1.8%) than women (1.4%). These declines are driven by continued decreases in death rates for the four major cancer sites: lung, breast, prostate, and colon. Lung cancer mortality declined 36% between 1990 and 2011 among males and 11% between 2002 and 2011 among females due to reduced tobacco use. Death rates for breast cancer (among

Cancer Stem Cells

Signal Pathways

Understanding M

alignancies, like normal adult tissue, have been shown to contain a subset of cells that have the capacity to both selfrenew and produce more differentiated progeny. Pre-clinical research suggests that these “cancer stem cells”, while a minority of the total cancer cell population, are part of a hierarchical structure within the tumor mass that retains the highest malignant potential.1,2 Cancer stem cells are also highly resistant to conventional chemotherapeutic drugs.3

Cancer stem cells may originate from either normal stem cells as a result of mutation or from daughter cells which are a progeny of stem cells that have acquired the ability to self-renew as a result of genetic and/or epigenetic changes. Cells that reproduce themselves are more likely

EDU-NPS-0009

12/2014

to live long enough to accumulate the mutations that lead to cancer.4 It has also been demonstrated that non-stem cancer cells can acquire stemness properties to become cancer stem cells.5,6 Our understanding of the role of cancer stem cells in the natural history of cancer is evolving. Cancer stem cells may not only lead to the development of the primary tumor, but migrate to distant sites and cause metastasis.7 Cancer stem cells not eradicated during chemotherapy may also lead to regrowth or recurrence. Cancer stem cells have been positively identified and isolated from a variety of human cancers, including hematological malignancies as well as solid tumors.8 Most chemotherapeutics target actively

ASCOPost.com | JANUARY 25, 2015

PAGE 43

News Estimates for the Current Year The report estimates there will be 1,658,370 new cancer cases and 589,430 cancer deaths in the United States in 2015. Prostate, lung, and colorectal cancers will account for about one-half of all cases in men, with prostate cancer alone accounting for about one-quarter

of new diagnoses. The three most commonly diagnosed types of cancer among women in 2015 will be breast, lung, and colorectal cancers, accounting for one-half of all cases in women. Breast cancer alone is expected to account for 29% of all new cancers among women in the United States. The report estimates that 589,430

Americans will die from cancer this year, corresponding to about 1,600 deaths per day. The most common causes of cancer death are lung, prostate, and colorectal cancers in men and lung, breast, and colorectal cancers in women. These four cancers account for almost onehalf of all cancer deaths, with more than

one-quarter (27%) of all cancer deaths due to lung cancer.

Additional Findings During the past 5 years for which there are data (2007–2011), the overall cancer incidence rate remained stable in women and declined by 1.8% per year in men. The decrease in incidence in men is driven by the rapid declines in colorectal (3.6% per year), lung (3.0% per year), and prostate (2.1% per year) cancers. While women in the United States have seen similar drops in colorectal and lung cancers, breast cancer incidence rates have flattened, and there’s

American Cancer Society Annual Statistics ■■ The 22% drop in cancer mortality over the past 2 decades averted more than 1.5 million cancer deaths that would have occurred had peak rates persisted.

Regrowth

Metastasis

Cancer Stem Cells proliferating cells, resulting in bulk tumor shrinkage; however these agents are not as effective at killing relatively slowly proliferating cancer stem cells. Moreover, it has been shown that conventional chemotherapy and radiation therapy can induce stemness properties in non-stem cancer cells.9,10 Cancer stem cells at primary and metastatic sites can be activated by signals from the tumor microenvironment.11 Targeting these signaling pathways may disrupt aberrant signaling in cancer stem cells while reducing the toxicity to normal tissues associated with chemotherapy.12

1. Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522-526. 2. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 3. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275-285. 4. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43-47. 5. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 6. Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146(4):633-644. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Korkaya H, Wicha MS. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs. 2007;21(5):299-310. 9. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer cell stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 10. Ghisolfi L, Keates AC, Hu X, Lee DK, Li CJ. Ionizing radiation induces stemness in cancer cells. PLoS One. 2012;7(8):e43628. 11. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 2006;66(4):1883-1890. 12. Boman BM, Huang E. Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838.

Boston Biomedical’s mission is to develop the next generation of cancer therapeutics by creating drugs designed to target cancer stem cell pathways.

www.bostonbiomedical.com

■■ The decline in the cancer death rate is the result of fewer Americans smoking, as well as advances in cancer prevention, early detection, and treatment. ■■ The report found substantial variation in the magnitude of these declines across the United States.

been a dramatic rise in thyroid cancer incidence rates (an average of 4.5% per year from 2007 to 2011). “The continuing drops we’re seeing in cancer mortality are reason to celebrate, but not to stop [research],” said John R. Seffrin, PhD, Chief Executive Officer of the American Cancer Society. “Cancer was responsible for nearly one in four deaths in the United States in 2011, making it the second leading cause of death overall. It is already the leading cause of death among adults aged 40 to 79 and is expected to overtake heart disease as the leading cause of death among all Americans within the next several years. The change may be inevitable, but we can still lessen cancer’s deadly impact by making sure as many Americans as possible have access to the best tools to prevent, detect, and treat cancer.” n References 1. Siegel RL, Miller KD, Jemal A: Cancer statistics, 2015. CA-Cancer J Clin. January 5, 2015 (early release online). 2. American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society, 2015.

The ASCO Post | JANUARY 25, 2015

PAGE 44

Chicago Multidisciplinary Symposium in Thoracic Oncology Thoracic Oncology

Top 10 Lessons Learned So Far About Treating Lung Cancer With Immunotherapy By Charlotte Bath

mmunotherapy agents “really work” in treating lung cancer, but they have unique toxicities, are challenging to combine with other therapies, and questions remain about dose and duration, Roy S. Herbst, MD, PhD, stated at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. “There are many agents—agonists, antagonists—some antibodies activate, some inhibit. We are quite lucky that there is such a fertile field,” he said. “It is very promising for our patients. We’re helping 20% now. How can we help the other 80% in the future?” Dr. Herbst is Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, and Associate Director for Translational Research and Clinical Research Program Leader, Thoracic Oncology Program, Yale Cancer Center, New Haven, Connecticut. At the Chicago meeting, he presented a countdown of the “top 10 lessons” learned about immunotherapy in treating lung cancer and shared his concerns and optimism about tackling the unknowns. 10. “These agents really work. It is clearly a breakthrough for the patients,” Dr. Herbst noted. “The activity is even a little bit better” than that displayed by epidermal growth factor receptor (EGFR) inhibitors when they were developed 10 or 15 years ago,” he said. “What is really striking is the durability [of immunotherapy agents],” he added. While resistance does develop, “many patients have a very long durability of the response, because the immune system can adapt.” Dr. Herbst cited a phase I study presented at the symposium, which found that the anti–programmed cell death protein 1 (PD-1) antibody pembrolizumab (Keytruda) provided robust antitumor activity as first-line therapy for patients with programmed death ligand-1 (PD-L1)–positive advanced non–small cell lung cancer (NSCLC).1 The overall response rate was 26% by RECIST criteria and 47% by immunerelated response criteria, and 100% of RECIST responders and 90% of immune-related response criteria responders had ongoing responses. In a phase II trial with another anti– PD-1 antibody, nivolumab (Opdivo),2 “while the response rate was 15%, a little bit lower than targeted, the median overall survival of 8.2 months and the

1-year survival of 41% are wonderful results in the third-line setting in squamous cell lung cancer,” Dr. Herbst said. 9. “It is still unclear what is the most appropriate endpoint,” Dr. Herbst pointed out. “Delayed response is something we need to keep in mind, and it does change the way we think about clinical trials. The endpoint should be response rate, sure. Do we need to have a 50% response rate to get these drugs approved in a breakthrough setting? I would think not, because of the large durability of response, but

6. “The PD-L1 biomarker has some flaws,” Dr. Herbst said. With four to five companies working on this, each one with a different marker, “this is really a mess,” Dr. Herbst said. There are a lot of issues to be considered, including heterogeneity of the tumor, type of biopsy, interval between biopsy and treatment, and primary vs metastatic disease. “This is a continuous variable. Patients can be 5% positive, 10% positive, 20% positive,” Dr. Herbst noted. “It’s a moving target,” he added, and “the assay is going to help define the field.”

I haven’t felt this type of excitement around new drugs since EGFR inhibitors were developed more than a decade ago. —Roy S. Herbst, MD, PhD

what number you should have is unclear. We should probably look at other endpoints, including survival endpoints, and perhaps survival endpoints at landmarks,” he suggested. “This needs to be thought out in an innovative way.” 8. “All checkpoint antibodies are not the same.” Dr. Herbst observed that the checkpoint antibodies all have different binding affinities, slightly different targets, and different abilities to avoid antibody-dependent cell-mediated cytoxicity. “Probably the major difference,” is between the anti–PD-1 and the anti–PD-L1 antibodies. “Which is better, only the clinical trials can tell. We need robust experiences to really compare them, perhaps someday headto-head experiences,” Dr. Herbst said. 7. “These agents, while different from chemotherapy, do have unique toxiocities,” Dr. Herbst noted. “As medical oncologists, lung cancer oncologists, we are now dealing in ‘itises’— colitis, renal nephritis, pneumonitis, hepatitis,” Dr. Herbst said. “Dermatologic effects do occur,” he added, “along with some neurologic autoimmunetype phenomena in rare cases” and “endocrinopathies, diseases of the pituitary, thyroid, and adrenal glands. You have to think about it, look for it, and manage it. Sometimes you need to talk about it with your endocrinologist.”

5. “Science can help ‘drive the show.’ This is [a lesson] that is close to my heart,” Dr. Herbst admitted. He reminded colleagues that lung cancer is linked to many mutations and that biopsies and immune monitoring should be done when possible. “Now we can make the clinic our lab and ask what is going on with the tumor,” he said. “With pretreatment and posttreatment biopsies, you can see dynamically what is happening in the immune process,” he continued. “You can also see when it doesn’t work. So if a patient is not responding, for example, you can see a rim of T cells not getting to the tumor.”3 Several companies are developing new assays for dynamic monitoring. 4. “Questions remain regarding the dose and duration of therapy,” Dr. Herbst said. “How long do you treat—1 year or 2 years? What is the right dose? No one really knows,” Dr. Herbst acknowledged. “Do you need to retreat if someone becomes refractory? These are all issues that might be helped with more immune monitoring.” 3. “Combination therapy is a must,” Dr. Herbst said, but what should immunotherapy be combined with? “Are we going to combine with chemotherapy, targeted therapy, immune therapy, other checkpoint in-

hibitors? Probably all of the above,” he predicted. “We have to think about this very carefully. We can’t just combine therapies like we used to. We have to say, ‘What is that small-molecule agent going to do to the T cell?’ We don’t want to do something to the tumor cell that is also going to inhibit the T cell. It is very complicated. We need personalized immunotherapy,” Dr. Herbst said. “The one combination that certainly deserves all of our interest in lung cancer is CTLA-4 and PD-1. Why? Because it works great in melanoma.,” Dr. Herbst said. “Our patients are different, but still, the idea that you target CTLA4, you target the T cell and prime it when it is in the lymph node, and then you work with the PD-1/PD-L1 in the tumor microenvironment—that is a proven mechanism for melanoma, with 1-year survival rates of up to 80%.” 2. “Immunotherapy will be used in all lines of therapy,” Dr. Herbst predicted. This will “absolutely” happen. 1. “It’s a horse race,” Dr. Herbst admitted. “I haven’t felt this type of excitement around new drugs since EGFR inhibitors were developed more than a decade ago,” he said. He couldn’t predict who would get the first checkpoint drug approved for lung cancer and what that drug would be, but the “winning group will be the one with the best drug, the best biomarker, the best strategy, and a little bit of luck.” The true winners, he noted, will be “our patients.” n Disclosure: Dr. Herbst reported no potential conflicts of interest.

References 1. Balmonoukian AS, Rivzi AN, Garon EB, et al: Safety and clinical activity of pembrolizumab (MK-3475) as initial therapy in patients with advanced nonsmall-cell lung cancer. Chicago Multidisciplinary Symposium in Thoracic Oncology. Abstract 2. Presented October 31, 2014. 2. Ramalingam SS, Mazières, Planchard D, et al: Phase II study of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients with advanced, refractory, squamous non-small-cell lung cancer. Chicago Multidisciplinary Symposium in Thoracic Oncology. Abstract LBA2. Presented October 31, 2014. 3. Herbst RS, Soria JC, Kowanetz M, et al: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563-567, 2014.

Joan is more than just a patient going through

CHEMOTHERAPY We see so much more than just cancer Joan is already busy enough with hockey practices, dance recitals, and science fair supply shopping. Now sheâ&#x20AC;&#x2122;s making room on the kitchen calendar for Q3W therapy sessions. People like Joan are at the heart of what drives Teva Oncology. With over 100 years of global pharmaceutical expertise, our mission is to develop and deliver solutions that advance cancer care and improve the lives of people affected by cancer.

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The ASCO Post | JANUARY 25, 2015

PAGE 46

Chicago Multidisciplinary Symposium in Thoracic Oncology Overdiagnosis May Be Overblown in Lung Cancer Screening By Charlotte Bath

“O

verdiagnosis has been overblown” in concerns voiced about lung cancer screening with low-dose computed tomography, A ndrea B. McKee, MD, told participants at the opening session of the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. Dr. McKee is Chair of the Department of Radiation Oncology, at the Sophia Gordon Cancer Center, Lahey Hospital & Medical Center, Burlington, Massachusetts. Although it has been reported that the rate of overdiagnosis using low-dose computed tomography in the National Lung

years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.”1 More than 40 national societies have endorsed that recommendation. “There is amazing consensus,” Dr. McKee noted, “but few are screened.” There are “lots of barriers,” she said, including costs, anxiety, and concerns about false-positive results and radiation exposure. Some fear that promoting screening could actually encourage smoking. The Rescue Lung, Rescue Life pro-

Access to quality computed tomography lung screening represents one of the greatest opportunities to improve outcomes for patients diagnosed with lung cancer in the history of the disease. —Andrea B. McKee, MD

Screening Trial was 18%, “this was calculated based on an assumption that the patients were only going to live 7 years,” Dr. McKee said, “and that’s actually not very accurate.” Using the actual expected lifetime of a patient in the screening program, “the overdiagnosis rate is 11% vs no screening, and 9% vs chest x-ray. It is about 2.6% vs no screening and 1.2% for chest x-ray,” she added. “Access to quality computed tomography lung screening represents one of the greatest opportunities to improve outcomes for patients diagnosed with lung cancer in the history of the disease,” Dr. McKee stated. The symposium was sponsored by ASCO, along with the American Society for Radiation Oncology (ASTRO), the International Association for the Study of Lung Cancer (IASLC), and the University of Chicago. The 787 participants included clinical, medical, radiation, and surgical oncologists; medical physicists; nurses and nurse practitioners; physician assistants; residents/fellows; and students. International participants represented countries in Europe, Australia, North American, and South America.

‘Amazing Consensus’ The U.S. Preventive Services Task Force “recommends annual screening for lung cancer with low-dose computed tomography in adults aged 55 to 80

gram was established at Lahey Hospital and Medical Center to deal with these concerns and put in place basic physical and organizational structures needed to run a safe and responsible lung cancer screening program. Based on experience with mammography, the Rescue Lung, Rescue Life program encourages the involvement of primary care physicians. About 4% of patients have a suspicious low-dose computed tomography result, and “we decide as a team” what to do next, Dr. McKee said. “A lot of times it ends up being a conservative approach.” Among patients screened and followed through June 2014, 25 of 1,654 had surgery; 20 (1.2% of all patients) were diagnosed with lung cancer (18 early stage); and 5 patients (0.3%) had either benign disease or metastatic disease to lung from another primary tumor. She noted that “80% of surgical cases actually had lung cancer, so we are doing a pretty good job of using this system and not intervening in patients who don’t have cancer.” Dr. McKee predicted, “After 2 years, based on our hospital size, we will be saving one life every 3 weeks or so.”

‘Sense of Urgency’ Needed To promote adequate use of screening, there has to be “a sense of urgency,” Dr. McKee said. “Lung cancer kills 450

people every day,” she noted. “That’s like a jumbo jet crashing every day.” The sense of urgency may receive added impetus from “failure-to-screen lawsuits,” Dr. McKee added. With the U.S. government and many medical organizations recommending screening, these lawsuits are expected to be brought by patients who met the National Lung Cancer Screening Trial criteria for high risk but were not offered screening and then presented with later-stage disease. Physicians and patients also need to know how fast and easy the screening is, Dr. McKee said. In the Rescue Lung, Rescue Life program, screening “takes less than 10 seconds, requires no changing, and no IV,” she reported. “More than 75% of patients come back the next year.”

Getting the Message Out A study presented at the symposium found that patients at high-risk for lung cancer are more likely to receive low-dose computed tomography lung screening when their primary care providers are familiar with the recommended guidelines. Conducted among primary care providers, including physicians, physician assistants, and nurse

Jennifer Lewis, MD

practitioners affiliated with Wake Forest Baptist Medical Center in North Carolina, the study also found that they reported ordering a chest x-ray, which is not recommended, more often than a low-dose computed tomography. In response to a question from The ASCO Post, the study’s lead author, Jennifer Lewis, MD, Assistant Chief of Medicine, Department of Internal Medicine at Wake Forest, said that they were not able to determine why a chest x-ray was ordered more often. “I have to wonder if it could be related to cost, because cost was the most reported barrier. It could also be that they know who to screen, but they don’t know the correct test,” she noted. The lack of adherence to the recommendations “is

Michael J. Simoff, MD

mainly because they are new, and primary care providers are just not aware of the data yet.” The study concluded that educational interventions are critical to increasing low-dose computed tomography screening.2

‘Imaging Is Not Diagnosis’ “Imaging is not diagnosis,” Michael J. Simoff, MD, Associate Professor of Medicine and Director of Bronchoscopy and Interventional Pulmonology at Henry Ford Hospital in Detroit, reminded participants. He cited a study that found that among 100 patients, all with computed tomography–negative lymph nodes, on staging, 22% were positive for malignancy. With positron-emission tomography and computed tomography for diagnosing lung cancer, “the accuracy is about 88%, not 100%. We can’t rely on them,” Dr. Simoff said. “Tissue is still required for a diagnosis.” Transthoracic needle aspiration is a commonly used approach to detected nodules and has the advantage “of not having to have a lot of technology,” Dr. Simoff said. “For large nodules, the accuracy is 96%, and for small nodules, defined as < 2 cm, 74%. But the risk of pneumothorax in this patient population is 21% to 24%, depending on the literature that you look at. The need for chest tubes is only about 5% to 7%, but still the risk in the population who have emphysema is significantly high.”

Advanced Diagnostic Techniques “Transbronchial biopsy with fluoroscopic guidance hasn’t really changed in 30 years,” Dr. Simoff said. “The yield for nodules < 2 cm is less than 20%.” The nodule usually has to be at least 2 cm and greater than 3 cm “to get a good piece of information.” Using computed tomography and then incorporating ultrasound has allowed for the identification of smaller lesions but didn’t improve the ability continued on page 47

ASCOPost.com | JANUARY 25, 2015

PAGE 47

Association of Molecular Pathology Annual Meeting Health-Care Policy

Molecular Pathologists vs the FDA: Proposed Regulation of Laboratory-Developed Tests Sparks Debate By Caroline McNeil

he packed ballroom looked like a plenary session at any big medical research meeting. But on the dais were representatives of the Food and Drug

What has happened since 1976, all parties agree, is dramatic growth and change in the field of diagnostic testing. With the rise of personalized medicine,

There are many tests currently launched that do not have any published data to support them. Use of published literature is not always an assurance of clinical validity. —Alberto Gutierrez, PhD

Administration (FDA), the subject was the Agency’s proposed regulation of laboratory-developed tests, and the attendees who lined up to ask questions for nearly an hour voiced only concern and opposition. The event at the Association of Molecular Pathology Annual Meeting in November 2014 highlighted the controversy that came to a head in July 2014, when the FDA announced it would issue long-discussed draft guidance with proposed regulations for laboratorydeveloped tests (see sidebar). The Agency’s authority to regulate laboratory-developed tests comes from the Medical Device Amendments of 1976, which explicitly include in vitro diagnostic devices. But for decades, it has exercised “enforcement discretion” for laboratory-developed tests, which it defines as “in vitro diagnostic devices that are intended for clinical use and are designed, manufactured, and used within a single laboratory.” Currently, laboratories are monitored by the Centers for Medicare and Medicaid Services through the Clinical Laboratory Improvement Amendments (CLIA).

Overdiagnosis continued from page 46

to reach them with a probe. “So we’ve moved into electromagnetic navigation bronchoscopy,” Dr. Simoff said. This technology incorporates computed tomography imaging with a GPS-like system to create three-dimensional information. “We place the patient into an electromagnetic field so that we can then use the technology to guide us to the lesion,” he explained. “The locatable guide has been the

complex and widely marketed genomic tests are increasingly used to make treatment decisions in common diseases—notably cancer. The risks when such tests produce a false-negative or false-positive result can be serious. “Failure of such tests to perform as intended can lead to patients receiving an inappropriate and potentially harmful treatment or, alternatively, not receiving treatment that has the potential to benefit them,” said Richard Schilsky, MD, Chief Medical Officer of ASCO, in a statement supporting the FDA’s action.

CLIA and Clinical Validity The FDA document outlines a riskbased approach to regulation (see sidebar). Premarket approvals would be required for existing tests in the highrisk category, including tests for which there is already an FDA-approved equivalent. For subsequent high-risk and moderate-risk tests, premarket approvals would be phased in over 9 years. Premarket approvals would not be required for traditional or low-risk laboratory-developed tests, those used for greatest tool in my eyes to allow us to move out peripherally, because when we rotate it, we can actually direct it in eight different directions. I can now have control out into those 16th, 18th, and 20th generation airways to allow me to move. Once we’ve gone through that airway, we leave a small catheter out there. We pull out the locatable catheter guide, and then we can put biopsy forceps, ultrasound probes, and other tools out into the periphery of the lung to make the diagnosis.” This has allowed diagnostic yields

rare diseases, or those that serve unmet needs, including tests for which there is no FDA-approved equivalent. Those opposed to the regulations argue that laboratories for these tests are stringently regulated under CLIA and that the proposed new regulations could seriously impact patient safety and timely access to treatment. CLIA requires lab inspections every other year by a certified inspector and on alternate years, an internal inspection, said Aaron Bossler, MD, PhD, Director of the Molecular Pathology Laboratory at the University of Iowa, who spoke at an Association of Molecular Pathology press conference. Inspectors review all reagents, instruments, and staff qualifications. In addition, each procedure must undergo proficiency testing every 6 months. Although CLIA inspections assure that tests are done properly, they do not

Richard Schilsky, MD

verify the clinical validity of the tests, says the FDA. Nor does CLIA provide for premarket review or the removal of unsafe tests from the market. Clinical validity and how to establish it are focal points of this debate. CLIA assures that a test detects what it claims to detect, such as a genetic variant, but not the clinical validity of the test (eg, that the variant correlates with a specific disease). Representatives of of 75% for nodules ≤ 2 cm in the outer third of the lung, Dr. Simoff reported. “The yields are moving up into the same category as transthoracic needle aspiration. The advantage is that our risk for pneumothorax is < 4% vs nearly 25%. The concomitant advantage is that we can go on and take a look at these patients for staging at the same time.” n Disclosure: Dr. McKee is an advisor/speaker for Covidien and a speaker for Varian. Drs. Lewis and Simoff reported no potential conflicts of interest.

the Association of Molecular Pathology argue that the correlation between gene variant and disease has been reported in the literature before they develop a test. Typically, a physician requests a test

Janina Longtine, MD

after a study of a targeted agent or biomarker is presented at a major meeting. “We use our experience and expertise to develop high-quality laboratory procedures to detect the DNA variants that have been well-documented in peer-reviewed medical literature to correlate with disease and significantly impact patient care. We make these decisions in partnership with our clinical colleagues—the treating physicians who request this information to properly treat their patients,” said Janina Longtine, MD, Vice-Chair, Molecular Pathology and Genetics, at Mount Sinai Medical Center in New York, speaking after the press conference. Many laboratory-developed tests do follow this path, agreed Alberto Gutierrez, PhD, Director of the FDA’s Office of In Vitro Diagnostics and Radiological Health, who spoke at the Association of Molecular Pathology meeting. But others do not, he added. “There are many tests currently launched that do not have any published data to support them,” he wrote in an e-mail. “Furthermore, given the continued on page 50

References 1. Moyer VA, on behalf of the U.S. Preventive Services Task Force: Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 160:330-338, 2014. 2. Lewis J, Petty WJ, Tooze A, et al: Low-dose CT lung cancer screening practices and attitudes among primary care providers at an academic medical setting. 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. Abstract 13.

Does your ovarian cancer patient have a BRCA mutation? Only testing will tell.

Screening based on family history or age misses a substantial number of ovarian cancer patients with a BRCA mutation. Approximately 15% of women with ovarian cancer have a deleterious BRCA mutation.1 Testing for a BRCA mutation provides powerful information for patients with ovarian cancer, their families, and their physicians. Yet most patients with ovarian cancer are not tested, leaving their BRCA status unknown.

positive ovarian cancer patients are aged 50 or older, and about one-third are aged 60 or older.8,9 BRCAm Ovarian Cancer Patients by Age at Diagnosis8

National guidelines recommend that all patients with epithelial ovarian cancer be considered for BRCA testing, regardless of family history, age, or ethnicity. 2,3

39% 29

[A]ll women diagnosed with ovarian, fallopian tube or peritoneal carcinoma, regardless of age or family history, should receive genetic counseling and be offered genetic testing.” - SGO Clinical Practice Statement, October 2014 4 In clinical practice, however, the decision to recommend genetic testing is too often based on certain patient and disease characteristics.5 Despite guidelines, every year less than a quarter of patients with ovarian cancer are tested for a BRCA1/2 mutation.6,7

Family history and age at diagnosis are poor predictors of BRCA status in ovarian cancer patients. 8,9 Nearly half of patients with ovarian cancer and a BRCA1/2 mutation have no signiﬁcant family history of ovarian or breast cancer. In addition, more than two-thirds of BRCABRCAm Ovarian Cancer Patients by Family History Status8

53%

47% No relevant family history Relevant family history

32%

71%

of patients with ovarian cancer and a BRCA mutation are aged 50 or older at diagnosis.8 <50 50-59 >60

Moreover, the prevalence of a BRCA mutation has been shown to be remarkably similar regardless of ethnicity, yet BRCA testing is not as common in women of non-European descent.10 Even sophisticated predictive models, which attempt to use a number of factors (including family history and age) to determine who should be tested for a BRCA mutation, fail to identify a signiﬁcant proportion of patients who carry a BRCA mutation.11,12

Ovarian cancer cells with a BRCA mutation have DNA repair deﬁciencies and therefore are particularly sensitive to DNA-damaging agents.13 Germline BRCA mutations are associated with improved survival and generally favorable response to platinum-based chemotherapy in ovarian cancer.9,13 Additionally, there is evidence to suggest that BRCA expression is predictive of a clinical beneﬁt for the use of IP-administered chemotherapy compared with IV-administered chemotherapy.14

Testing ALL of your ovarian cancer patients for their BRCA status provides powerful information for you, your patient, and her family.

REFERENCES: 1. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2014. 3. Lu KH, Wood ME, Daniels M, et al; American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 4. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. October 2014. http://www.sgo.org/clinical-practice/ guidelines/genetic-testing-for-ovarian-cancer/. Accessed October 23, 2014. 5. Norquist BM, Pennington KP, Agnew KW, et al. Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identiﬁed by clinical testing. Gynecol Oncol. 2013;128(3):483-487. 6. Myriad Genetics. http://www.myriadpro.com. Accessed November 4, 2014. 7. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 8. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 9. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. 10. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 11. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 12. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 13. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 14. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237. ©2014 AstraZeneca. All Rights Reserved. 3061900 Last Updated 11/14

The ASCO Post | JANUARY 25, 2015

PAGE 50

Association of Molecular Pathology Annual Meeting Laboratory-Developed Tests continued from page 47

number of claims in the literature that have not been reproduced, use of published literature is not always an assurance of clinical validity.” CLIA also does not evaluate the clinical validity of the test, ie, whether or not patient outcomes are improved by using the test. However, the guidance document states, “the FDA intends to work with the laboratory community, the health-care professional community, and other stakeholders to identify those laboratory-developed tests for which the clinical validity of the analyte/marker has already been established in the literature.”

Concerns Over Patient Access and Reporting Requirements Another major concern of members of the Association of Molecular Pathology is patient access. When the results of studies with targeted agents are published, laboratories can respond quickly, developing tests for a new biomarker

Jan Nowak, MD, PhD

with little delay, said Jan Nowak, MD, PhD, Medical Director of the Molecular Diagnostics Laboratory at the NorthShore University Hospital System in Chicago.

“The traditional process works and serves a very important service,” he said in an interview. “And it occurs much faster than anything that goes through the FDA.” Tests for which there is no FDA equivalent would not have to go through the premarket approval pro-

Elaine Lyon, PhD

cess but would have to be reported to the FDA. Laboratory professionals also worry about the extra burden of the new reporting requirements. Reporting existing tests would involve tens of thousands of records, said the Association of Molecular Pathology President Elaine Lyon, PhD, of ARUP Laboratories and the University of Utah’s School of Medicine, speaking at the press conference. Laboratories already have websites that list all their tests, she said, and there are registries at the National Institutes of Health and CLIA. “I would ask the FDA to learn from existing sources before putting additional burden on labs.”

Professionals, Not Manufacturers Another recurring theme at the meeting was the difference between traditional and commercial laboratories. Traditional diagnostic laboratories are usually affiliated with a hospital or aca-

FDA’s Draft Guidance for Laboratory-Developed Tests

he FDA’s proposed regulatory framework is based on a test’s level of risk to the patient. • Premarket approvals would be required of the tests in the highest-risk category within a year of the final guidance; that would include tests for which there is already an FDA-approved equivalent. • For subsequent high-risk tests and moderate-risk tests, premarket approvals would be phased in over a 9-year period. Priorities and risk status would be determined through a public process. • Premarket approvals would not be required for traditional tests, tests for rare diseases, and those that serve an unmet need, including tests for which there is no FDA-approved equivalent, as long as these tests met the FDA’s definition of a laboratory-developed test. • Laboratories would be required to notify the FDA of existing and new tests and to begin reporting adverse events. The FDA has issued two documents: one describing the proposed regulatory framework and the other focusing on the notification process. Comments on each may be submitted by February 2, 2015 (visit http://www.regulations.gov/#!home). n

demic medical center and work closely with physicians. But with the advent of genomic testing, a different business model has emerged. Commercial companies have become involved, often with large marketing budgets. “Clearly, what is happening now is that there are many tests being developed by companies that look more like test manufacturers than traditional laboratory-developed test laboratories,” said the FDA’s Dr. Gutierrez. On this point, representatives of the Association of Molecular Pathology agree. “Some entities have bypassed the FDA process by establishing a laboratory and getting a CLIA license,” said Dr. Nowak. “They are proprietary … but

that’s not the traditional process.” He and others would like the FDA to distinguish between large commercial companies and traditional laboratories. “They are lumping too many things together, trying to deal with several issues with one guidance,” Dr. Nowak said. He and others emphasized that diagnostic testing is a process, not a manufactured product, and they prefer the term laboratory-developed procedure rather than laboratory-developed test. “This is the practice of medicine,” said Dr. Longtine. “We are not manufacturers.” n Disclosure: Drs. Schilsky, Gutierrez, Nowak, Lyon, and Longtine reported no potential conflicts of interest.

Don’t Miss These Important Reports in This Issue of The ASCO Post Mark A. Socinski, MD, on Sunitinib and Advanced NSCLC see page 37

Ruth O’Regan, MD, on Targeting HER2 in Estrogen Receptor-Positive Breast Cancers see page 106

Ronald Levy, MD, on Checkpoint Inhibitors in Hematologic Cancers see page 129

Sean Smith, MD, on Physical Medicine and Rehabilitation In Palliative Care see page 153

Heather A. Greenlee, ND, PhD, MPH, on SIO Guidelines on Integrative Therapies for Breast Cancer see page 165

Margaret A. Tempero, MD, FASCO, on Deviation from Treatment Guidelines see page 180

Visit The ASCO Post online at ASCOPost.com

The Merck Access Program for KEYTRUDA for Injection Visit

merckaccessprogram-keytruda.com OR

Call

855-257-3932 • Speak with a dedicated representative Monday to Friday between 8 AM and 8 PM ET.

• Ask to be contacted by a field reimbursement associate.

For patients For patientswith withunresectable unresectableorormetastatic metastaticmelanoma melanomaand anddisease diseaseprogression progressionfollowing followingipilimumab ipilimumaband, and, if BRAF V600 if BRAF V600mutation mutationpositive, positive,a aBRAF BRAFinhibitor inhibitor

KEYTRUDA: KEYTRUDA: DURABILITY DURABILITY OF OF RESPONSE RESPONSE 24% 24%overall overallresponse responserate rate(complete (completeresponse+partial response+partialresponse) response) with withsingle-agent single-agentKEYTRUDA KEYTRUDA(95% (95%CI, CI,15–34) 15–34) Data Datafor for2 2mg/kg mg/kgevery every33weeks weeks(n=89) (n=89)

11%% 23 23%%

• •There Therewere wereobjective objectiveresponses responsesininpatients patientswith withand and without withoutBRAF BRAFV600 V600mutation–positive mutation–positivemelanoma. melanoma.

Complete CompleteResponse Response(CR) (CR)(n=1) (n=1)

Partial PartialResponse Response(PR) (PR)(n=20) (n=20) (%(% ofof patients) patients)

• •Similar Similaroverall overallresponse responserate rateresults resultswere wereobserved observed in in the the10-mg/kg 10-mg/kgarm. arm. • •Patients Patientscontinued continuedtreatment treatmentwith with KEYTRUDA KEYTRUDA until until unacceptable unacceptable toxicity toxicity or or disease disease progression progression that that was wassymptomatic, symptomatic,was wasrapidly rapidlyprogressive, progressive, required required urgent urgent inter intervention, vention, occurred occurred with with aa decline decline in in performance performancestatus, status,ororwas wasconfirmed confirmedat at44to to66 weeks weeks with withrepeat repeatimaging. imaging.

Study design: AA multicenter, open-label, Study design: multicenter, open-label,randomized, randomized,dose-comparative dose-comparativestudy studycohort cohortofofthe theongoing ongoingKEYNOTE-001 KEYNOTE-001Phase Phase1b1btrial trialininpatients patientswith with unresectable or or metastatic melanoma and progression unresectable metastatic melanoma and progressionofofdisease. disease.Key Keyeligibility eligibilitycriteria criteriaincluded includedprior priortreatment treatmentwith withipilimumab ipilimumab(2(2orormore moredoses doses at at 3 mg/kg or or higher) and a BRAF oror MEK inhibitor, if BRAF 3 mg/kg higher) and a BRAF MEK inhibitor, if BRAFV600 V600mutation–positive; mutation–positive;and anddisease diseaseprogression progressionwithin within2424weeks weeksfollowing followingthe thelast lastdose dose of of ipilimumab. Patients were randomized to toreceive ipilimumab. Patients were randomized receive2 mg/kg 2 mg/kg(n=89) (n=89)oror1010mg/kg mg/kg(n=84) (n=84)ofofKEYTRUDA KEYTRUDAevery every3 3weeks weeksuntil untilunacceptable unacceptabletoxicity toxicityoror disease progression. The major efficacy disease progression. The major efficacyoutcome outcomemeasures measureswere wereconfirmed confirmedoverall overallresponse responserate, rate,asasassessed assessedbybyblinded blindedindependent independentcentral central review using Response Evaluation Criteria in in Solid review using Response Evaluation Criteria SolidTumors Tumors(RECIST (RECIST1.1), 1.1),and andduration durationofofresponse. response.Tumor Tumorresponse responsewas wasassessed assessedevery every1212weeks. weeks.

SELECTED SELECTEDSAFETY SAFETYINFORMATION INFORMATION • Pneumonitis • Pneumonitisoccurred occurredin in1212(2.9%) (2.9%)ofof411 411patients, patients,including including Grade 2 or 3 cases in in 8 (1.9%) and 1 (0.2%) Grade 2 or 3 cases 8 (1.9%) and 1 (0.2%)patients, patients,respectively, respectively, receiving KEYTRUDA. Monitor patients forfor signs and receiving KEYTRUDA. Monitor patients signs andsymptoms symptomsofof pneumonitis. Evaluate pneumonitis. Evaluatesuspected suspectedpneumonitis pneumonitiswith withradiographic radiographic imaging. imaging.Administer Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greater pneumonitis. TRUDA pneumonitis.Withhold WithholdKEY KEY TRUDAforforGrade Grade2;2;permanently permanently discontinue KEYTRUDA forfor Grade 3 or 4 pneumonitis. discontinue KEYTRUDA Grade 3 or 4 pneumonitis. • Colitis • Colitis(including (includingmicroscopic microscopiccolitis) colitis)occurred occurredinin4 4(1%) (1%)ofof411 411 patients, including patients, includingGrade Grade2 2oror3 3cases casesinin1 1(0.2%) (0.2%)and and2 2(0.5%) (0.5%) patients, respectively, receiving KEYTRUDA. Monitor patients, respectively, receiving KEYTRUDA. Monitorpatients patientsforfor signs and symptoms signs and symptomsofofcolitis. colitis.Administer Administercorticosteroids corticosteroidsfor for Grade 2 or greater colitis. Withhold Grade 2 or greater colitis. WithholdKEYTRUDA KEYTRUDAforforGrade Grade2 2oror3;3; permanently discontinue KEYTRUDA forfor Grade 4 colitis. permanently discontinue KEYTRUDA Grade 4 colitis. • Hepatitis (including autoimmune hepatitis) occurred • Hepatitis (including autoimmune hepatitis) occurredinin2 (0.5%) 2 (0.5%)ofof 411411 patients, including a Grade 4 case in in 1 (0.2%) patient, receiving patients, including a Grade 4 case 1 (0.2%) patient, receiving KEY TRUDA. KEY TRUDA.Monitor Monitorpatients patientsforforchanges changesininliver liverfunction. function. Administer Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greaterhepatitis hepatitis and, based onon severity ofof liver enzyme elevations, and, based severity liver enzyme elevations,withhold withholdoror discontinue KEYTRUDA. discontinue KEYTRUDA. • Hypophysitis occurred in in 2 (0.5%) ofof 411411 patients, including • Hypophysitis occurred 2 (0.5%) patients, includinga aGrade Grade2 2 case in in 1 and a Grade 4 case case 1 and a Grade 4 casein in1 (0.2% 1 (0.2%each) each)patient, patient,receiving receiving KEY TRUDA. KEY TRUDA.Monitor Monitorpatients patientsforforsigns signsand andsymptoms symptomsofof hypophysitis. Administer hypophysitis. Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greater hypophysitis. hypophysitis.Withhold WithholdKEYTRUDA KEYTRUDAforforGrade Grade2;2;withhold withholdoror discontinue forfor Grade 3; 3; and permanently discontinue discontinue Grade and permanently discontinueKEYTRUDA KEYTRUDA forfor Grade 4 hypophysitis. Grade 4 hypophysitis.

• Nephritis • Nephritisoccurred occurredinin3 3(0.7%) (0.7%)patients, patients,consisting consistingofofone onecase caseofof Grade Grade2 2autoimmune autoimmunenephritis nephritis(0.2%) (0.2%)and andtwo twocases casesofofinterstitial interstitial nephritis nephritiswith withrenal renalfailure failure(0.5%), (0.5%),one oneGrade Grade33and andone oneGrade Grade4.4. Monitor Monitorpatients patientsfor forchanges changesininrenal renalfunction. function. Administer Administer corticosteroids corticosteroidsfor forGrade Grade2 2ororgreater greater nephritis. nephritis. Withhold Withhold KEYTRUDA KEYTRUDAfor forGrade Grade2;2;permanently permanentlydiscontinue discontinueKEYTRUDA KEYTRUDAfor for Grade Grade3 3oror4 4nephritis. nephritis. • Hyperthyroidism • Hyperthyroidismoccurred occurredinin5 5(1.2%) (1.2%)ofof411 411patients, patients,including including Grade Grade2 2oror3 3cases casesinin2 2(0.5%) (0.5%)and and1 1(0.2%) (0.2%)patients, patients,respectively, respectively, receiving receivingKEYTRUDA. KEYTRUDA.Hypothyroidism Hypothyroidismoccurred occurredinin34 34(8.3%) (8.3%)ofof411 411 patients, patients,including includinga aGrade Grade3 3case caseinin11(0.2%) (0.2%)patient, patient,receiving receiving KEY TRUDA. KEY TRUDA.Thyroid Thyroiddisorders disorderscan canoccur occuratatany anytime timeduring during treatment. treatment.Monitor Monitorpatients patientsfor forchanges changesininthyroid thyroidfunction function(at (atthe the start startofoftreatment, treatment,periodically periodicallyduring duringtreatment, treatment,and andas asindicated indicated based basedononclinical clinicalevaluation) evaluation)and andfor forclinical clinicalsigns signsand andsymptoms symptomsofof thyroid thyroiddisorders. disorders.Administer Administercorticosteroids corticosteroidsfor forGrade Grade33ororgreater greater hyperthyroidism. hyperthyroidism.Withhold WithholdKEYTRUDA KEYTRUDAfor forGrade Grade3;3;permanently permanently discontinue TRUDA for discontinueKEY KEYTRUDA forGrade Grade4 4hyperthyroidism. hyperthyroidism.Isolated Isolated hypothyroidism hypothyroidismmay maybebemanaged managed with with replacement replacement therapy therapy without withouttreatment treatmentinterruption interruptionand andwithout withoutcorticosteroids. corticosteroids. • Other • Otherclinically clinicallyimportant importantimmune-mediated immune-mediatedadverse adverse reactions reactions can canoccur. occur.The Thefollowing followingclinically clinicallysignificant significantimmune-mediated immune-mediated adverse adversereactions reactionsoccurred occurredininless lessthan than1% 1%ofofpatients patientstreated treated with withKEYTRUDA: KEYTRUDA:exfoliative exfoliativedermatitis, dermatitis,uveitis, uveitis,arthritis, arthritis,myositis, myositis, pancreatitis, pancreatitis,hemolytic hemolyticanemia, anemia,partial partialseizures seizuresarising arisingininaapatient patient with withinflammatory inflammatoryfoci fociininbrain brainparenchyma, parenchyma,adrenal adrenalinsufficiency, insufficiency, myasthenic myasthenicsyndrome, syndrome,optic opticneuritis, neuritis,and andrhabdomyolysis. rhabdomyolysis.

KEYTRUDA responded KEYTRUDA provided provided ongoing responses in patients who responded

86%

(n=18/21) (n=18/21)

Of responses were ongoing in patients patients who who responded responded to KEYTRUDA

••Among progression of of disease disease 2.8, 2.8, 2.9, 2.9, and and 8.2 8.2 months months Among the the 21 21 patients patients with with an an objective response, 3 (14%) had progression after after initial initial response. response. •• The durations ranging ranging from from 1.4+ 1.4+ to to 8.5+ 8.5+ months, months,which which The remaining remaining 18 18 patients patients (86%) (86%) had ongoing responses with durations included included 88 patients patients with with ongoing ongoing responses of 6 months or longer. •• One first tumor tumor assessment assessment concurrent concurrentwith withaa Oneadditional additional patient patient developed developed 2 new asymptomatic lesions at the first 75% 75% decrease decrease in in overall overall tumor tumor burden. —KEYTRUDA was durable durable for for 5+ 5+ months. months. —KEYTRUDA was was continued continued and and this reduction in tumor burden was

SELECTED SELECTED SAFETY SAFETY INFORMATION INFORMATION (CONTINUED) common adverse adverse reactions reactions (reported (reported inin at at least least ••For For suspected suspected immune-mediated immune-mediated adverse reactions, ensure • The most common patients) were were fatigue fatigue (47%), (47%), cough cough (30%), (30%), nausea nausea adequate 20% of patients) adequate evaluation evaluation to to confirm confirm etiology or exclude other pruritus (30%), (30%), rash rash (29%), (29%), decreased decreasedappetite appetite(26%), (26%), causes. (30%), pruritus causes.Based Basedon on the the severity severity of of the the adverse reaction, withhold (21%), arthralgia arthralgia (20%), (20%),and anddiarrhea diarrhea(20%). (20%). KEYTRUDA constipation (21%), KEYTRUDA and and administer administer corticosteroids. corticosteroids. Upon improvement of ofthe theadverse adversereaction reaction to to Grade Grade 11 or or less, initiate corticosteroid • It is not known known whether whether KEYTRUDA KEYTRUDA isis excreted excreted ininhuman humanmilk. milk. taper taper and and continue continue to to taper taper over over at least 1 month. Restart drugsare areexcreted excretedin inhuman humanmilk, milk,instruct instructwomen women Because many drugs KEYTRUDA KEYTRUDA ifif the the adverse adverse reaction reaction remains at Grade 1 or less. nursing during during treatment treatmentwith withKEYTRUDA. KEYTRUDA. to discontinue nursing Permanently Permanently discontinue discontinue KEYTRUDA KEYTRUDA for any severe or Grade 3 effectiveness of KEYTRUDA have notbeen been • Safety and effectiveness of KEYTRUDA have not immune-mediated immune-mediated adverse adverse reaction reaction that recurs and for any lifeestablished in pediatric pediatric patients. patients. threatening immune-mediated adverse reaction. threatening immune-mediated adverse ••Based Based on on its its mechanism mechanism of of action, action, KEYTRUDA may cause the Brief Brief Summary Summary of of the the Please see the fetal fetal harm harm when when administered administered to to aa pregnant woman. If used Information on on the the adjacent adjacent pages. pages. Prescribing Information during during pregnancy, pregnancy, or or ifif the the patient patient becomes pregnant during treatment, treatment,apprise apprise the the patient patient of of the the potential hazard to a fetus. Merck Oncology Oncology Advise Advisefemales females of of reproductive reproductive potential potential to use highly effective 2014 Merck Merck Sharp Sharp && Dohme DohmeCorp., Corp., Copyright © 2014 contraception contraception during during treatment treatment and and for 4 months after the last a subsidiary of of Merck Merck & & Co., Co., Inc. Inc. dose doseof ofKEYTRUDA. KEYTRUDA. All rights reserved. reserved. ONCO-1116177-0000 ONCO-1116177-000011/14 11/14 keytruda.com keytruda.com

Questions Questions about about access for KEYTRUDA? Call Call The The Merck Merck Access Access Program at 855-257-3932.

Scan Scan here here or visit keytruda.com keytruda.com to to learn learn more.

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use INDICATIONS AND USAGE KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis: Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to development of pneumonitis was 5 months (range 0.3 weeks–9.9 months). The median duration was 4.9 months (range 1 week–14.4 months). Five of eight patients with Grade 2 and the one patient with Grade 3 pneumonitis required initial treatment with high-dose systemic corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. The median initial dose of high-dose corticosteroid treatment was 63.4 mg/day of prednisone or equivalent with a median duration of treatment of 3 days (range 1–34) followed by a corticosteroid taper. Pneumonitis led to discontinuation of KEYTRUDA in 3 (0.7%) patients. Pneumonitis completely resolved in seven of the nine patients with Grade 2–3 pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for moderate (Grade 2) pneumonitis, and permanently discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) pneumonitis. Immune-Mediated Colitis: Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset of colitis was 6.5 months (range 2.3– 9.8). The median duration was 2.6 months (range 0.6 weeks–3.6 months). All three patients with Grade 2 or 3 colitis were treated with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) with a median initial dose of 70 mg/day of prednisone or equivalent; the median duration of initial treatment was 7 days (range 4–41), followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to colitis. All four patients with colitis experienced complete resolution of the event. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) colitis. Immune-Mediated Hepatitis: Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The time to onset was 22 days for the case of Grade 4 hepatitis which lasted 1.1 months. The patient with Grade 4 hepatitis permanently discontinued KEYTRUDA and was treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA. Immune-Mediated Hypophysitis: Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 4 case (0.2% each), in patients receiving KEYTRUDA in Trial 1. The time to onset was 1.7 months for the patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 hypophysitis. Both patients were treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) corticosteroids followed by a corticosteroid taper and remained on a physiologic replacement dose. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for moderate (Grade 2) hypophysitis, withhold or discontinue KEYTRUDA for severe (Grade 3) hypophysitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) hypophysitis. Renal Failure and Immune-Mediated Nephritis: Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. The time to onset of autoimmune nephritis was 11.6 months after the first dose of KEYTRUDA (5 months after the last dose) and lasted 3.2 months; this patient did not have a biopsy. Acute interstitial nephritis was confirmed by renal biopsy in two patients with Grades 3–4 renal failure. All three patients fully recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for moderate (Grade 2) nephritis, and permanently discontinue KEYTRUDA for severe (Grade 3), or life-threatening (Grade 4) nephritis. Immune-Mediated Hyperthyroidism and Hypothyroidism: Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset was 1.5 months (range 0.5–2.1). The median duration was 2.8 months (range 0.9 to 6.1). One of two patients with Grade 2 and the one patient with Grade 3 hyperthyroidism required initial treatment with highdose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to hyperthyroidism. All five patients with hyperthyroidism experienced complete resolution of the event. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The median time to onset of hypothyroidism was 3.5 months (range 0.7 weeks–19 months). All but two of the patients with hypothyroidism were

treated with long-term thyroid hormone replacement therapy. The other two patients only required short-term thyroid hormone replacement therapy. No patient received corticosteroids or discontinued KEYTRUDA for management of hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism, withhold KEYTRUDA for severe (Grade 3) hyperthyroidism, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Other Immune-Mediated Adverse Reactions: Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA in Trial 1: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, and adrenal insufficiency. Across clinical studies with KEYTRUDA in approximately 2000 patients, the following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients: myasthenic syndrome, optic neuritis, and rhabdomyolysis. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. Embryofetal Toxicity: Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PDL-1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment with KEYTRUDA and for 4 months after the last dose of KEYTRUDA. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail above. • Immune-mediated pneumonitis. • Immune-mediated colitis. • Immune-mediated hepatitis. • Immune-mediated hypophysitis. • Renal failure and immune-mediated nephritis. • Immune-mediated hyperthyroidism and hypothyroidism. • Immune-mediated adverse reactions. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS and PRECAUTIONS section reflect exposure to KEYTRUDA in Trial 1, an uncontrolled, open-label, multiple cohort trial in which 411 patients with unresectable or metastatic melanoma received KEYTRUDA at either 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 24.6 months) with a median of 10 doses (range 1 to 51). The study population characteristics were: median age of 61 years (range 18–94), 39% age 65 years or older, 60% male, 97% white, 73% with M1c disease, 8% with brain metastases, 35% with elevated LDH, 54% with prior exposure to ipilimumab, and 47% with two or more prior systemic therapies for advanced or metastatic disease. KEYTRUDA was discontinued for adverse reactions in 9% of the 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients in Trial 1 were renal failure, dyspnea, pneumonia, and cellulitis. Table 1 presents adverse reactions identified from analyses of the 89 patients with unresectable or metastatic melanoma who received KEYTRUDA 2 mg/kg every three weeks in one cohort of Trial 1. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This cohort of Trial 1 excluded patients with severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of pneumonitis or interstitial lung disease; or any active infection requiring therapy, including HIV or hepatitis B or C. Of the 89 patients in this cohort, the median age was 59 years (range 18–88), 33% were age 65 years or older, 53% were male, 98% were white, 44% had an elevated LDH, 84% had Stage M1c disease, 8% had brain metastases, and 70% received two or more prior therapies for advanced or metastatic disease. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 15.3 months) with a median of nine doses (range 1 to 23). Fifty-one percent of patients were exposed to KEYTRUDA for greater than 6 months and 21% for greater than 1 year. KEYTRUDA was discontinued for adverse reactions in 6% of the 89 patients. The most common adverse reactions (reported in at least 20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use (continued)

DRUG INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

THE 1 ST FDA-APPROVED ANTI–PD-1 THERAPY USE IN SPECIFIC POPULATIONS Table 1: Adverse Reactions in ≥10% of Patients with Unresectable or Metastatic Melanoma

Pregnancy: Pregnancy Category D.

Risk Summary: Based on its mechanism of action, KEYTRUDA may cause fetal harm when In appropriate patients with advanced melanoma administered to a pregnant woman. Animal models link the PD-1/PDL-1 signaling pathway KEYTRUDA 2 mg/kg every 3 weeks N=89

Adverse Reaction

KEYTRUDA: All Grades (%)

Grade 3* (%)

with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data: Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development, but an assessment of the effects General Disorders and Administration Site Conditions on reproduction was provided. A central function of the PD-1/PD-L1 pathway is to preserve Fatigue 47 7 pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 Peripheral edema 17 1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus Chills 14 0 and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA Pyrexia 11 0 during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, Gastrointestinal Disorders there were no malformations related to the blockade of PD-1 signaling in the offspring of Nausea 30 0 these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Constipation 21 0 Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab Diarrhea 20 0 has the potential to be transmitted from the mother to the developing fetus. Based on its Vomiting 16 0 mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing Abdominal pain 12 0 immune-mediated disorders or of altering the normal immune response. Respiratory, Thoracic And Mediastinal Disorders Nursing Mothers: It is not known whether KEYTRUDA is excreted in human milk. No studies Cough 30 1 have been conducted to assess the impact of KEYTRUDA on milk production or its presence in Dyspnea 18 2 breast milk. Because many drugs are excreted in human milk, instruct women to discontinue Skin And Subcutaneous Tissue Disorders nursing during treatment with KEYTRUDA. Pruritus 30 0 Pediatric Use: Safety and effectiveness of KEYTRUDA have not been established in Rash 29 0 pediatric patients. Vitiligo 11 0 Geriatric Use: Of the 411 patients treated with KEYTRUDA, 39% were 65 years and over. Metabolism and Nutrition Disorders No overall differences in safety or efficacy were reported between elderly patients and Decreased appetite 26 0 younger patients. Musculoskeletal and Connective Tissue Disorders Renal Impairment: Based on a population pharmacokinetic analysis, no dose adjustment is Arthralgia 20 0 needed for patients with renal impairment. Pain in extremity 18 1 KEYTRUDA is indicated of patients with pharmacokinetic unresectable Hepatic Impairment: Based on a population analysis, noor dosemetastatic adjustment is Myalgia 14 for the 1 treatment needed for patients with mild hepatic impairment [total bilirubin (TB) less than or equal to ULN Back pain 12 1 melanoma and disease progression following ipilimumab and, if BRAF V600 mutation and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST]. KEYTRUDA has Nervous System Disorders not been studied in patients withunder moderate (TB greater than 1.5 to 3 times ULN and anybased AST) positive, a BRAF inhibitor. This indication is approved accelerated approval Headache 16 0 or severe (TB greater than 3 times ULN and any AST) hepatic impairment. on tumor response rate11and durability of response. An improvement in survival or diseaseDizziness 0 Females and Males of Reproductive Potential: Based on its mechanism of action, KEYTRUDA Blood and Lymphatic System Disorders related symptoms has not yet been established. Continued approval this may may cause fetal harm when administered to a pregnant for woman. Adviseindication females of Anemia 14 5 reproductive potential to use highly effective contraception during treatment with KEYTRUDA of clinical benefit in the confirmatory trials. Psychiatric Disordersbe contingent upon verification and description and for at least 4 months following the last dose of pembrolizumab. Insomnia 14 0 OVERDOSAGE Infections and Infestations There is no information on overdosage with KEYTRUDA. Upper respiratory tract infection 11 1 *There were no Grade 5 adverse reactions reported. Of the ≥10% adverse reactions, none was reported as Grade 4. PATIENT COUNSELING INFORMATION

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

Other clinically important adverse reactions observed in up to 10% of patients treated with KEYTRUDA were: Infections and infestations: sepsis Table 2: Laboratory Abnormalities Increased from Baseline in ≥20% of Patients with Unresectable or Metastatic Melanoma KEYTRUDA 2 mg/kg every 3 weeks N=89 Laboratory Test

All Grades (%)

Grades 3–4 (%)

Chemistry Hyperglycemia 40 2* Hyponatremia 35 9 Hypoalbuminemia 34 0 Hypertriglyceridemia 25 0 Increased Aspartate Aminotransferase 24 2* • Immune-mediated adverse24reactions Hypocalcemia 1 Hematology occurred with KEYTRUDA, including Anemia 55 8*

SELECTED SAFETY INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). • Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA, including: — Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath. —Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain. —Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding. —Hypophysitis: Advise patients to contact their healthcare provider immediately for persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes. —Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis. —Hyperthyroidism and Hypothyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperthyroidism and hypothyroidism. • Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests. • Advise women that KEYTRUDA may cause fetal harm. Instruct women of reproductive potential to use highly effective contraception during and for 4 months after the last dose of KEYTRUDA.

pneumonitis, colitis, hepatitis, hypophysitis, • Advise nursing mothers not to breastfeed while taking KEYTRUDA. For more detailed information, please read the Prescribing Information. nephritis, hyperthyroidism, and hypothyroidism. uspi-mk3475-iv-1409r000 Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity. Based on the severity of the adverse reaction, Because trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) Revised: 09/2014 assay results, a subset analysis was performed in the patients with a concentration KEYTRUDA should be withheld or ofdiscontinued pembrolizumab below the drug tolerance level of the anti-product antibody assay. In this © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. corticosteroids For moreCopyright information analysis, none of and the 97 patients who were treated with administered. 2 mg/kg every 3 weeks tested All rights reserved. positive for treatment-emergent anti-pembrolizumab antibodies. regarding immune-mediated adverse reactions, please 11/14 read ONCO-1116177-0000 The detection of antibody formation is highly dependent on the sensitivity and specificity of the additional Selected Safety Information on the next page. the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) *Grade 4 abnormalities in this table limited to hyperglycemia, increased aspartate aminotransferase, and anemia (one patient each).

positivity in an assay may be influenced by several factors including assay methodology, sample handling,Please timing of sample concomitant medications, and underlying see collection, additional Selected Safety Information on the disease. For these reasons, comparison of incidence of antibodies to KEYTRUDA with the next page and the Brief Summary of Prescribing Information incidences of antibodies to other products may be misleading.

on the adjacent pages.

The Merck Access Program for KEYTRUDA for Injection Visit

merckaccessprogram-keytruda.com OR

Call

855-257-3932 • Speak with a dedicated representative Monday to Friday between 8 AM and 8 PM ET.

• Ask to be contacted by a field reimbursement associate.

ASCOPost.com | JANUARY 25, 2015

PAGE 51

State of the Art Gastrointestinal Oncology

Colorectal Cancer 2015 A Conversation With John L. Marshall, MD By Ronald Piana

espite advances in detection and treatment, colorectal cancer remains the third deadliest cancer among men and women in the United States. To get a better understanding of the current state of this disease and what lies ahead, The ASCO Post recently spoke with colorectal cancer expert John L. Marshall, MD, Director, Ruesch Center for the Cure of GI Cancers, Washington, DC.

Major Advance What has been the most important advance in colorectal cancer during your career in the field? I believe the biggest advance is the recognition that colon cancer is more than one disease, which was not yet understood when I began my career. Back then we treated every colon cancer in the same way; we bunched young people and old people and right side and left side into colon cancer buckets of the same disease. We now know it is not one disease, and our approach to treatment and research has changed accordingly. Certainly, factors such as discovering the role of RAS mutations and detecting microsatellite instability in colon tumors have helped us recognize the diverse nature of colorectal cancer. And this knowledge is going to transform colorectal cancer care and expedite the discovery of promising new agents that will revolutionize the way we treat our patients.

Screening Issues Screening methods in various cancers such as breast and prostate have come under scrutiny for their effectiveness in mortality reduction. Where are we with colorectal screening with regard to compliance and reduction in mortality? We are clearly seeing—at least in the United States—a drop in the incidence and mortality in colon cancer, and we attribute this, in large part, to screening with colonoscopy. That said,

we have fallen far short of doing a good job in screening our populations for colon cancer. There are several reasons for this failure to achieve comprehensive screening, but much of the blame falls on the cancer community, because we haven’t taken the time to properly study how to deliver the most cost-effective population-based colon cancer screening. It’s quite simple. Colonoscopy is a prevention tool, and if we increase screening compliance, we will see the incidence and mortality of colon cancer decrease markedly. However, the other piece to this story is that we are failing to incorporate the shifting demographics in our screening populations. For example, it is recommended that African Americans begin screening at the age of 45, but that recommendation is not widely recognized or conformed to at the primary care level. Interestingly, we’ve seen a decrease in the incidence of colon cancer, but we’re also seeing the incidence shifting

have had your mammogram. But everyone seems to put off having a regular colonoscopy. This is an issue that needs to be addressed by all the stakeholders. We simply have to do a better job of getting the message out there that a timely colonoscopy could save your life. That said, even if we had perfect screening and compliance, there would still be a large number of people who are going to develop colon cancer and die of it. So while it is imperative to continue to screen and decrease incidence, we need to aggressively pursue the development of new treatments for this disease.

Biologic Agents What are some of the unanswered questions about the use of biologic agents in earlier-stage disease? When we talk about biologics in colon cancer, there are really only two: vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors. We have

We simply have to do a better job of getting the message out there that a timely colonoscopy could save your life. —John L. Marshall, MD

toward younger people. To that end, we’re not seeing any studies or research looking at this trend and perhaps adjusting age-specific screening guidelines accordingly. Even though it is widely publicized that we’re overscreening in breast cancer, mammography compliance among women is solid across the board, whereas in colonoscopy, which is proven as the gold standard for prevention, we only see a meager 30% to 40% rate of compliance in the target populations. This is a huge disconnect between the medical community and its patients. Part of the problem lies in advocacy and messaging. It’s uncool not to

miles to go in this area of therapeutics. In earlier-stage disease, I think we’ve been asking the wrong questions. We’ve been aiming our therapeutic approach at traditional metastatic adenocarcinoma under the mindset that if the drugs work in that setting, they’ll work in every disease stage. And that has not held true in colon cancer, probably because the target cell in the adjuvant setting may be a different cell that doesn’t respond the same way. While fluorouracil (5FU) cures some of these cancers and oxaliplatin cures others, traditional use of systemic therapy has not proven effective in dealing with that adjuvant cell.

That’s why advancing the science in biologics in this setting is vital. I also feel that immunotherapies will have an important role in early-stage disease. As yet, we haven’t seen the results with immunotherapy in colon cancer that have been seen in kidney cancer and melanoma, but we’ll keep working hard in this promising area. To pull all these new therapeutic directions together, we need better molecular profiling and specific RAS testing. As we get more specific around EGFR targeting and understand which pathways and mutations really matter, we are getting better response rates and longer survival times for our patients. We’re also learning which patients need treatment and which patients do not.

Promising Strategies Is there any current trial or study looking at a therapeutic avenue that could change the standard-of-care in colorectal cancer? Well, we have TAS-102, which in a sense is a new 5-FU (in that it has a similar mechanism of action), a novel antimetabolite after all these years. I think the biggest impact in how we treat our patients will be seen by using different treatments for different molecular subgroups, which is how we’ll shift our standard or care. In short, it will move us away from the one-size-fits-all strategy with our drugs.

Cost and Value In today’s new world of cost-effectiveness and value, are we delivering cost-effective care in colorectal cancer? Cost-effectiveness is a relative term. If you ask people in the United States, they would probably answer yes to that question, because patients who were once living for a year with colorectal cancer are now living close to 3 years. To most Americans, spending $25,000 a month for that added survival is costcontinued on page 52

The ASCO Post | JANUARY 25, 2015

PAGE 52

State of the Art John L. Marshall, MD continued from page 51

effective use of our resources. In most other countries around the world, our colorectal cancer care would not be deemed cost-effective because the gains would not outweigh the costs. So I think the important tensions between cost and value are now hitting our shores, as we begin to wrestle with

health-care cost issues. Moving forward, our health-care delivery will be judged not by our rate of consumption, but by the outcomes of our care delivery. As international markets begin to grow and compete with each other, we will see a leveling off of the prices of these very expensive compounds. Just as cost-effectiveness is a relative term, so is value.

Closing Thoughts Any last words on a disease that you’ve devoted much of your career to? If we look at colorectal cancer, and more broadly, gastrointestinal cancers, they are the most common and most fatal cancers on the planet. Furthermore, we haven’t yet seen the huge wave of increased incidence due to people living longer and more people

around the world being diagnosed. We have a huge challenge ahead in colorectal cancer. But given the rapid advances we’re seeing, especially in molecular profiling and promising new areas of research, such as immunotherapy, we will be able to make significant strides in reducing mortality and increasing survival. n Disclosure: Dr. Marshall reported no potential conflicts of interest.

Announcements

ASCO and AACR Call for Regulation of E-Cigarettes and Other Electronic Nicotine Delivery Systems

he American Association for Cancer Research (AACR) and ASCO have outlined steps in a joint statement to guide policymakers as they work to minimize the potential negative consequences of electronic cigarettes (ecigarettes) and other electronic nicotine delivery systems without undermining their potential to reduce harm as a smoking cessation tool. The two organizations’ recommendations were published in ASCO’s Journal of Clinical Oncology1 and the AACR’s Clinical Cancer Research.2

Prudent Steps Needed “We are concerned that e-cigarettes may encourage nonsmokers, particularly children, to start smoking and develop nicotine addiction. While ecigarettes may reduce smoking rates and attendant adverse health risks, we will not know for sure until these products are researched and regulated,” said ASCO President Peter Paul Yu, MD, FACP, FASCO. “The FDA has signaled its willingness to regulate e-cigarettes and other electronic nicotine delivery systems, and we urge the agency to follow through on this intention.” “As a physician scientist who treats patients with cancer, I am concerned about the delayed time course that’s needed to assess the adverse impacts of [electronic nicotine delivery systems] use,” said C arlos L. Arteaga, MD, AACR President, and Professor of Medicine and Cancer Biology and Director of the Center for Cancer Targeted Therapies and the Breast Cancer Program at the VanderbiltIngram Cancer Center of Vanderbilt University in Nashville. “Therefore, although we call for additional research to determine with certainty the potential negative public health consequences of these products, particularly in youth, we cannot afford to wait to take prudent steps

to stop those under 18 from using e-cigarettes. This is especially important since e-cigarette use is growing fast among this age group, as reported in the most recent National Youth Tobacco Survey.” Unlike combustible cigarettes and many other tobacco products, e-cigarettes and other electronic nicotine delivery systems are not currently regulated by the U.S. Food and Drug Administration (FDA). Some state and local governments have enacted e-cigarette regulations, including imposing restrictions on the sale of ecigarettes to minors and prohibiting use of e-cigarettes in public places. Federal regulations have yet to be adopted, and manufacturing standards and quality controls on e-cigarettes are also absent.

•

• •

including nicotine concentration. Packaging and advertising for these products should be required to carry safety labels that include a warning regarding nicotine addiction. All youth-oriented electronic nicotine delivery systems advertising and marketing should be prohibited. Internet and mail-order sellers of these products should be required to check the age and identification of customers at the point of purchase and delivery. Childproof caps should be required for all e-liquid containers. Electronic nicotine delivery systems and liquid-containing candy and other youth-friendly flavors should be banned unless there is evidence

While e-cigarettes may reduce smoking rates and attendant adverse health rates, we will not know for sure until these products are researched and regulated. —Peter Paul Yu, MD, FACP, FASCO

Policy Recommendations Noting that additional research is needed to inform the regulation of ecigarettes and other electronic nicotine delivery systems, the AACR and ASCO statement outlines steps that can be taken now in the interest of public health. Specifically, the policy recommendations include the following: • The FDA Center for Tobacco Products should regulate all electronic nicotine delivery systems that meet the statutory definition of tobacco products. Those that do not meet the statutory definition of tobacco products should be regulated by the FDA through other appropriate authorities. • Manufacturers of these products should be required to register with the FDA and report all ingredient listings,

demonstrating these products do not encourage youth uptake. • Electronic nicotine delivery systems use should be prohibited in places where combustible tobacco product use is prohibited by federal, state, or local law until the safety of secondhand aerosol exposure is established. • Funding generated through tobacco product taxes, including any potential taxes levied on electronic nicotine delivery systems, should be used to help support research on electronic nicotine delivery systems and other tobacco products, and should not preclude the allocation of federal funding for this research. • All data related to electronic nicotine delivery system composition, use, and health effects should be disclosed for

dissemination and should inform policy decisions for product regulation. • State and local governments should implement related regulations to protect public health, including restricting the sale, distribution, marketing, and advertising of electronic nicotine delivery systems to youth. In addition, the AACR and ASCO encourage all oncologists to recommend FDA-approved cessation medications instead of e-cigarettes to individuals who are interested or trying to quit smoking combustible cigarettes.

Further Research Required “Further research and regulation are needed to determine if e-cigarettes can help people stop smoking combustible cigarettes,” said Roy S. Herbst, MD, PhD, Ensign Professor of Medicine, Professor of Pharmacology, and Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, who served as Chair of the joint AACR/ASCO committee that developed the statement. “In the meantime, oncologists should encourage patients to use FDA-approved cessation medications, refer them for smoking cessation counseling, and provide education about the potential risks and lack of known benefits of long-term e-cigarette use.” n References 1. Brandon TH, et al: Electronic nicotine delivery systems: A policy statement from the American Association for Cancer Research and the American Society of Clinical Oncology. Clin Cancer Res. January 8, 2015 (early release online). 2. Brandon TH, et al: Electronic nicotine delivery systems: A policy statement from the American Association for Cancer Research and the American Society of Clinical Oncology. J Clin Oncol. January 8, 2015 (early release online).

AV NO AI W LA BL E

NEW—A LIQUID FORMULATION—TREANDA® (bendamustine HCl) Injection Preparing for IV administration is:

Fast

Precise

Convenient

Less preparation time

No reconstitution necessary

Fewer steps prior to admixing

What else is new about TREANDA? NEW CONCENTRATION

mg/mL

NEW DOSAGE STRENGTHS

NEW NDCs

180 mg/2 mL 63459-396-02 45 mg/0.5 mL 63459-395-02 J Code 9033

It may be necessary to update your pharmacy and/or patient medication management systems. FOR MORE INFORMATION, CALL 1-800-896-5855 OR VISIT TREANDAHCP.COM

Supplied in single-use, 2-mL vials.

Indications TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Important Safety Information Contraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. The most common nonhematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities for both indications (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia. Please see accompanying brief summary of Full Prescribing Information on the following pages.

™

Brief Summary of Prescribing Information 1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established. 1.2 Non-Hodgkin Lymphoma (NHL) TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Instructions for CLL Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. 2.2 Dosing Instructions for NHL Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. 2.3 Preparation for Intravenous Administration Each vial of TREANDA Injection is intended for single use only. Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution. Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 - 0.7 mg/mL. The admixture should be a clear colorless to yellow solution. Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/ 0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. 2.4 Admixture Stability TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature 15°-30°C (59°-86°F) and room light. Administration of TREANDA must be completed within this period. 3 DOSAGE FORMS AND STRENGTHS TREANDA Injection is supplied in single-use vials containing either 45 mg/0.5 mL or 180 mg/2 mL of bendamustine HCl. 4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy.

TREANDA® (bendamustine hydrochloride) Injection

Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration (2.1) and (2.2)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection. 5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergictype reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)]. 5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. 5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. 6 ADVERSE REACTIONS The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections of the label [See Warnings and Precautions]: Myelosuppression (5.1); Infections (5.2); Anaphylaxis and Infusion Reactions (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasation injury (5.7). The data described below reflect exposure to TREANDA in 329 patients who participated in an activelycontrolled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1 Clinical Trials Experience in CLL The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. Nonhematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis.

Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients

System organ class Preferred term Total number of patients with at least 1 adverse reaction Gastrointestinal disorders Nausea Vomiting Diarrhea General disorders and administration site conditions Pyrexia Fatigue Asthenia Chills Immune system disorders Hypersensitivity Infections and infestations Nasopharyngitis Infection Herpes simplex Investigations Weight decreased Metabolism and nutrition disorders Hyperuricemia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash Pruritus

TREANDA (N=153) All Grade Grades 3/4

Chlorambucil (N=143) All Grade Grades 3/4

121 (79) 52 (34)

96 (67)

25 (17)

31 (20) 24 (16) 14 (9)

1 (<1) 1 (<1) 2 (1)

21 (15) 9 (6) 5 (3)

1 (<1) 0 0

36 (24) 14 (9) 13 (8) 9 (6)

6 (4) 2 (1) 0 0

8 (6) 8 (6) 6 (4) 1 (<1)

2 (1) 0 0 0

7 (5)

2 (1)

3 (2)

10 (7) 9 (6) 5 (3)

0 3 (2) 0

12 (8) 1 (<1) 7 (5)

0 1 (<1) 0

11 (7)

5 (3)

11 (7)

3 (2)

2 (1)

6 (4)

1 (<1)

7 (5)

1 (<1)

12 (8) 8 (5)

4 (3) 0

7 (5) 2 (1)

3 (2) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA N=150 Laboratory Abnormality

Chlorambucil N=141

All Grades Grade 3/4 All Grades Grade 3/4 n (%) n (%) n (%) n (%)

Hemoglobin Decreased

134 (89)

20 (13)

115 (82)

12 (9)

Platelets Decreased

116 (77)

16 (11)

110 (78)

14 (10)

Leukocytes Decreased

92 (61)

42 (28)

26 (18)

4 (3)

Lymphocytes Decreased

102 (68)

70 (47)

27 (19)

6 (4)

Neutrophils Decreased

113 (75)

65 (43)

86 (61)

30 (21)

In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur. 6.2 Clinical Trials Experience in NHL The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥ 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥ 5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

TREANDA® (bendamustine hydrochloride) Injection

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176)

Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies

Number (%) of patients* System organ class Preferred term All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 176 (100) 94 (53) Cardiac disorders 0 Tachycardia 13 (7) Gastrointestinal disorders 7 (4) Nausea 132 (75) 5 (3) Vomiting 71 (40) 6 (3) Diarrhea 65 (37) 1 (<1) Constipation 51 (29) 1 (<1) Stomatitis 27 (15) 2 (1) Abdominal pain 22 (13) 0 Dyspepsia 20 (11) 0 Gastroesophageal reflux disease 18 (10) 1 (<1) Dry mouth 15 (9) 0 Abdominal pain upper 8 (5) 0 Abdominal distension 8 (5) General disorders and administration site conditions 19 (11) Fatigue 101 (57) 3 (2) Pyrexia 59 (34) 0 Chills 24 (14) 1 (<1) Edema peripheral 23 (13) 4 (2) Asthenia 19 (11) 1 (<1) Chest pain 11 (6) 0 Infusion site pain 11 (6) 0 Pain 10 (6) 0 Catheter site pain 8 (5) Infections and infestations 5 (3) Herpes zoster 18 (10) 0 Upper respiratory tract infection 18 (10) 4 (2) Urinary tract infection 17 (10) 0 Sinusitis 15 (9) 9 (5) Pneumonia 14 (8) 11 (6) Febrile neutropenia 11 (6) 2 (1) Oral candidiasis 11 (6) 0 Nasopharyngitis 11 (6) Investigations 3 (2) Weight decreased 31 (18) Metabolism and nutrition disorders 3 (2) Anorexia 40 (23) 8 (5) Dehydration 24 (14) 1 (<1) Decreased appetite 22 (13) 9 (5) Hypokalemia 15 (9) Musculoskeletal and connective tissue disorders 5 (3) Back pain 25 (14) 0 Arthralgia 11 (6) 2 (1) Pain in extremity 8 (5) 0 Bone pain 8 (5) Nervous system disorders 0 Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) Psychiatric disorders 0 Insomnia 23 (13) 1 (<1) Anxiety 14 (8) 0 Depression 10 (6) Respiratory, thoracic and mediastinal disorders Cough 1 (<1) 38 (22) Dyspnea 3 (2) 28 (16) Pharyngolaryngeal pain 1 (<1) 14 (8) Wheezing 0 8 (5) Nasal congestion 0 8 (5) Skin and subcutaneous tissue disorders Rash 1 (<1) 28 (16) Pruritus 0 11 (6) Dry skin 0 9 (5) Night sweats 0 9 (5) Hyperhidrosis 0 8 (5) Vascular disorders Hypotension 2 (1) 10 (6) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category. Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

Percent of patients Hematology variable

All Grades

Grades 3/4

Lymphocytes Decreased

Leukocytes Decreased

Hemoglobin Decreased

Neutrophils Decreased

Platelets Decreased

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)] 10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. TREANDA is a cytotoxic drug. Follow special handling and disposal procedures1. 16.2 How Supplied TREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution as follows: NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-use vial NDC 63459-396-02: 180 mg/2 mL of solution in an amber single-use vial Vials are supplied in individual cartons. 16.3 Storage TREANDA Injection must be stored refrigerated between 2°-8°C (36°46°F). Retain in original package until time of use to protect from light.

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2014 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates. All rights reserved. Iss. 09/2013 (Label Code: 00016287.06) TRE-40206 This brief summary is based on TRE-009 TREANDA full Prescribing Information.

The ASCO Post | JANUARY 25, 2015

PAGE 56

Third Annual World Cutaneous Malignancies Congress Treatment Paradigm in Advanced Melanoma Poised for Change … Again By Caroline Helwick

PharmaGraphics

Disk

The most potent biomarker we S&H found was the presence of T cells in and just outside the tumor. But at this point, I am not going to stop treatment if I don’t see T cells, and I won’t stop if PD-L1 is not expressed. SIGNOFF

DATE

—Caroline Robert, MD, PhD

TC AD CD CW AE/AS

Axel Hauschild, MD, PhD ED

In contrast to ipilimumab, she said, “The drugs also have a very good risk/ benefit ratio,” with most toxicity limited to immune-related side effects. She agreed that the combination of the two immunotherapy classes is exciting and logical. The rationale for the combination is that CTLA-4 and PD-1 Communications 1 Q1 Q2 areCosmos nonredundant immune checkpoints C M Y K ej in T-cell differentiation and 1function, 29452a 11.25.14 133 and antitumor synergy has been demonstrated in animal models, she explained. The phase I CA209-004 study evaluated several different dosing combinaPROD

Galley: 1

Axel Hauschild, MD, PhD, Head of the Skin Cancer Working Group at the University Hospital Schleswig-Holstein in Germany and Co-Chair of the Global Melanoma Task Force, agreed that the availability of anti–PD-1/PD-L1 antibodies will turn the current treatment algorithm on its head but maintains that symptomatic load will still be relevant. He predicted that all symptomatic patients, regardless of BRAF status, will receive immunotherapy first—ipilimumab, alone or in combination with an anti–PD-1/PD-L1 antibody. BRAF status will become important when the disease progresses. Retreatment with combined immunotherapy or with BRAF inhibitors will also be part of the future algorithm, according to Dr. Hauschild. This strategy

phase III CA209-037 trial, response rates were 32% to nivolumab and 11% to dacarbazine, and overall survival, which she and her colleagues recently reported in The New England Journal of Medicine,2 was 72.9% at 1 year, vs 42.1%, representing a 58% reduction in mortality risk (P < .0001). QC

Symptom Load May Still Matter

presence of CD8, PD-1/PD-L1—will receive an anti–PD-1 or PD-L1 antibody up front. Other patients will most likely be treated with combinations or novel approaches, especially strategies that “can bring T cells into the tumor,” he said. Dr. Robert agreed. “In an ideal world, we would biopsy the tumor, look for the biomarker, and be able to tell whether the levels are higher enough for a PD-1 blocker or whether the patient should get anti–CTLA-4 up front.”

PRINT SCALE: 82.94%

tumor at baseline trigger the expression of PD-1 and PD-L1, and their interaction limits the response of the immune system and can be unblocked by anti– PD-1/PD-L1 agents.1

Dr. Robert reviewed the encouraging findings for nivolumab that are contributing to the excitement over anti–PD-1/PD-L1 antibodies. In the

ROUND: 3 Last Saved: 11-21-2014 6:50 PM

Antoni Ribas, MD, PhD

Nivolumab Survival Data

DATE: 11-21-2014 6:50 PM CW: L Gibbons INK Spec: 4C

Today, patients are initially evaluated for BRAF status, burden of disease, and the growth kinetics of the tumor. Then they are offered BRAF/MEK inhibitors, the anti–CTLA-4 (anti-cytotoxic Tlymphocyte–associated protein 4) agent ipilimumab, or interleukin-2. “However, this is not how we are going to treat melanoma in 2 years,” Dr. Ribas predicted. “We will be evaluating the interaction between the cancer cell and the immune system, and that will tell us what to do.” The mechanism of action of the PD-1/PD-L1 blockers—which currently include nivolumab (Opdivo), pembrolizumab (Keytruda), MPDL3280A, MEDI4736, and MSB0010718C—may allow for the prediction of response. CD8-positive T cells observed in the

is not yet evidence-based and must prove its superiority to the selection of treatment by BRAF status, he added. The future approach will be greatly informed by results of trials comparing BRAF/MEK inhibition followed by anti–PD-1/PD-L1 plus ipilimumab, vs the opposite strategy, and those evaluating the combination of anti–PD-1/PDL1 plus ipilimumab.

GNH_HER_Q40680_JA_D03.indd

Management of Cancer in the Anti–PD-1/PD-L1 Era

Caroline Robert, MD, PhD, Head of the Dermatology Unit at the Institut Gustave-Roussy in Paris, France, indicated she had collaborated with Dr. Ribas on this finding and noted, “The most potent biomarker we found was the presence of T cells in and just outside the tumor. But at this point, I am not going to stop treatment if I don’t see T cells, and I won’t stop if PD-L1 is not expressed.” Dr. Ribas added, “We need to learn more about this. It sounds complicated now, but this will become a simpler thing we can all detect.” Only patients with this characteristic immune profile—demonstrating the

JOB#: 40680 CLIENT: Genentech DESC: Journal Ad 3-pg FILE NAME: GNH_HER_Q40680_JA_D03.indd PG: CordobaR/MerinoR AD: R Vetrano-Pyke x4077 PM: B Fu x4416 AE: K McGinty x3950 TRIM: 15.5” x 10.5” BLEED: 17.5” x 11.5” SAFETY: 14.75” x 9.875” PROD: M Haight x4245 FONTS: Myriad Pro (Bold, Regular, Light), Helvetica Neue LT Std (45 Light) IMAGES: 40680_JA_1_fn.tif (CMYK; 300 ppi; 100%), 40680_glow_fn.psd (CMYK; 300 ppi; 100%), Perjeta_US_MBC_NEO_4C.eps (69.5%) INKS: Cyan, Magenta, Yellow, Black DOC PATH: Macintosh HD:Users:cordobar:De...sk_prep:GNH_HER_Q40680_JA_D03.indd NOTES: None

n the treatment of advanced/metastatic melanoma, recent debate has focused on the choice of initial therapy: ipilimumab (Yervoy) or, for patients with BRAF-mutant cancer, a BRAF/ MEK inhibitor. This issue is now taking a back seat to the emerging conversation about the positioning of antibodies that target programmed cell death protein-1 (PD-1) and its ligand, PD-L1. At the 3rd Annual World Cutaneous Malignancies Congress in Los Angeles, melanoma researchers weighed in on this topic and made predictions for the future. Antoni Ribas, MD, PhD, Professor of Medicine, Surgery, and Molecular and Medical Pharmacology, and Director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, predicted that the current treatment algorithm for advanced/metastatic melanoma is poised for change.

tions and schedules for the two drugs.3 In the combined concurrent cohorts (which included maintenance nivolu mab), overall survival at 1 year was 85%, and 2-year survival was 79%. In one of these individual cohorts, 1-year survival reached 94%, Dr. Robert reported. Clinical activity was seen in patients with and without PD-L1 expression and regardless of BRAF status. In patients with residual ipilimumab in plasma, the response appeared to be enhanced, suggesting that “maybe we don’t need a lot of ipilimumab,” she added.

Toxicity May Be an Issue The combination was, however, difficult to tolerate. In the dose-finding study, 64% of patients reported grade 3/4 events with the concurrent treatment, primarily gastrointestinal (14%) and hepatic (14%). Toxicity was much less with sequential treatment. “These [side effects] occur early and are not trivial,” Dr. Robert noted. “We will need to see if the efficacy of this combination is worth the toxicity.” She suggested that the viability of this combination “will depend on the results of the studies…. Maybe we will use the combination for patients with a good performance status. If the patient can overcome the toxicity and have a good response, of course it will be worth it.” When asked what magnitude of benefit will justify the toxicity, Dr. Robert responded, “Survival of 80% without grade 5 adverse events.” Dr. Hauschild indicated the gamble may be worth it for many patients. “Why not argue that if the combination shows a strong overall survival improvement, vs the single agent, toxicity doesn’t much matter, if the patient just needs four infusions to get the job done. You could go ahead with a single agent and get a median survival time of 20 months or go with the combination and get 30 months. It’s a dramatic difference.” n

Disclosure: Dr. Robert has been a consultant for BMS, MSD, GSK, Roche, Amgen, and Novartis. Drs. Ribas and Hauschild reported no potential conflicts of interest.

References 1. Tumeh PC, et al: Nature 515:568571, 2014. 2. Robert C, et al: N Engl J Med. November 16, 2014 (early release online). 2. Kluger H, et al: 2014 ESMO Congress. Abstract 10850. Presented September 27, 2014.

ASCOPost.com | JANUARY 25, 2015

PAGE 57

Announcements

FDA’s Janet Woodcock, MD, Receives Lifetime Achievement Award From the Institute for Safe Medication Practices

anet Woodcock, MD, Director of the U.S. Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research, has been awarded the Institute for Safe Medication Practices Lifetime Achievement Award, which recognizes

care information holders • Launched the new Office of Pharmaceutical Quality and served initially as its Acting Director “Through all of these accomplish-

ments, and many others, Janet Woodcock has helped ensure that the FDA can fulfill B:8.75” its mission effectively,” stated FDA Commissioner Margaret A.T:7.75” Hamburg, MD. “She has championedS:6.875” the use of innova-

tive new tools and approaches and has forged and enriched many partnerships with industry, academia, health-care providers, patients, and colleagues in government, including across the FDA.” n

Janet Woodcock, MD

“an individual who has had a significant career history of making ongoing contributions to patient safety and has had a major impact on safe medication practices.”

A Distinguished Career During her nearly 30-year career with the FDA, she has served in several different capacities in addition to her current position, including Director of the Office of Therapeutics Research and Review in the Center for Biologics Evaluation and Research and as the FDA’s Deputy Commissioner and Chief Medical Officer. Throughout her career, Dr. Woodcock has helped the Agency elevate and transform its approach to medical product safety, personally leading the way on many key safety initiatives from their beginning to implementation. During her career, Dr. Woodcock: • Conceived and oversaw the creation of the Adverse Event Reporting System, to manage the increasing number of spontaneous reports of adverse drug reactions submitted to the FDA • Co-led the FDA Task Force on Risk Management, one of the Agency’s first efforts to delineate premarket and postmarket safety surveillance and management of medical product risks; • Chaired the Council on Pharmaceutical Quality, launched in 2007 • Led the rollout of the Safe Use Initiative, to reduce preventable harms related to drug use • Led the launch of Safety First, a program created to help ensure alignment between premarket drug safety review and postmarket surveillance • Led the creation of the Sentinel Initiative, a data-driven national system that allows active safety surveillance using electronic data from health-

STRENGTHEN HER DEFENSE

Treatment guidelines recommend PERJETA-based therapy as the preferred first-line option • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend pertuzumab (PERJETA) + trastuzumab (Herceptin) + docetaxel as a (category 1) preferred option for the first-line treatment of patients with HER2+ MBC1 • ASCO® Clinical Oncology Practice Guidelines recommend pertuzumab + trastuzumab + docetaxel as first-line therapy for advanced HER2+ breast cancer 2 NCCN®=National Comprehensive Cancer Network®; HER2=human epidermal growth factor receptor 2 ; ASCO®=American Society of Clinical Oncology®.

Indication

PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity

PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for eﬀective contraception. Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages.

Oncologists, Pathologists Partner to Improve Practice and Optimize Patient Care

he American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have announced a new partnership to optimize patient care and foster excel-

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lence in the practices of pathology and oncology through interprofessional education, advocacy, quality improvement, international outreach, and development of practice guidelines.

With the complexity of cancer care, communication between pathologists S:6.875” and clinical oncologists has become critical to accurately diagnose cancer, optimize cancer treatment, and advance can-

cer research. ASCO and the CAP aim to improve the development, application, interpretation, and dissemination of pathology tests in cancer care, including tumor markers and molecular diagnostics.

PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly extend progression-free survival (PFS) in first-line HER2+ metastatic breast cancer Combining PERJETA with Herceptin + docetaxel added 6 months median PFS3

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6.1-month improvement in median PFS by independent review (primary endpoint)3 Placebo + Herceptin + docetaxel

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• At the first interim analysis, PFS events occurred in 191 (47.5%) patients treated with PERJETA + Herceptin + docetaxel and 242 (59.6%) patients treated with Herceptin + docetaxel3

Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

HR=hazard ratio; CI=confidence interval. Median PFS was reached at the first interim analysis.3 Results of the phase III, randomized, double-blind, placebo-controlled CLEOPATRA trial in patients (N=808) with HER2+ locally recurrent, unresectable, or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. Patients received PERJETA + Herceptin + docetaxel or placebo + Herceptin + docetaxel every 3 weeks until progression or unacceptable toxicity. Primary endpoint: PFS, assessed by independent review.3

Important Safety Information

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• PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception —Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant —If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Additional Important Safety Information

PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Left Ventricular Dysfunction (LVD)

• In Study 1, for patients with MBC, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel • Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and in 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions

• PERJETA has been associated with infusion reactions • In Study 1, for patients with MBC, on the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

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Announcements

“Oncology and pathology professionASCO and the CAP plan to collab- sharing the skills and strengths of both als and their patients will benefit from orate on a range of projects aimed at organizations, and their respective closer collaboration and mutual understanding between these two specialties,” A healthy flow of information between oncologists and said ASCO President Peter Paul Yu, MD, pathologists is critical to meeting each patient’s unique FACP, FASCO. “ASCO’s partnership S:6.875” with the CAP has the potential to greatly goals and needs during cancer treatment. facilitate advances in cancer research that —Gene N. Herbek, MD, FCAP could improve the quality of patient care.”

members, to improve the integration of clinical oncology and pathology and to optimize the use of pathology services and tests in the care of cancer patients. “More accurate diagnoses and precise treatments through molecular diagnostics offer new hope for the milcontinued on page 60

Overall survival (OS) data PERJETA demonstrated an OS improvement when combined with Herceptin + docetaxel at the final analysis4 • In the second interim analysis, there was a statistically significant improvement in OS (secondary endpoint)3 — Median not yet reached in the PERJETA-containing arm vs 37.6 months with Herceptin + docetaxel (HR=0.66; 95% CI: 0.52-0.84; P=0.0008)

15.7-month improvement in median OS in the final analysis (secondary endpoint)4 Placebo + Herceptin + docetaxel

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• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy 3

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• At the final analysis, the OS benefit was maintained (HR=0.68, 95% CI: 0.56-0.84; P=0.0002) and the median was reached in the PERJETA + Herceptin + docetaxel arm (56.5 months vs 40.8 months in the Herceptin + docetaxel arm)4

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At the second interim analysis (30 months median follow-up, 1 year after the first interim analysis), the HR and P value for OS crossed the predefined efficacy stopping boundary (HR ≤0.739, P≤0.0138). OS improvement with PERJETA + trastuzumab + docetaxel was statistically significant at the second interim analysis (HR=0.66, P=0.0008).3 The final analysis was performed when 221 patient deaths occurred in the placebo-treated group and 168 in the PERJETA-treated group. The statistically significant OS benefit in favor of the PERJETA-treated group was maintained (HR=0.68, P=0.0002).4

• In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCICTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

HER2 Testing

• Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

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Most Common Adverse Reactions

• In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555. For more information about PERJETA, contact your local representative or visit www.PERJETA.com/hcp. Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages. References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.3.2014. © National Comprehensive Cancer Network, Inc. 2014. All rights reserved. Accessed May 12, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32(19):2078-2099. 3. PERJETA Prescribing Information. Genentech, Inc. September 2013. 4. Data on file. Genentech, Inc. 5. Swain SM, Kim S-B, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471. 6. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

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Hypersensitivity Reactions/Anaphylaxis

• Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

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• Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

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• In the second interim analysis, PERJETA improved both PFS and OS when combined with Herceptin + docetaxel in patients, including the visceral metastasis subgroup5,6 —There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.42 [95% CI: 0.71-2.84])3

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Announcements ASCO-CAP Partnership

Joint Initiatives

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Initiatives on which ASCO and the CAP will likely collaborate include: • Continuing medical education on the use, interpretation, and application of molecular diagnostic tests; Joint evidence-based practice guidelines for oncologists and pathologists; • International workshops in which

lions of patients battling cancer each year,” said CAP President Gene N. Herbek, MD, FCAP. “A healthy flow of information between oncologists and pathologists is critical to meeting each patient’s unique goals and needs during cancer treatment.”

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: CARDIOMYOPATHY and EMBRYO-FETAL TOXICITY Cardiomyopathy PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.2, 6.1) Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)]. Limitations of Use: • The safety of PERJETA as part of a doxorubicin-containing regimen has not been established. • The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established. 4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF.

oncologists and pathologists from low- and middle- income countries can learn and share what is needed to advance cancer diagnosis and characterization across practice settings; • Advocacy and patient information about cancer diagnostics and other issues affecting the optimal use of In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxeltreated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients. In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) Grade 1 – 2. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebotreated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.

pathology services in oncology practice. • Launched through a jointly signed Memorandum of Understanding, ASCO and the CAP will continue to update members and other stakeholders as the details of this first-ever formal collaboration between the two medical specialty societies unfold. n In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCICTCAE (version 3) Grade 3 – 4. Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)]. 5.5 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

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FDA Update

FDA Drug Approvals 2014 • Nivolumab (Opdivo), a monoclonal antibody, was approved for treatment of metastatic melanoma. Approved December 22, 2014. • Olaparib (Lynparza), a poly (ADP-ribose) polymerase (PARP) inhibitor, was approved for treatTable 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1 PERJETA Placebo + trastuzumab + trastuzumab + docetaxel + docetaxel n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % All Grades All Grades Grades, % 3–4, % Grades, % 3–4, %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3 Asthenia 26.0 2.5 30.2 1.5 Edema peripheral 23.1 0.5 30.0 0.8 Mucosal inflammation 27.8 1.5 19.9 1.0 Pyrexia 18.7 1.2 17.9 0.5 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3 Rash 33.7 0.7 24.2 0.8 Nail disorder 22.9 1.2 22.9 0.3 Pruritus 14.0 0.0 10.1 0.0 Dry skin 10.6 0.0 4.3 0.0 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0 Nausea 42.3 1.2 41.6 0.5 Vomiting 24.1 1.5 23.9 1.5 Constipation 15.0 0.0 24.9 1.0 Stomatitis 18.9 0.5 15.4 0.3 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8 Anemia 23.1 2.5 18.9 3.5 Leukopenia 18.2 12.3 20.4 14.6 Febrile neutropenia* 13.8 13.0 7.6 7.3 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0 Headache 20.9 1.2 16.9 0.5 Dysgeusia 18.4 0.0 15.6 0.0 Dizziness 12.5 0.5 12.1 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8 Arthralgia 15.5 0.2 16.1 0.8 Infections and infestations Upper respiratory tract 16.7 0.7 13.4 0.0 infection Nasopharyngitis 11.8 0.0 12.8 0.3 Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 2.0 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 1.5 Eye disorders Lacrimation increased 14.0 0.0 13.9 0.0 Psychiatric disorders Insomnia 13.3 0.0 13.4 0.0 *In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in Study 1: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebotreated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo-treated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). Neoadjuvant Treatment of Breast Cancer (Study 2) In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2.

ment of BRCA-mutated advanced ovarian cancer. Approved December 19, 2014. • Lanreotide (Somatuline) depot injection, a somatostatin analog, was approved for treatment of gastroenteropancreatic neuroendocrine tuTable 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

Body System/ Adverse Reactions

PERJETA PERJETA PERJETA Trastuzumab + trastuzumab + docetaxel + trastuzumab + docetaxel + docetaxel n=108 n=108 n=107 n=107 Frequency rate Frequency rate Frequency rate Frequency rate % % % % All Grades All Grades All Grades All Grades Grades 3–4 Grades 3–4 Grades 3–4 Grades 3–4 % % % % % % % %

General disorders and administration site conditions Fatigue 27.1 0.0 26.2 0.9 12.0 0.0 25.5 1.1 Asthenia 17.8 0.0 20.6 1.9 2.8 0.0 16.0 2.1 Edema 10.3 0.0 2.8 0.0 0.9 0.0 5.3 0.0 peripheral Mucosal 21.5 0.0 26.2 1.9 2.8 0.0 25.5 0.0 inflammation Pyrexia 10.3 0.0 16.8 0.0 8.3 0.0 8.5 0.0 Skin and subcutaneous tissue disorders Alopecia 66.4 0.0 65.4 0.0 2.8 0.0 67.0 0.0 Rash 21.5 1.9 26.2 0.9 11.1 0.0 28.7 1.1 Gastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 54.3 4.3 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 36.2 1.1 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 16.0 2.1 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 9.6 0.0 Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 64.9 57.4 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 13.8 8.5 Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 12.8 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 7.4 0.0 Peripheral 12.1 0.9 8.4 0.9 1.9 0.0 10.6 0.0 Sensory Neuropathy Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 21.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 9.6 0.0 Metabolism and nutrition disorders Decreased 6.5 0.0 14.0 0.0 1.9 0.0 14.9 0.0 appetite Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0 8.5 0.0 The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel) Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm) Immune system disorders: Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm) Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm) Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm) Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm) Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm) Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm) Neoadjuvant Treatment of Breast Cancer (Study 3) In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCICTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for

mors. Approved December 16, 2014. • Ramucirumab (Cyramza) injection, a recombinant monoclonal antibody, was approved for treatment (in combination with docetaxel) of metastatic non–small cell lung cancer. Approved December 12, 2014. patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3. Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

Body System/ Adverse Reactions

PERJETA + trastuzumab PERJETA + FEC followed + trastuzumab by PERJETA + docetaxel + trastuzumab following FEC PERJETA + TCH + docetaxel n=75 n=76 n=72 Frequency rate, % Frequency rate, % Frequency rate, % All Grades Grades 3 – 4 % %

All Grades All Grades Grades 3 – 4 Grades 3 – 4 % % % %

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 3.9 Asthenia 9.7 0.0 14.7 1.3 13.2 1.3 Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0 Mucosal 23.6 0.0 20.0 0.0 17.1 1.3 inflammation Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0 Skin and subcutaneous tissue disorders Alopecia 48.6 0.0 52.0 0.0 55.3 0.0 Rash 19.4 0.0 10.7 0.0 21.1 1.3 Dry skin 5.6 0.0 9.3 0.0 10.5 0.0 Palmar-Plantar Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 0.0 Syndrome Gastrointestinal disorders Diarrhea 61.1 4.2 61.3 5.3 72.4 11.8 Dyspepsia 25.0 1.4 8 0.0 22.4 0.0 Nausea 52.8 0.0 53.3 2.7 44.7 0.0 Vomiting 40.3 0.0 36.0 2.7 39.5 5.3 Constipation 18.1 0.0 22.7 0.0 15.8 0.0 Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0 Blood and lymphatic system disorders Neutropenia 51.4 47.2 46.7 42.7 48.7 46.1 Anemia 19.4 1.4 9.3 4.0 38.2 17.1 Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8 Febrile 18.1 18.1 9.3 9.3 17.1 17.1 neutropenia Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8 Immune system disorders Hypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6 Nervous system disorders Neuropathy 5.6 0.0 1.3 0.0 10.5 0.0 peripheral Headache 22.2 0.0 14.7 0.0 17.1 0.0 Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0 Dizziness 8.3 0.0 8.0 1.3 15.8 0.0 Musculoskeletal and connective tissue disorders Myalgia 16.7 0.0 10.7 1.3 10.5 0.0 Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0 Respiratory, thoracic, and mediastinal disorders Cough 9.7 0.0 5.3 0.0 11.8 0.0 Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3 Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3 Oropharyngeal 8.3 0.0 6.7 0.0 11.8 0.0 pain Metabolism and nutrition disorders Decreased 20.8 0.0 10.7 0.0 21.1 0.0 appetite Eye disorders Lacrimation 12.5 0.0 5.3 0.0 7.9 0.0 increased Psychiatric disorders Insomnia 11.1 0.0 13.3 0.0 21.1 0.0 Investigations ALT increased 6.9 0.0 2.7 0.0 10.5 3.9 FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab) Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/ Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm) Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm)

• Ruxolitinib (Jakafi), a Janusassociated kinase ( JAK1 and JAK2) inhibitor, was approved for the treatment of polycythemia vera. Approved December 4, 2014. • Blinatumomab (Blincyto), a continued on page 62

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FDA Update Drug Approvals 2014 continued from page 61

bispecfic CD-19 directed CD3 TCell engager (BiTE®), was granted accelerated approval for the treatment of relapsed or refractory acute lymphoblastic leukemia. Accelerated approval granted December 3, 2014.

Respiratory, thoracic, and mediastinal disorders: Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm) Cardiac disorders: Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms) 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in Study 1 were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-therapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to

• Bevacizumab (Avastin), a vascular endothelial growth factor–specific angiogenesis inhibitor, was approved for treatment (in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan) of ovarian, fallopian tube, or primary peritoneal cancer. Approved November 14, 2014.

20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryofetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in Study 1, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety

• Ramucirumab (Cyramza), a recombinant monoclonal antibody, was approved for treatment (in combination with paclixatel) of advanced gastric or gastroesophageal junction adenocarcinoma. Approved November 5, 2014. • Pembrolizumab (Keytruda), a PD-1–blocking antibody, was grant-

of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab.

•

10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

• PERJETA (pertuzumab) ®

Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

•

ed accelerated approval for the treatment of unresectable or metastatic melanoma. Accelerated approval granted September 4, 2014. Bevacizumab (Avastin), a vascular endothelial growth factor– specific angiogenesis inhibitor, was approved for treatment (in combination with paclitaxel/cisplatin or paclitaxel/topotecan) of cervical cancer. A pproved August 14, 2014. Idelalisib (Zydelig) tablets, a kinase inhibitor, was approved for the treatment of relapsed chronic lymphocytic leukemia. Approved July 23, 2014. Belinostat (Beleodaq), a histone deacetylase inhibitor, was granted accelerated approval for treatment of relapse or refractory peripheral T-cell lymphoma. Accelerated approval granted July 3, 2014. Ceritinib (Zykadia), a kinase inhibitor, was granted accelerated approval for treatment of anaplastic lymphoma kinase (ALK)-positive, non–small cell lung cancer. Accelerated approval granted April 29, 2014. Mercaptopurine (Purixan) oral suspension, a nucleoside metabolic inhibitor, was approved for treatment of acute lymphoblastic leukemia (ALL). Approved April 28, 2014. Siltuximab (Sylvant) injection, an interleukin-6 (IL-6) antagonist, was approved for treatment of multicentric Castleman’s disease. Approved April 23, 2014. Ofatumumab (Arzerra) injection, a CD20-directed cytolytic monoclonal antibody, was approved for treatment of chronic lymphocytic leukemia (CLL). Approved April 17, 2014. Ibrutinib (Imbruvica), a kinase inhibitor, was granted accelerated approval for treatment of chronic lymphocytic leukemia (CLL). Accelerated approval granted February 12, 2014. Trametinib (Mekinist) and dabrafenib (Tafinlar), two kinase inhibitors, were granted accelerated approval for use in combination, for treatment of unresectable or metastatic melanoma. Accelerated approval granted January 10, 2014. n

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In the Clinic

Anti–PD-1 Antibody Nivolumab in Previously Treated Unresectable or Metastatic Melanoma By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n December 22, 2014, the anti– PD-1 (programmed cell death protein 1) monoclonal antibody nivolumab (Opdivo) was granted accelerated approval for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy) treatment and, if BRAF V600 mutation–positive, a BRAF inhibitor.1,2 As a condition of accelerated approval, Bristol-Myers Squibb is required to conduct a multicenter randomized trial establishing the superiority of nivolumab over standard therapy in this setting to verify and describe the clinical benefit of nivolumab.

Supporting Study Approval was based on objective response rate and durability of response in the first 120 patients treated with nivolumab who had at least 6 months of follow-up from an ongoing open-label trial in which 370 patients with unresectable or metastatic melanoma were randomized to receive intravenous nivolumab 3 mg/ kg every 2 weeks (n = 268) or investigator choice of chemotherapy (n = 102). Chemotherapy consisted of either dacarbazine or the combination of carboplatin/paclitaxel. Patients were treated until disease progression or unacceptable toxicity. Patients had to have disease progression after ipilimumab treatment and after BRAF inhibitor treatment if BRAF V600 mutation–positive. Patients were excluded from the study if they had an autoimmune disease, a medical condition that required corticosteroids or immunosuppression, or a history of severe ipilimumab-related adverse reactions. Among the first 120 patients, the median age was 58 years (68% younger than age 65), 65% were male, 98% were white, 58% and 42% had a baseline Eastern Cooperative Oncology Group performance status of 0 and 1, 22% had BRAF V600– mutant disease, 56% had an elevated LDH level, 76% had M1c disease, 18% had a history of brain metastases, and 68% had received at least two prior ther-

apies for advanced or metastatic disease. On blinded independent review, the objective response rate was 32% (95% confidence interval = 23%–41%), including four complete responses. At the time of reporting, 33 of the 38 responders had an ongoing response of 2.6+ to 10+ months, with 13 having a response of at least 6 months. Responses occurred in patients with and without BRAF V600–mutant disease.

How It Works Nivolumab binds the PD-1 receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2, thereby blocking the PD-1 pathway– mediated inhibition of the immune response, including the antitumor immune response. Binding of PD-L1 and

line level, and any other severe or grade 3 treatment-related adverse reaction. There are no recommended dose modifications for hypothyroidism or hyperthyroidism. Nivolumab can be resumed when adverse reactions resolve to grade 0 or 1. No dose modifications are required in patients with renal impairment or mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment. Nivolumab should be discontinued for any life-threatening or grade 4 adverse reaction, grade 3 or 4 pneumonitis, grade 4 colitis, an alanine transaminase or aspartate transaminase level more than 5 times the upper limit of normal or total bilirubin more than 3 times the upper limit of normal, serum creatinine more than 6 times the upper limit of normal, any recurring

Nivolumab for Metastatic Melanoma ■■ The anti–PD-1 (programmed cell death protein 1) monoclonal antibody nivolumab was granted accelerated approval to treat patients with unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation–positive, a BRAF inhibitor. ■■ The recommended dose of nivolumab is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. ■■ Nivolumab binds the PD-1 receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2, thereby blocking the PD-1 pathway–mediated inhibition of the immune response, including the antitumor immune response.

PD-L2 to the PD-1 receptor inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse tumor models, blocking PD-1 activity results in decreased tumor growth.

How It Is Given The recommended dose of nivolumab is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Nivolumab treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, an alanine transaminase or aspartate transaminase level more than 3 to 5 times the upper limit of normal or total bilirubin more than 1.5 to 3 times the upper limit of normal, serum creatinine more than 1.5 to 6 times the upper limit of normal or more than 1.5 times base-

severe or grade 3 treatment-related adverse reaction, inability to reduce the corticosteroid dose to ≤ 10 mg/day of prednisone or equivalent within 12 weeks, and persistent grade 2 or 3 treatment-related adverse reactions that do not recover to grade 0 or 1 within 12 weeks after the last dose.

Safety Profile Adverse event data are from 268 nivolumab and 102 chemotherapy patients in the randomized trial. Adverse events of any grade that occurred in at least 10% of the nivolumab group and at an incidence at least 5% higher vs the chemotherapy group were rash (21% vs 7%), pruritus (19% vs 4%), cough (17% vs 6%), upper respiratory tract infection (11% vs 2%), and peripheral edema (19% vs 5%). Grade 3 or 4 adverse events occurred in 42% of nivolumab patients, with the most frequent (all 2% to 5%) being abdominal pain, hyponatremia, increased aspartate transaminase level, and increased lipase level. Clinical-

OF NOTE Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, nephritis/ renal dysfunction, hypothyroidism and hyperthyroidism, as well as embryo-fetal toxicity.

ly significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, hypothyroidism, and hyperthyroidism. The most common laboratory abnormalities of any grade occurring at an incidence of more than 5% higher vs the chemotherapy group were an increased aspartate transaminase level (28% vs 12%, 2.4% vs 1.0% grade 3/4), hyponatremia (25% vs 18%, 5% vs 1.1% grade 3/4), increased alkaline phosphatase level (22% vs 13%, 2.4% vs 1.1% grade 3/4), increased alanine transaminase level (16% vs 5%, 1.6% vs 0% grade 3/4), and hyperkalemia (15% vs 6%, 2.0 vs 0% grade 3/4). Serious adverse events occurred in 41% of nivolumab patients, and adverse events led to treatment delay in 26% and treatment discontinuation in 9%. Nivolumab carries warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, hypothyroidism and hyperthyroidism, as well as embryo-fetal toxicity. Patients should receive corticosteroid treatment for immune-mediated adverse reactions based on reaction severity. Patients should be monitored for liver and kidney function. Thyroid hormone replacement should be used as needed. n For information on nivolumab in previously untreated advanced melanoma, see page 93. References 1. US FDA Press Release: Approved drugs. Nivolumab. Available at http:// www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm427807.htm. Accessed January 7, 2015. 2. Opdivo (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, December 2014. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf. Accessed January 7, 2015.

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

GRANIX is another option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

The ASCO Post | JANUARY 25, 2015

PAGE 66

Announcements

Rare-Cancer Expert Richard Carvajal, MD, Appointed Director of Experimental Therapeutics

ichard D. Carvajal, MD, has been named Director of the Experimental Therapeutics/Phase I program and melanoma service in medical oncology at New York-Presbyterian/

Columbia University Medical Center effective November 1, 2014. Dr. Carvajal, a medical oncologist, has extensive clinical expertise in melanomas and leadership experience in early-stage

clinical trials for patients with advanced cancers, as well as in the development of novel therapies for rare cancers. He joins New York-Presbyterian/Columbia from Memorial Sloan Kettering

Richard D. Carvajal, MD

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

Cancer Center, where he was Director of Developmental Therapeutics and the Elizabeth and Felix Rohatyn Chair for Junior Faculty. “Dr. Carvajal has spearheaded the development of important treatments that have transformed the lives of patients with rare cancers,” said Gary Schwartz, MD, Professor of Medicine at Columbia University Medical Center and Chief of the Division of Hematology/Oncology at New York-Presbyterian/Columbia. “We are excited to have him on board, with his experience and talent for innovation, and we look forward to his future contributions to patient-centered health care as he leads our experimental therapeutics program. He brings with him a wealth of knowledge on the development of new agents for patients with a wide range of tumor types, including rare cancers. But, more important, he brings the compassion and humanism that characterize the doctors at New York-Presbyterian/ Columbia.”

Focus on Rare, Challenging Cancers Dr. Carvajal’s work has focused on uncommon, difficult-to-treat cancers, such as melanomas arising from the eye (uveal melanomas), from the mucosal surfaces of the body (mucosal melanomas), and from the palms of the hands, soles of the feet, and surface beneath the nails (acral melanomas). His approach combines study of the underlying biology of cancer with personalized medicine, where genetic profiles of tumors are used to match individual patients with promising therapies. His research has led to the first positive clinical trials of drugs for a number of cancers. The drugs include imatinib (Gleevec), which was effective in treating patients with melanomas that have a mutation in the KIT gene, and selumetinib, which shrank tumors in half of treated patients with metastatic uveal melanoma. n

ASCOPost.com | JANUARY 25, 2015

PAGE 67

Inside the Black Box

Top 10 Myths About FDA’s Office of Hematology and Oncology Products By Gideon Blumenthal, MD, and Tatiana Prowell, MD

INSIDE THE BLACK BOX is an occasional column providing insight into the U.S. Food and Drug Administration (FDA) and its policies and procedures. In this installment, FDA oncologists Gideon Blumenthal, MD, and Tatiana Prowell, MD, discuss 10 common myths about FDA’s Office of Hematology and Oncology Products. Dr. Blumenthal is Clinical Team Leader of the Thoracic and Head and Neck Oncology Team in the Division of Oncology Products 2, and Dr. Prowell is a Medical Officer and Breast Cancer Scientific Lead in the Division of Oncology Products 1. Both divisions are in the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research.

ver the years, clinical reviewers in the FDA’s Office of Hematology and Oncology Products (OHOP) have heard many urban legends about FDA and the oncology approval process from the media, industry, and academia alike. In this article, we will attempt to dispel some of these myths with facts. Myth #1: FDA takes longer to approve oncology drugs than other countries. Fact: Although the drug approval process is not a race and different regulatory bodies must adhere to different laws, a recent study published in Health Affairs1 found that from 2003 to 2010, FDA approved 32 new anticancer drugs while the European Medicines Agency (EMA) approved 26. Of the 23 drugs approved by both agencies, the median time from marketing application subNote: In the November 15, 2014, issue of The ASCO Post, page 113, the portrait of Tatiana Prowell, MD, was incorrect. (The portrait published was Suparna Wedam, MD, a contributor to a previous “Inside the Black Box” installment.) The publisher and editorial staff apologize to Dr. Prowell and Dr. Wedam for this error, and we apologize to our readers for this inaccuracy. We have reproduced the article in its entirety here with the correct portrait. The article is also available on ASCOPost.com at http:// bit.ly/1AqOMVC.

mission to approval was 6 months for the FDA vs 11.5 months for the EMA. When an oncology drug has definitively demonstrated safety and efficacy, FDA reviewers work diligently to approve the drug as expeditiously as possible. Myth #2: FDA’s OHOP only lets you study drugs at their approved doses and schedules. Fact: This myth has two facets— doses of approved drugs in the experimental arm and in the control arm of a study. In the experimental arm, you can study a different dose and schedule of

tor with docetaxel in the second-line metastatic lung cancer setting, FDA would not object to lowering the dose of docetaxel to 60 mg/m2 from the approved dose of 75 mg/m2. With respect to the control arm, as long as the dose represents an established practice in the community, it is acceptable to use a different dose from that in the label. For example, in a randomized study in advanced breast cancer, it would be acceptable to treat control patients with 1,000 mg/m2 of capecitabine on days 1 through 14 every 21 days, a dose and schedule commonly used in clinical practice. Myth #3: FDA’s OHOP requires randomized trials with overall survival as the endpoint, requires enrollment of U.S. patients, and does not permit crossover. Fact: Actually, there are at least three myths embedded in this one statement. In oncology, as opposed to other therapeutic areas, FDA approves most drugs based on a single trial due to the challenges involved in repeating a positive trial given the high unmet medical need in oncology. Although randomized controlled trials are the gold standard design, and overall survival is considered the ultimate clinical benefit endpoint

Contrary to popular belief, FDA allows, and indeed often encourages, crossover at the time of disease progression. —Gideon Blumenthal, MD, and Tatiana Prowell, MD

an already approved drug. An example of this is sunitinib (Sutent), which was initially studied and approved in renal cell carcinoma at a dose of 50 mg daily, 4 weeks on and 2 weeks off, and was subsequently studied and approved in pancreatic neuroendocrine tumor at a dose of 37.5 mg daily continuously. In addition, if you are adding an experimental drug to an FDA-approved drug, in many settings (such as advanced incurable cancer with limited treatment options) it would be acceptable to reduce the dose of the backbone therapy. For example, if you were to combine a MEK inhibi-

because it captures critical efficacy and safety data, OHOP has repeatedly approved drugs on the basis of single-arm trials with high objective response rates and long durations of response. For randomized trials, OHOP has approved numerous drugs based on clinically meaningful improvements in progression-free survival with a favorable risk-benefit profile. For example, in the past decade, six drugs to treat renal cell carcinoma were approved based upon a progression-free survival endpoint. Drug development in this day and age is an international endeavor, and FDA accepts trial data from outside the

FDA Clinical Reviewers

Gideon Blumenthal, MD

Tatiana Prowell, MD

United States so long as the population studied reflects the U.S. population and is treated according to standard U.S. clinical practice. For example, it would not be acceptable in 2014 to study patients with metastatic breast cancer without assessing HER2 and hormone receptor status. Finally, contrary to popular belief,2 FDA allows, and indeed often encourages, crossover at the time of disease progression. The 2013 approvals of dabrafenib (Tafinlar) and trametinib (Mekinist) in metastatic melanoma, and erlotinib (Tarceva), afatinib (Gilotrif), and crizotinib (Xalkori) in non– small cell lung cancer are examples of approvals based on progression-free survival where crossover was allowed at the time of progression.3 Myth #4: FDA advisory committees, such as the Oncologic Drugs Advisory Committee (ODAC), are the final decision-makers in drug approval. Fact: Although some in the lay press interpret an ODAC vote as akin to a U.S. Supreme Court vote, ODAC’s role is not to render a decision on approval but rather to provide the FDA with scientifcontinued on page 68

The ASCO Post | JANUARY 25, 2015

PAGE 68

Inside the Black Box Top 10 OHOP Myths continued from page 67

ic advice. Typically, when we ask ODAC a question on a particularly complicated new drug application or policy issue, we are more interested in the members’ thought process and rationale for their votes than the vote tally. Myth #5: FDA staff lack scientific and clinical expertise. Fact: When a drug is submitted as a new drug application or biologics license application, the FDA review team is multidisciplinary and includes, among others, experts in chemistry and manufacturing, microbiology, pharmacology/toxicology, clinical pharmacology, biostatistics, and clinical medicine. In OHOP, all clinical reviewers are trained in hematology and/or oncology, and 20 of our clinicians are still practicing medicine. FDA reviewers also publish in high-impact journals, speak at national and international meetings, organize disease-specific workshops, write guidance and policy papers to further science and drug development, teach, and conduct independent research. Myth #6: FDA rejects most requests for expanded access to investigational drugs (aka compassionate use), and adverse events observed in an expanded access program could jeopardize approval. Fact: The first step in requesting compassionate use of an investigational drug is to have the treating physician contact the company that makes the drug. The reason for this is that FDA has no legal authority to mandate companies to provide patients investigational drugs outside of clinical trials. Since treatment with an investigational drug is only possible if the drug is available, a singlepatient investigational new drug (IND) application should only be submitted to FDA once the company has agreed to provide the drug to the patient. The goal of FDA’s review of a singlepatient IND is to make sure that no appropriate standard therapy or clinical trial has been overlooked and to ensure that adequate safety measures are being taken. Over the past 4 years, FDA has allowed more than 99% of single-patient expanded access requests to proceed, and most compassionate use requests are processed by OHOP within 1 to 2 business days. It is always challenging to determine causality of adverse events in patients with advanced cancer. This is particularly the case in the compassionate use setting, where patients generally have late-stage disease, are heavily pretreated, and there is no control group for comparison. As a result, although reporting of adverse events from single-

patient INDs is required and monitored by FDA for the safety of the patients being treated, OHOP is unaware of any drug applications for which adverse event information obtained from expanded access use of the drug has resulted in denial of approval. Myth #7: FDA determines the cost of anticancer agents. Fact: Regulatory decisions in the United States are made solely on the basis of a clinical risk-benefit determination and are cost-blind. We have no knowledge of a drug’s cost at the time of review or approval and no control over drug pricing at any point. There is growing societal attention to cost-benefit considerations in American health care, reflected in such initiatives as the American Board of Internal Medicine’s Choosing Wisely campaign and the American Society of Clinical Oncology’s Value Initiative, but decisions based on cost-benefit analyses rest with insurers, physicians, patients, and society, not with the FDA. Myth #8: The FDA is responsible for all of the recent drug shortages due to changes in manufacturing standards that impose burdens on companies. Fact: Actually, FDA has been part of the solution. While the most common reasons for drug shortages have been issues related to manufacturing and quality, FDA’s standards have not recently changed. A number of alarming drug quality incidents have been highlighted in the lay press.4 In addition to these issues, many companies have halted production of older drugs, including many sterile injectable agents, to devote greater resources to newer drugs that are more profitable, leaving fewer manufacturers to make older drugs and rendering them more vulnerable to shortages. The FDA has no authority to require a company to produce any drug, and prior to 2012, manufacturers were not required to report anticipated drug shortages to us. In 2012, Title X of the FDA Safety & Innovation Act was passed, which required manufacturers to notify FDA about potential manufacturing interruptions or discontinuations for all drugs and biologics, including the reasons and expected duration. This has enabled us to intervene proactively with strategies such as expediting review processes for new sources of raw materials or production lines for use by alternate manufacturers, as well as temporary redirection of drugs available outside the United States into the U.S. market. In 2012, FDA successfully prevented 282 anticipated drug shortages. FDA

has developed a strategic plan for preventing and mitigating drug shortages that is available on its website.5 Myth #9: FDA does not take the voice of the patient into account in approval decisions and discourages use of patient-reported outcome measures. Fact: The FDA is very interested in the patient perspective and has long supported use of patient-reported outcome measures in clinical trials. ODAC has a voting patient representative, and FDA first drafted a Guidance on use of patient-reported outcomes in trials nearly a decade ago. The final Guidance was published in 2009 after considerable discussion with all stakeholders, including patient advocates. Patient-reported outcomes can provide the basis for both efficacy and safety claims and have been used successfully, but we do believe that patientreported outcome data should be as rigorously collected and analyzed as any other data being used to support regulatory approval. There is an entire team known as the Study Endpoints and Labeling Development Staff at FDA dedicated to helping companies develop and validate novel patient-reported outcome tools for use in clinical trials. A familiar example is ruxolitinib (Jakafi) for myelofibrosis. The company originally had a development strategy that would have relied upon splenic response rate as the basis for accelerated approval. FDA worked with the company to develop a simple six-item patient-reported outcome tool called the Myelofibrosis Total Symptom Score that documented meaningful symptomatic improvements in patients receiving ruxolitinib and served, along with splenic response rate, as the basis for regular approval. Myth #10: The FDA chooses to withhold its reasons for a negative review and nonapproval of a drug. Fact: For drugs that are approved by the FDA, the reviews and approval letters are posted on the Drugs@FDA website6 and are subject to Freedom of Information Act requests. For drugs that are not approved, we are prohibited by law from releasing either our reviews or the letters issued to the drug company that explain the rationale for the negative decision, as well as from discussing the application publicly. The only exception to this rule is in the setting of presentation of the application at an ODAC meeting. In fact, a common reason to convene an ODAC meeting is not only to hear the Committee’s thoughts but also to discuss problematic issues in the application in a public forum. Without a public discussion at

GUEST EDITOR

Richard Pazdur, MD

Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. ODAC, the reasons for a negative decision may not be apparent. It would be impossible to present every application at an ODAC meeting due to constraints on time and resources, but we have identified numerous errors in oncology drug development that would likely be less common if FDA could release its reviews of every application, whether approved or not. This cannot happen in the absence of a change in the law. However, two of our colleagues are currently researching the common errors in drug development and plan to publish these results without identifying specific drugs or applications. n Disclosure: Drs. Blumenthal and Prowell reported no potential conflicts of interest.

References 1. Roberts S, Allen JD, Sigal EV: Despite criticism of the FDA review process, new cancer drugs reach patients sooner in the United States than in Europe. Health Affairs 30:1375-1381, 2011. 2. O’Brien S: Ibrutinib CLL trial: Where is the equipoise? ASCO Post 4:1, 2013. 3. de Claro R, Kaminskas E, Farrell A, et al: FDA on CLL drug approval and expanded access (letter to the editor). ASCO Post 4:111, 2013. 4. Harris G: Medicines made in India set off safety worries. NY Times. February 14, 2014. Available at nyti.ms/1duVUbc. Accessed October 24, 2014. 5. Food and Drug Administration: Strategic Plan for Preventing and Mitigating Drug Shortages. October 2013. Available at www.fda.gov/downloads/Drugs/ DrugSafety/DrugShortages/UCM372566 .pdf. Accessed October 24, 2014. 6. Food and Drug Administration: Drugs at FDA: FDA Approved Drug Products. Available at www.accessdata.fda .gov/Scripts/cder/drugsatfda/index.cfm. Accessed October 24, 2014.

INLYTA® (axitinib) for the treatment of advanced RCC after failure of one prior systemic therapy

Choose a 2nd-line treatment with 2nd-line evidence The ONLY treatment option with superior phase 3 efficacy vs an active comparator, sorafenib, in 2nd-line mRCC* *Based on MEDLINE® literature review for phase 3 trials in metastatic RCC (mRCC) as of August 2014.

Primary endpoint: progression-free survival (PFS) HR=0.67 (95% CI: 0.54, 0.81); P<.0001

Proportion progression-free

1.0 0.9

6.7 months with INLYTA

0.8

Based on MEDLINE® literature review for phase 3 trials in metastatic RCC (mRCC) as of August 2014.

†

(n=361)

Data are from a multicenter, open-label, phase 3 trial of 723 patients with mRCC after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokinecontaining regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included objective response rate, overall survival, and safety and tolerability.1,2

(95% CI: 6.3, 8.6)

0.7

AXIS is the ONLY positive phase 3 trial that was designed to evaluate an exclusively 2nd-line patient population1†

0.6 0.5

National Comprehensive Cancer Network® (NCCN®) category 1 recommendation

0.4 0.3

4.7months with sorafenib

0.2 0.1

(95% CI: 4.6, 5.6)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer include axitinib (INLYTA) as a category 1 recommendation in patients with advanced predominantly clear-cell RCC who have failed one prior systemic therapy3

(n=362)

0.0 0

Time (months)

Important Safety Information Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment

For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%) The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%) The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine (55% vs 41%), decreased bicarbonate (44% vs 43%), hypocalcemia (39% vs 59%), decreased hemoglobin (35% vs 52%), decreased lymphocytes (absolute) (33% vs 36%), increased ALP (30% vs 34%), hyperglycemia (28% vs 23%), increased lipase (27% vs 46%), increased amylase (25% vs 33%), increased ALT (22% vs 22%), and increased AST (20% vs 25%) Please see brief summary on the following pages.

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AXU678601

AXIS14CDNY5539_BS_LblUpdt_r4.indd 1

hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment. Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (≥20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in ≥10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib INLYTA Sorafenib (N=359) (N=355) All Grade All Grade Gradesb 3/4 Gradesb 3/4 % % % % Diarrhea 55 11 53 7 Hypertension 40 16 29 11 Fatigue 39 11 32 5 Decreased appetite 34 5 29 4 Nausea 32 3 22 1 Dysphonia 31 0 14 0 Palmar-plantar erythrodysesthesia syndrome 27 5 51 16 Weight decreased 25 2 21 1 Vomiting 24 3 17 1 Asthenia 21 5 14 3 Constipation 20 1 20 1 Hypothyroidism 19 <1 8 0 Cough 15 1 17 1 Mucosal inflammation 15 1 12 1 Arthralgia 15 2 11 1 Stomatitis 15 1 12 <1 Dyspnea 15 3 12 3 Abdominal pain 14 2 11 1 Headache 14 1 11 0 Pain in extremity 13 1 14 1 Rash 13 <1 32 4 Proteinuria 11 3 7 2 Dysgeusia 11 0 8 0 Dry skin 10 0 11 0 Dyspepsia 10 0 2 0 Pruritus 7 0 12 0 Alopecia 4 0 32 0 Erythema 2 0 10 <1 a Percentages are treatment-emergent, all-causality events b National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 Adverse Reactiona

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%). The following table presents the most common laboratory abnormalities reported in ≥10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in ≥10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality Hematology Hemoglobin decreased Lymphocytes (absolute) decreased Platelets decreased White blood cells decreased Chemistry Creatinine increased Bicarbonate decreased Hypocalcemia ALP increased Hyperglycemia Lipase increased Amylase increased ALT increased AST increased Hypernatremia Hypoalbuminemia Hyperkalemia Hypoglycemia Hyponatremia Hypophosphatemia a

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

336 314 336 336 336 338 338 331 331 338 337 333 336 338 336

55 44 39 30 28 27 25 22 20 17 15 15 11 13 13

0 <1 1 1 2 5 2 <1 <1 1 <1 3 <1 4 2

318 291 319 319 319 319 319 313 311 319 319 314 319 319 318

41 43 59 34 23 46 33 22 25 13 18 10 8 11 49

<1 0 2 1 2 15 2 2 1 1 1 3 <1 2 16

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib) and hypercalcemia (6% for INLYTA versus 2% for sorafenib). DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/ kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INLYTA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were ≥65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were ≥65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only August 2014.

References: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet. 2011;378(9807):1931-1939. 2. Data on file. Pfizer Inc, New York, NY. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed July 1, 2014. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.

National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

September 2014

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INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be coadministered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see Adverse Reactions]. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Cardiac Failure. In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe

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Direct From ASCO

Cancer.Net Launches PRE-ACT Patient Clinical Trial Education Program

linical trials are the key to driving advances in the prevention, diagnosis, and treatment of cancer, yet, it is estimated that only about 5% of patients with cancer participate in clinical trials. That is why Cancer.Net, ASCO’s patient-facing educational website, has teamed up with Neal Meropol, MD, FASCO, and PRE-ACT (Preparatory Education About Clinical Trials) to help improve patients’ knowledge and attitudes about clinical trials (www.cancer.net/pre-act). PRE-ACT is an interactive videobased program that provides patients with tailored information about clinical trials in an effort to help them to be better prepared to make an informed decision about clinical trial participation. “Video can be a powerful tool for patient education,” said Robert S. Miller, MD, FACP, FASCO, Editor-in-Chief of Cancer.Net. “Cancer.Net is pleased to have access to a theory-guided and professionally produced educational program such as PRE-ACT on our site to further clinical trial enrollment.”

Barriers to Clinical Trials Previous research has shown that multiple barriers exist when it comes to patient participation in clinical trials. Among the more frequently cited bar-

riers are the fear of side effects, concern about randomization to placebo, a lack of awareness of clinical trials, and concerns about the costs associated with participating in a clinical trial. “We developed PRE-ACT to attempt to address patient knowledge gaps and attitudes about clinical trials before they ever see a physician to better prepare them to consider a clinical trial should one be available and appropriate for them,” said Dr. Meropol, Chief of Hematology and Oncology at UH Case Medical Center, and developer of the PREACT program. With the help of funding from the National Cancer Institute (NCI), Dr.

We developed PRE-ACT to attempt to address patient knowledge gaps and attitudes about clinical trials before they ever see a physician to better prepare them to consider a clinical trial should one be available and appropriate for them. —Neal Meropol, MD, FASCO

Results of the trial showed that the PRE-ACT videos were more effective in improving patient knowledge about and attitudes toward clinical trials. There was also a trend toward greater self-reported preparedness to consider clinical trials among those patients exposed to the PRE-ACT program.

Access for All

Robert S. Miller, MD, FACP, FASCO

Meropol and colleagues tested the efficacy of the PRE-ACT program in a phase III clinical trial that randomly assigned 1,255 patients to either the PRE-ACT tailored videos or to receive general text about clinical trials from the NCI. All patients completed a survey to assess baseline knowledge, attitudes, and values.

Dr. Meropol and Cancer.Net are now making the full video library of the PRE-ACT program available to all users for free. Since the program was originally tested, it has been enhanced and updated with new and up-to-date information. Patients visiting Cancer.Net will have a choice of viewing the full video library or having videos recommended for them. Those who want a personalized experience may complete a survey assessing opinions and knowledge about clinical trials, values, and their decision-

making process. Based on the responses, PRE-ACT will tailor a video-based educational program for each patient. For example, if a patient expressed concerns about clinical trials because of a fear of side effects, the program might recommend a video that discusses how researchers ensure safety in clinical trials and how they work to manage side effects. In addition to providing education, the PRE-ACT program was designed to empower patients to ask questions and obtain more information, Dr. Meropol said. “My hope is that by making this program available, patients who are interested in learning more about clinical trials will access PRE-ACT, and, in doing so, PRE-ACT will deliver specific video content directed at their informational needs,” he said. n © 2015. American Society of Clinical Oncology. All rights reserved.

Latest ASCO-SEP® Edition Includes 20-Point Maintenance of Certification Course

he 4th edition of ASCO-SEP®, ASCO’s self-evaluation program, was released in October and not only includes 21 chapters of up-to-date information on all major cancer types, cancer prevention and more, but now also includes a Maintenance of Certification (MOC) Course in addition to its traditional Continuing Medical Education offerings. Beginning in 2014, the American Board of Internal Medicine’s (ABIM) MOC program requirements changed to require that all diplomates actively participate in MOC activities in order to be

Jamie H. Von Roenn, MD, FASCO

listed as “Meeting MOC Requirements” on the ABIM website. The new requirements call for participation in some MOC activity every 2 years, earning 100 MOC points every 5 years, and passing a secure MOC exam every 10 years. As part of its ongoing effort to assist members in meeting these new requirements, ASCO has continued to adapt its educational offerings to include MOC points, when possible.

Featured Updates The new edition of ASCO-SEP® offers members 21 chapters of current information on a variety of cancer types, in addition to chapters on cancer prevention, epidemiology, molecular biology, palliative care, symptom management, and cancer in the elderly. In addition, the 4th edition includes a new feature, “Updates from 2012,” found at the beginning of each chapter, highlighting advances in knowledge since the release of

the 3rd edition of ASCO-SEP®. Past editions of ASCO-SEP® offered participants 45 CME credits. The 4th edition offers those same credits, but now also offers for purchase an Online Question Bank with 100 bonus questions for additional CME credit, a 200-card flashcard deck based off of the book, and an MOC Course. The ASCO-SEP® MOC course consists of 60 multiple-choice questions addressing a wide variety of cancer sites including breast, lung, head and neck, gynecologic, hematologic malignancies, genitourinary, and more. Each question includes patient case information, educational links, and answer rationales. After successful completion of the MOC activity, diplomates are eligible to receive 20 points toward their medical knowledge requirement. “ASCO is going to be developing more and more innovative ways to help members meet MOC credit requirements

through activities that they already participate in,” said Jamie H. Von Roenn, MD, FASCO, Senior Director of Education, Science, and Professional Development at ASCO. “We want to streamline this process so that people can stay up to date.” The ASCO-SEP® print edition and eBook is available for $468, but the program can also be bundled together with the Online Question Bank ($227) and the MOC course ($227) at a discounted price. In addition to the new MOC offerings available through ASCO-SEP®, members can visit ASCO University to earn medical knowledge points by completing any of a series of ASCO-developed medical knowledge courses worth 10 MOC points each, including courses on palliative care, prevention/screening, leukemia/lymphoma, breast cancer, and gastrointestinal cancers. n © 2015. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | JANUARY 25, 2015

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Direct From ASCO

Palliative Care in the Middle East While some seek peace in the Middle East through political means, others are looking to help patients with cancer find peace through palliative care. This endeavor is bringing oncology professionals together across the region’s national borders and cultural boundaries to implement solutions and improve patient care.

n the Middle East, cancer has become an increasing burden, more so than in the United States. While the cancer mortality incidence ratio is 0.38 in the United States, it is 0.58 in the world, and a staggering 0.66 in the Middle East.1 As most of the countries in the Middle East are considered low- to middle-income, health resources are usually scarce and unreliable, limiting the availability of pre-

the United Arab Emirates in November 2014. She pointed out that the limitations of care and treatment are directly affected by the political and often violent conflict in the region. Dr. Schapira also serves as an ASCO faculty member at the International Palliative Care Workshops in Turkey, as a member of the International Development and Education Award Working Group, and as an Associate Editor for Cancer.Net, ASCO’s patient information website. This dire situation is one that ASCO and MECC seek to resolve by offering training and resources for oncology professionals. Dr. Silbermann believes that through the development of palliative care programs and better communication between oncology professionals and patients, palliative care will become more widely accepted in the region. MECC has helped in initiating

…It’s not about religion or politics, but rather about humanity, interpersonal relationships, peace, and setting aside prejudices. —Michael Silbermann, DMD, PhD

ventive and screening measures. As a result, when patients are diagnosed with cancer, it tends to be in the late stages of the disease.2 Michael Silbermann, DMD, PhD, the Executive Director of the Middle East Cancer Consortium (MECC), believes that palliative care is often the best form of treatment in these cases; however, it is not always offered or utilized. Access to pain medicines in the region is limited, and even when drugs and palliative care services are available to patients, they are not always accepted. Additionally, stigmas related to beliefs about the hereditary or genetic aspects of cancer can often deter patients from accepting treatments, let alone seeking medical help. Stigmas concerning pain medications and mental health issues related to a cancer diagnosis can often lead to patients keeping their condition a secret and choosing to forgo any palliative care. Moreover, “cancer isn’t a patient’s only concern in the Middle East,” said Lidia Schapira, MD, FASCO, a speaker at the MECC Conference in

palliative care programs in many Middle Eastern countries. “In many cases these countries don’t recognize each other,” says Dr. Silbermann, “but it’s not about religion or politics, but rather about humanity, interpersonal relationships, peace, and setting aside prejudices.”

Overcoming Barriers to Care One of the biggest hurdles to overcome is a lack of communication and understanding of cultural and faith differences between providers and patients. MECC trains oncology providers to have more open, and ultimately, more fruitful discussions with patients in the region. Dr. Silbermann offers the following suggestions on how oncologists can overcome cultural, faith, and communication barriers to provide the best possible care to their patients in the Middle East: 1. Become aware of any sensitivity. Start by listening to the patient’s concerns and asking questions about what he or she wants their cancer care to look like. “Personalized medicine isn’t just genetics,” said Dr. Silbermann, who suggests

oncology professionals ask patients some personal questions so they can better get to know their patients and learn what barriers to care and treatment they may face.

Lidia Schapira, MD, FASCO

While the United States is a “death denying” culture, according to Dr. Schapira, other cultures have a different perspective on death. Dr. Schapira believes that patients should be given choices for “mapping out their care based on what gives their lives meaning.” By better understanding the cultural and religious beliefs of patients, oncology professionals may be able to offer alternative solutions, while still respecting the patient’s customs and faith. 2. Involve the patient’s family. “In the Middle East, it’s not uncommon for families to know the diagnosis before the patients,” Dr. Silbermann said. In many cases, the family tries to shield the patient from their prognosis and hides the disease from them. While this would be considered unethical in the United States, it demonstrates

the importance of the family’s role in a patient’s treatment. Collective care involving the family is often paramount, so include the family, with the patient’s permission, whenever possible. 3. Provide resources and options, especially those that are family- and community-oriented. Some patients from the Middle East may be wary of Western medicine and may seek to rely more on the support of their family or religious community. One of MECC’s primary tasks is to build trust with communities and families. Oncology professionals should support their patients’ choices, while helping to dispel misconceptions and advocating for the best care and treatment. Additionally, oncology professionals should provide resources and options for home care and help find community support groups for patients. To learn more about palliative care and find tools for your practice as well as resources for patients, visit www.asco.org/practice-research and select “Palliative Care in Oncology.” n References 1. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr 2. Silbermann, M, ed. Palliative Care to the Cancer Patient: The Middle East as a Model for Emerging Countries. Nova Science Pub Inc.; 2014.

ASCO’s International Palliative Care Workshops

SCO, in collaboration with international oncology societies, hosts International Palliative Care Workshops (IPCWs) designed to teach participants about palliative care best practices. IPCWs share communication strategies (such as how to deliver bad news), pain assessment methods, methods to manage medications, comprehensive care and symptom management practices, and strategies to implement palliative care services in their practice setting (hospitals, community clinics, etc.). Since ASCO held the first IPCW in 2009, workshops have taken place in countries including Egypt, Oman,

Mexico, Ghana, Turkey, Honduras, and Argentina. In 2014, ASCO held courses in three countries and trained 161 participants. This year, ASCO plans to hold IPCWs in India, Morocco, and Nepal. All cancer care professionals in the respective country/region are invited to participate. Visit www.asco.org/ international-programs and select “Educational Opportunities” to find more information on IPCWs. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Palliative Care in the Middle East.” ASCO Connection, January 2015: 30-31. All rights reserved.

ASCOPost.com | JANUARY 25, 2015

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Direct From ASCO

Save the Date: World Cancer Day 2015

ave you marked your calendar for World Cancer Day? Each year on February 4, World Cancer Day unites people from across the globe in the fight against cancer. The initiative is organized by the Union for International Cancer Control (UICC) to raise cancer awareness and encourage governments and individuals to take action against

the disease. Right now, cancer causes more than 8 million deaths globally, and disparities in access to quality care continue to grow between people from different backgrounds and settings. The Conquer Cancer Foundation of ASCO (CCF) works hard to support tools for quality care that will help reduce these disparities—no matter who you are or where you live. CCF also funds breakthrough cancer research and trusted education resources for patients and their physicians. Cancer is certainly a growing global burden, but thanks in part to organizations like CCF and ASCO and movements like World Cancer Day, we are making progress. The theme of World Cancer Day 2015 is “Not Beyond Us,” which the UICC states “will take a positive and proactive approach to the fight against cancer, highlighting that solutions do exist across the continuum of cancer, and that they are within our reach.” The Conquer Cancer Foundation supports such solutions by funding programs and research that make a real impact on the lives of people with cancer, including research to improve the care of patients in low resource environments worldwide. In particular, CCF’s International Innovation Grant funds innovative research that

can have a significant impact on cancer control in low- and middle- income countries. CCF draws on the expertise of the world’s leading cancer doctors and researchers to build a world free from the fear of cancer. Such a world is, in fact, “not beyond

us”—but we need the support of generous friends and donors to make it possible. This February, please join the Foundation in commemorating World Cancer Day by making a donation to improve cancer care worldwide. Visit

www.conquercancerfoundation.org/ donate to make your gift today. To learn more about World Cancer Day visit www.worldcancerday.org. n © 2015. American Society of Clinical Oncology. All rights reserved.

WHAT DOES THE BLOOD-BRAIN BARRIER HAVE TO DO WITH ALK+ NSCLC? In up to 46% of ALK+ NSCLC patients, the CNS is the first site of progression while receiving an ALK-directed therapy1 • The blood-brain barrier, composed of numerous efflux transporters, forms a sanctuary for metastatic disease by actively preventing some therapeutic molecules from entering the CNS2 • Therapies with minimal exposure in the CNS may be unable to inhibit progression in the CNS1,2 • Patients with CNS metastases often experience poor outcomes and significant morbidity3

Discover more at ResearchALK.com

ALK=anaplastic lymphoma kinase; CNS=central nervous system; NSCLC=non-small cell lung cancer. References: 1. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non–small-cell lung cancer. J Thorac Oncol. 2012;7:1807-1814. 2. Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13:1663-1674. 3. Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010;2:2100-2137. © 2014 Genentech USA, Inc. All rights reserved. BIO/100814/0053 Printed in USA.

The ASCO Post | JANUARY 25, 2015

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Direct From ASCO

New ASCO Study Aims to Learn From Patient Access to Targeted Cancer Drugs Used Off-Label

SCO plans to launch a first-ever study that will offer cancer patients access to molecularly targeted cancer drugs and collect “real-world” data on clinical outcomes to help oncologists learn the best uses of these drugs outside of approved indications.

Richard L. Schilsky, MD, FACP, FASCO

“One of the major challenges to implementing personalized medicine is the lack of information about the risks and benefits of targeted drugs that are used off label to treat patients whose tumor harbors a genomic abnormality,” ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO, said at the Friends of Cancer Research-Brookings Institution Conference on Clinical Cancer Research. “Other difficulties are lack

of access to these agents for patients and interpretation by oncologists of the complex genomic test results. This ASCO-led clinical trial will address both challenges.”

TAPUR Study The ASCO project, called the Targeted Agent and Profiling Utilization Registry (TAPUR) Study, will be the first clinical trial ever led by the Society in its 50-year history. The two primary study objectives are: • To describe the antitumor activity and toxicity of commercially available, targeted cancer drugs used off label for treatment of patients with advanced solid tumors with a known genomic variant. • To facilitate patient access to commercially available, targeted anticancer drugs of potential efficacy prescribed off label for treatment of patients with an advanced solid tumor with a known genomic variant. The prospective, nonrandomized clinical trial would enroll patients who have an advanced solid tumor and are no longer benefitting from standard anticancer treatment or for whom no

Highlights From the 2015 Gastrointestinal Cancers Symposium

he 2015 Gastrointestinal Cancers Symposium was held January 15 to 17. Direct your patients to www.cancer .net/blog to read the latest research on

the treatment of colorectal cancer, including what it means for patient care. On the Cancer.Net blog, your patients can also listen to a podcast explaining the latest findings on vitamin D and colorectal cancer. n © 2015. American Society of Clinical Oncology. All rights reserved.

seek concurrence from the TAPUR molecular tumor board for a different treatment plan. Approved targeted therapies would be provided by participating pharmaceutical companies. For additional information and new developments on the TAPUR study, please visit www.asco.org/TAPUR. n

such treatment is available. Patients would be screened for acceptable performance status and organ function, and a tumor genomic test must identify at least one genomic variant that can be targeted with drugs that will be offered through the study. The study will provide a list of eligible drug variant matches. The treating physician could propose treatment according to one of the matches or

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al

Top 5 most-accessed articles recently published in Journal of Clinical Oncology Top 10 most-accessed articles published in 2011 in Journal of Clinical Oncology

What’s Hot in

JCO

Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

JCO.org How Long Is Long Enough? Extended Anticoagulation for the Treatment of Cancer-Associated Deep Vein Thrombosis by Jeffrey I. Zwicker, et al

Optimal Duration of Low Molecular Weight Heparin for the Treatment of Cancer-Related Deep Vein Thrombosis: The CancerDACUS Study by Mariasanta Napolitano, et al Effect of Radiotherapy After Breast-Conserving Surgery for Ductal Carcinoma in Situ: 20 Years Follow-Up in the Randomized SweDCIS Trial by Fredrik Wärnberg, et al Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/

Save the Date

2015 Genitourinary Cancers Symposium February 26-28, 2015 Rosen Shingle Creek Orlando, Florida

International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline by Natasha B. Leighl, et al

New Information Prompts Old Question: Is Sentinel Lymph Node Sampling Equivalent to Axillary Lymph Node Dissection? by Richard Cedric Zellars

ASCOPost.com | JANUARY 25, 2015

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Announcements

Gary Levine, MD, President of National Consortium of Breast Centers, to Lead MemorialCare Health System Breast Centers in Southern California

ary Levine, MD, a breast radiologist, is joining MemorialCare Health System as Medical Director of MemorialCare Breast Centers in Orange and Los Angeles counties. Dr.

Levine, President of the National Consortium of Breast Centers, will partner with physician leadership teams at MemorialCare hospitals, including breast surgeons, medical oncologists, radia-

tion oncologists, diagnostic radiologists, pathologists, genetic counselors, certified breast patient navigators, and other clinicians that work together in interdisciplinary teams to prevent, de-

tect, and treat breast cancer. Dr. Levine has more than 20 years of experience in breast imaging and breast center leadership, including 10 years as Medical continued on page 76

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The ASCO Post | JANUARY 25, 2015

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Announcements Gary Levine, MD continued from page 75

Director of Breast Imaging for Hoag Breast Care Center. Dr. Levine serves as an Associate Clinic Professor of Radiology at the University of Southern California School of Medicine and as an Assistant Clinical Professor in the Department of

Gary Levine, MD,

Radiological Services at University of California Irvine. “The addition of a renowned and highly regarded breast radiologist with Dr. Levine’s experience, expertise, and national reputation furthers MemorialCare’s leadership as among the top centers for breast health and breast cancer,” says Barry Arbuckle, PhD,

President and CEO of MemorialCare Health System. Dr. Levine is considered a pioneer in the technique of breast tumor cryoablation, a procedure that involves freezing breast tumors, and assisted by ultrasound guidance, removing those tumors with a minimally invasive procedure. n

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ASCOPost.com | JANUARY 25, 2015

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Announcements

Victor Filadora, MD, MBA, Named Chief of Clinical Services at Roswell Park Cancer Institute

oswell Park Cancer Institute (RPCI) has named Victor Filadora, MD, MBA, as Chief of Clinical Services. In this new role, Dr. Filadora, an anesthesiologist first appointed

to the Institute’s medical staff in 2003, is responsible for managing the comprehensive cancer center’s Ambulatory Services, Perioperative Services, Sterile Processing, Pharmacy, Patient and

Family Experience, Endoscopy Services and Therapeutic Services programs, and will also provide leadership and guidance to clinical department administrators throughout the Institute.

Dr. Filadora continues in his roles as Clinical Chief of Perioperative Medicine and Associate Dean for Graduate Medical Education at Roswell Park and a Clinical Assistant Professor within the Department of Anesthesiology at the University at Buffalo (UB). “Since we first recruited him to Roswell Park a decade ago to establish our

Victor Filadora, MD, MBA

preoperative services program, Dr. Filadora has led the design and implementation of several key clinical projects,” says Roswell Park President and CEO Candace Johnson, PhD. “His experience and his thoughtful, strategic, patient-centered approach make him an outstanding match for this new opportunity.”

Career Path

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Dr. Filadora joined RPCI in 2003 from Brigham and Women’s Hospital in Boston, an affiliate of Harvard Medical School, where he served as Chief Resident for the Department of Anesthesiology. He served on the staff of Newton-Wellesley Hospital and the Tufts University School of Medicine faculty from 2004 to 2005, at which point he returned to RPCI as Chief of Perioperative Medicine and Director of the Center for Preoperative Evaluation. A member of RPCI’s Medical Staff Executive Committee, he serves on the UB School of Medicine and Biomedical Sciences’ Faculty Council and its Resident Grievance, Graduate Medical Education and Anesthesiology Admissions committees, and is a Senior Business and Healthcare Advisor to the UB School of Management. An accredited Royal College of Physicians educator, Dr. Filadora has helped lead several collaborative projects involving the UB School of Medicine and Biomedical Sciences and UB School of Management. He frequently extends his expertise in perioperative services as a consultant to health-care systems in the areas of operations and governance. n

The ASCO Post | JANUARY 25, 2015

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San Antonio Breast Cancer Symposium Breast Cancer

Low-Fat Diet Reduces Mortality in Breast Cancer Subset By Caroline Helwick

he final survival analysis of the landmark Women’s Intervention Nutrition Study (WINS) confirmed that a low-fat diet can reduce the risk of dying for a subset of breast cancer patients.1 At the San Antonio Breast Cancer Symposium, Rowan T. Chlebowski, MD, PhD, of the Los Angeles Biomedical Research Institute at the HarborUCLA Medical Center, reported that, after more than 15 years of follow-up, the dietary intervention for early-stage breast cancer patients was effective at improving survival among women with hormone receptor–negative tumors. In women with estrogen receptor (ER)-negative tumors, a 36% statistically significant reduction in deaths was seen with intervention. The benefit

was even greater—a 54% reduction in deaths—among women whose tumors were negative for both estrogen receptor and progesterone receptor (PR), Dr. Chlebowski reported. “Exploratory analyses suggest a favorable lifestyle influence on survival in hormone receptor–negative subgroups,” he said. Dr. Chlebowski suggested that one’s “take” on the data might differ, depending on whether it’s viewed scientifically or clinically. “From a scientific standpoint, others will have to look at this exploratory analysis and decide if the data support a randomized clinical trial to confirm them. On an operational basis, however, there are multiple health benefits associated with a 5%, or 5-pound, weight loss,

Exploratory analyses suggest a favorable lifestyle influence on survival in hormone receptor–negative subgroups. —Rowan T. Chlebowski, MD, PhD

and this is a separate issue that women should consider,” he suggested. C. Kent Osborne, MD, Director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, who moderated a press briefing where the results were presented, was

impressed. “These results are pretty remarkable,” he suggested. “We have welloutfitted infusion centers, but I’d bet that few oncologists take dietary intervention as seriously as we take our other treatments. The reduction in deaths for ER/PR-negative patients is as good

No Benefit for Adjuvant Capecitabine Monotherapy in Elderly Patients With Early-Stage Breast Cancer By Alice Goodman

djuvant therapy with capecitabine plus ibandronate failed to improve outcomes vs ibandronate alone in elderly patients with moderate-to-high-risk early-stage breast cancer in the ICE study— the largest study to date conducted in elderly women with breast cancer.1 “Capecitabine is frequently used in elderly patients with metastatic disease who cannot tolerate the side effects of conventional chemotherapy. However, if chemotherapy for early breast cancer is indicated due to the biology or the stage of disease, a combination chemotherapy using more than one drug either in sequence or simultaneously is necessary, as the ICE study has shown that monochemotherapy with capecitabine is not working,” said lead author and Chair of the German Breast Group, Gunter von Minckwitz, MD, of the University of Frankfurt, Germany. “The study showed that one drug is not effective,” he emphasized. “Oncologists should try to give appropriate combination chemotherapy [for stage and aggressiveness] irrespective of age.”

Primary Endpoint Results of the ICE trial showed no difference between the two treatment arms for the primary endpoint of 3-year invasive disease-free survival: 85.4% in women treated with capecitabine/ibandronate vs 84.3% in the ibandronate-alone

arm. The 5-year invasive disease-free survival was 78.8% vs 75%, respectively. “At 5 years, there was an absolute difference between the arms of 3.8%, but

Gunter von Minckwitz, MD

thereafter, the two curves crossed,” Dr. von Minckwitz told listeners.

Closer Look at the ICE Trial ICE was a prospective, randomized, multicenter trial that enrolled 1,358 patients with node-negative or high-risk node-negative early-stage breast cancer. Women aged 65 or older were randomly assigned 1:1 to receive capecitabine plus ibandronate or ibandronate alone for 2 years of treatment. Commenting on the study inclusion criteria and treatment arms, Dr. von Minckwitz said: “We excluded patients who were too vulnerable to receive conventional combination chemotherapy and included patients not fit enough for taxane-based chemotherapy. Ibandronate was selected as the backbone for

this trial to avoid an untreated control group. We believe these women are at risk for bone-related events anyway, and in 2004 when the trial was started, evidence suggested that ibandronate might prevent breast cancer relapse,” he added. The mean age was 71 years, and about 25% were aged 75 or older. About 10% had a Charlson comorbidity score of 2, indicating frailty. One-third of patients were on three or more medications for comorbidities. About 14% had triple-negative breast cancer, about 80% had hormone receptor–positive breast cancer, and about 70% were on aromatase inhibitors only. Interestingly, bone-related events were still frequent in both arms despite the use of a bisphosphonate, he continued. Fractures, surgery, or new osteoporosis (excluding bone metastases) occurred in 25% of the capecitabine/ibandronate group vs 24.7% of the ibandronate-alone

arm. About 65% of patients opted to use oral ibandronate, and nearly 35% chose monthly intravenous injections; the mode of administration had no effect on bone-related or other outcomes. Subgroup analysis mirrored the primary analysis of the trial, with no preferential benefit or deficit for either treatment arm evident in any subgroup. “In general, despite elderly age and randomization, at the time of the analysis, patients had a favorable 5-year disease-free survival on ibandronate alone. The fact that 75% and 78% were free of disease at 5 years demonstrates that these patients have a lot of life left and should be treated sufficiently, yet they are often undertreated,” Dr. von Minckwitz said.

Combination Chemotherapy In his view, the result of ICE, together with the results of CALGB 49907 continued on page 79

Adjuvant Capecitabine in Older Breast Cancer Patients ■■ The largest randomized trial to date in elderly patients with early-stage breast cancer found no benefit in invasive disease-free survival for use of monotherapy with capecitabine; the study combined capecitabine with ibandronate and compared that combination with ibandronate alone. ■■ Although capecitabine is often used in the metastatic setting for elderly patients because it is thought to be less toxic than chemotherapy, this study showed there was no role for capecitabine monotherapy in the treatment of early-stage breast cancer in older patients.

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San Antonio Breast Cancer Symposium

C. Kent Osborne, MD

as, or greater than, what we see with our best treatments.”

WINS Initiated in 1994 The randomized phase III WINS trial was initiated in 1994 to evaluate whether dietary fat reduction could influence relapse-free survival in early-stage breast cancer patients receiving standard-ofcare treatment. At enrollment, the 2,437 women were required to have a dietary fat intake > 20% of calories and were randomly assigned to a dietary intervention group or a control group. The intervention aimed to reduce fat intake for 5 years while maintaining nutritional adequacy. Women were given

weight was nearly 6 pounds less in the intervention group, compared to controls, Dr. Chlebowski reported. “If you adhere to a low-fat diet, it’s pretty easy to lose weight,” he noted. “In the intervening 20 years, it’s become clear that weight loss is probably more important than dietary fat in influencing breast cancer outcome.”

Survival Data In previous reports, after 5 years of follow-up, relapses were 24% lower in the intervention group. (P = .03). After 9 years of follow-up, there was no impact on overall survival in the whole population, but deaths in the ER/PRnegative subgroups were reduced by 64% (P = .003). In the final survival analysis, with follow-up through 2013 (19.4 years maximum), there was still no overall survival benefit in the whole population—mortality rates were 17.0% in the intervention arms and 13.6% in the control arm (hazard ratio [HR] = 0.94, P = NS)—however, there was a fairly

Low-Fat Diet and Survival After Breast Cancer ■■ Final survival analyses from the Women’s Intervention Nutrition Study (WINS) found that a dietary intervention aimed at lowering fat had no impact on survival in the overall population but had a highly significant impact in hormone receptor–negative patients. ■■ After 5 years of the intervention, women with ER-negative tumors had a 36% reduced risk of death, and women with ER/PR-negative tumors had a 54% risk reduction.

a fat-gram goal by centrally trained, registered dietitians implementing a lowfat eating plan. The women underwent eight biweekly individual counseling sessions, were subsequently contacted every 3 months, and self-monitored their fat-gram intake using a “keeping score” book. Fat intake was externally monitored by unannounced 24-hour telephone recalls performed annually. After 5 years of intervention, calories from fat were lowered by 9.2% and body

striking impact on survival in the ERnegative and ER/PR-negative groups, Dr. Chlebowski indicated. In this exploratory analysis, median survival in the control arm was 11.7 years but was increased in the intervention group to 13.6 years among 478 ERnegative patients (HR = 0.64, P = .045) and to 14.0 years in the 362 women whose tumors were ER/PR-negative (HR = 0.46, P = .006). “In the dietary intervention arm,

Adjuvant Capecitabine

“The more aggressive the subtype, the more chemotherapy I would use. A patient has to be really unfit before I would not give her chemotherapy,” he said. In a discussion following his presentation, Dr. von Minckwitz said that when the study was started, there was insufficient evidence of tolerability of combination chemotherapy in elderly women. “Elderly women did not get this treatment when we started the study. Now the data are available and show we can do it,” he said.

continued from page 78

(which showed efficacy for combination chemotherapy vs capecitabine monotherapy), strongly supports the use of combination chemotherapy in elderly women.2 However, toxicity with the combination chemotherapy was twice as high as that with capecitabine (64% vs 33%), which could tip the balance away from combination chemotherapy depending on the patient’s fitness level and disease characteristics.

EXPERT POINT OF VIEW

my H. Comander, MD, a medical oncologist at the Massachusetts General Hospital Cancer Center and Instructor in Medicine at Harvard Medical School, Boston, told The ASCO Post that the findings will clearly help her in counseling patients. “I am excited to be able to discuss the study with my patients,” she said. “My patients tend to be highly motivated, always on the Internet searching for the next diet or supplement that can help lower their risk for recurrence,” she said. “For those patients, I am already telling them to maintain a healthy weight,

Particularly for the high-risk ER-negative group, I can tell patients that we have data … indicating that if they can adhere to a low-fat diet for 5 years and lose 5 pounds, this potentially can improve their survival. —Amy H. Comander, MD

limit excessive alcohol consumption, and follow the CDC’s general recommendation to exercise for 150 minutes a week. Now, particularly for the high-risk [estrogen receptor]-negative group, I can tell patients that we have data from a large randomized clinical trial indicating that if they can adhere to a low-fat diet for 5 years and lose 5 pounds, this potentially can improve their survival. Although these data are from an exploratory analysis that merits confirmation, it is a good answer for when patients ask ‘what else can I do?’ If validated, this is a particularly striking effect for our highest-risk breast cancer patients.” n Disclosure: Dr. Comander reported no potential conflicts of interest.

median survival was almost 2 years greater,” Dr. Chlebowski noted. For the ER/PR-negative patients, in the first 10 years poststudy, there were 69% fewer deaths in that group, after which the survival impact diminished somewhat, he indicated. While HER2 status was not available at the time the study was conducted, recently published data by the Surveillance, Epidemiology, and End Results (SEER) program indicate that 73% of these ER/ PR-negative women would have triplenegative tumors, he said. “This suggests there’s a 54% improvement in survival, Commenting on these results at a press conference, Carlos Arteaga, MD, of Vanderbilt-Ingram Cancer Center in Nashville, and current President of the American Association for Cancer Research, said: “The use of capecitabine in elderly patients with early-stage breast cancer is not supported based on this study. However, that does not exclude the use of other chemotherapy regimens, which may make a difference in outcomes.” n

Disclosure: This study was funded by Roche and AstraZeneca. Drs. von Minckwitz

and a 2.3-year increase in median survival for triple-negative breast cancer patients,” he emphasized. n

Disclosure: Drs. Chlebowski and Osborne reported no potential conflicts of interest.

Reference 1. Chlebowski RT, Blackburn GL, for the Women’s Intervention Nutrition Study Investigators: Final survival analyses from the Women’s Intervention Nutrition Study (WINS) evaluating dietary fat reduction as adjuvant breast cancer therapy. San Antonio Breast Cancer Symposium. Abstract S5-08. Presented December 12, 2014.

and Arteaga reported no potential conflicts of interest.

References 1. von Minckwitz G, Reimer T, Potenberg J, et al: The phase III ICE study: Adjuvant ibandronate with or without capecitabine in elderly patients with moderate or high risk early breast cancer. 2014 San Antonio Breast Cancer Symposium. Abstract S3-04. Presented December 11, 2014. 2. Muss HB, Berry DA, Cirrincione CT, et al: Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 360:2055-2065, 2009.

IMBRUVICA® demonstrated single-agent survival in previously treated CLL INDICATIONS: IMBRUVICA® is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with: • Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy • CLL with 17p deletion

Superior overall survival (OS) with IMBRUVICA® vs ofatumumab—secondary endpoint (HR=0.43; 95% CI: 0.24, 0.79); P<0.05 • 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA® arm • Median OS not yet reached in either treatment arm

Superior progression-free survival (PFS) with IMBRUVICA® vs ofatumumab— primary endpoint • Median PFS not yet reached with IMBRUVICA® vs 8.1 months with ofatumumab

(HR for progression or death: 0.22; 95% CI: 0.15, 0.32); P<0.0001

78% statistically significant reduction in the risk of death or progression (independent review) 100

PFS (%)

80 60 40 20 0

Ofatumumab

P<0.0001 by log-rank test 0

Number at risk IMBRUVICA® 195 Ofatumumab 196

183 161

116 83

Months

Results from the randomized, multicenter, open-label, Phase 3 RESONATE™ trial of IMBRUVICA® vs ofatumumab in patients with previously treated CLL. Patients (N=391) were randomized 1:1 to receive either IMBRUVICA® 420 mg orally daily until disease progression or unacceptable toxicity or IV ofatumumab at an initial dose of 300 mg, followed 1 week later by a dose of 2000 mg weekly for 7 doses, and then every 4 weeks for 4 additional doses. Fifty-seven patients randomized to ofatumumab crossed over following Independent Review Committee (IRC)-confirmed progression to receive IMBRUVICA®. Primary endpoint: PFS as assessed by an IRC according to modified International Workshop on CLL Criteria. HR=hazard ratio.

38 15

7 1

0 0

In patients with previously treated del 17p CLL, IMBRUVICA® demonstrated a 75% reduced risk of progression or death (HR=0.25; 95% CI: 0.14, 0.45) • Median PFS not reached with IMBRUVICA® (n=63) vs 5.8 months with ofatumumab (n=64)

Oral, once-daily dosing In CLL studies, approximately 5% of patients discontinued due to adverse events Please review the Important Safety Information on adjacent page.

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®. The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving anti-platelet or anti-coagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred with IMBRUVICA®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly. Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly. Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification. Second Primary Malignancies - Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in

patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%). Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. ADVERSE REACTIONS The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® discontinued treatment due to adverse events. These included infections, subdural hematomas, and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose. CYP3A Inducers - Avoid co-administration with strong CYP3A inducers. SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with baseline hepatic impairment. Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit us at

www.IMBRUVICA.com

Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICA® (ibrutinib) capsules

INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Improvements in survival or disease-related symptoms have not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in full Prescribing Information]. Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in full Prescribing Information]. Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Twenty-five percent of patients with MCL and 26% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly. Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in full Prescribing Information]. Second Primary Malignancies: Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%). Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Cytopenias [see Warnings and Precautions] • Atrial Fibrillation [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) System Organ Class Gastrointestinal disorders

Infections and infestations

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis

All Grades (%) 51 31 25 24 23 17 11

Grade 3 or 4 (%) 5 0 0 5 0 1 0

34 14 14 14 13

0 3 7 5 1

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) (continued) System Organ Class

Preferred Term

General disorders and administrative site conditions

Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

All Grades (%)

Grade 3 or 4 (%)

41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. Approximately five percent of patients receiving IMBRUVICA in Study 1 and 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions

Skin and subcutaneous tissue disorders Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders

Preferred Term Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection Fatigue Pyrexia Peripheral edema Asthenia Chills Bruising Rash Petechiae Cough Oropharyngeal pain Dyspnea Musculoskeletal pain Arthralgia Muscle spasms Dizziness Headache Peripheral neuropathy Decreased appetite

Metabolism and nutrition disorders Neoplasms benign, malignant, Second malignancies* unspecified Injury, poisoning and Laceration procedural complications Psychiatric disorders Anxiety Insomnia Vascular disorders Hypertension *One patient death due to histiocytic sarcoma.

All Grades (%) 63 23 21 21 19 15 13

Grade 3 or 4 (%) 4 2 2 0 2 0 0

48 21 17 10 10 31 25 23 13 13 54 27 17 19 15 10 27 23 19 21 19 10 17

2 6 6 8 0 4 2 0 4 0 2 0 0 0 0 0 6 0 2 0 2 0 2

10*

10 10 17

0 0 8

IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) 71 10 54 27 44 0

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2. Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Vomiting General disorders and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue disorders Rash* Petechiae Bruising* Musculoskeletal and connective tissue disorders Musculoskeletal Pain* Arthralgia Nervous system disorders Headache Dizziness Injury, poisoning and procedural complications Contusion Eye disorders Vision blurred

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%)

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%)

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

28 17

2 1

18 7

1 0

14 11

1 0

6 5

0 0

Subjects with multiple events for a given ADR term are counted once only for each ADR term. The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%) 51 23 52 5 36 0

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%) 57 26 45 10 21 0

* Based on laboratory measurements per IWCLL criteria DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in full Prescribing Information]. Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions]. • Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. • Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration. Active ingredient made in China. Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics, Inc. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 PRC-00526 07/14

The ASCO Post | JANUARY 25, 2015

PAGE 84

San Antonio Breast Cancer Symposium Breast Cancer

Oncotype DX Ductal Carcinoma in Situ Score Reliably Predicts Tumor Recurrence By Alice Goodman

uctal carcinoma in situ, which accounts for 30% of all newly diagnosed breast cancers, does not always evolve into a lesion with metastatic potential. Only a proportion of these cases will progress to invasive breast cancer, but up until recently, it has not been possible to identify reliably which patients require adjuvant radiation to prevent tumor recurrence in the breast following surgical excision. The Oncotype DX Ductal Carcinoma in Situ (DCIS) promises to fill that need. Similar to Oncotype DX in the adjuvant setting, Oncotype DX DCIS is a 12-panel gene test with a scoring system that categorizes cancers as low, intermediate, or high risk for local tumor recurrence over 10 years following treatment with breast-conserving surgery alone. A large population-based study presented at the 2014 San Antonio Breast Cancer Symposium validated the Oncotype DX DCIS in a diverse population of women with ductal carcinoma in situ.1 The current study is important, because the E5194 study that showed Oncotype DX DCIS was predictive of local tumor recurrence was based on a select population of women. “Our results confirm the E5194 results in a more diverse

population,” explained lead author Eileen Rakovitch, MD, of Sunnybrook Health Sciences Centre, University of Toronto, Canada. “This is the first multigene biomarker assay to provide individualized estimates of the risk of local tumor recurrence in women treated by breast conservation alone. The DCIS Score can be used for discussions between patients and physicians to

DCIS Score of less than 39 indicates a low risk for tumor recurrence, a DCIS Score of 39 to 54 indicates an intermediate risk for tumor recurrence, and a DCIS Score of 55 or higher indicates a high risk for tumor recurrence.

Predicting Tumor Recurrence A population-based study was undertaken to validate the score in women diagnosed with pure ductal

The Oncotype DX DCIS improves risk stratification and provides individualized estimates of risk, which will help clinicians and patients better understand the risk of tumor recurrence. —Eileen Rakovitch, MD

decide upon a course of further treatment. It is hoped that this will improve individualized management of ductal carcinoma in situ and reduce overtreatment of women at low risk of recurrence and undertreatment of women at higher risk of recurrence,” Dr. Rakovitch stated. The Oncotype DX DCIS is expressed in variables from 0 to 100. A

carcinoma in situ and treated with breast-conserving surgery alone in Ontario, Canada. Of 1,658 cases that met these criteria, tissue blocks were available for 858, and 257 were excluded, leaving a study cohort of 571 individuals. At a median follow-up of 9.6 years, 101 cases of local tumor recurrence were identified (57, invasive; 44, ductal carcinoma in situ).

When the DCIS Score was used retrospectively, the 10-year risk of local tumor recurrence was estimated at 13% for low-risk patients, 28% for intermediate-risk patients, and 33% for high-risk patients. The DCIS Score also predicted invasive tumor recurrence and ductal carcinoma in situ recurrence, she said. “Comparing the Ontario cohort with the more highly selected E5194 cohort, outcomes were remarkably similar,” Dr. Rakovitch said. “The Oncotype DX DCIS improves risk stratification and provides individualized estimates of risk, which will help clinicians and patients better understand the risk of tumor recurrence, and individuals can weigh their own risk in making treatment decisions.” n

Disclosure: Dr. Rakovitch is the principal investigator for this study, and her institution received research funding from Genomic Health Inc.

Reference 1. Rakovitch E, Nofech-Mozes S, Hanna W, et al: A large prospectively designed study of the DCIS score: Predicting recurrence risk after local excision for ductal carcinoma in situ patients with and without irradiation. 2014 San Antonio Breast Cancer Symposium. Abstract S5-04. Presented December 12, 2014.

EXPERT POINT OF VIEW

ommenting on this study, Benjamin O. Anderson, MD, Director of the Breast Health Clinic, Seattle Cancer Care Alliance, Washington, said: “This new analysis of the Oncotype DX DCIS assay strength-

and high-recurrence risk subgroups of patients treated with complete surgical excision without radiotherapy. In this Canadian cohort, low-score patients treated by complete surgical excision alone had a recurrence rate

This new analysis of the Oncotype DX DCIS assay strengthens the findings of earlier studies performed in more limited subgroups. —Benjamin O. Anderson, MD

ens the findings of earlier studies performed in more limited subgroups, validating that the assay accurately segregates lower- from intermediate-

of 12.7% at 10 years.” Dr. Anderson pointed out that the assay does not directly assess the efficacy of radiation therapy for ductal

carcinoma in situ, since no patients in this cohort were radiated. “However, for patients who prefer to undergo lumpectomy alone for ductal carcinoma in situ and thereby avoid radiation treatment, the assay may provide reassurance for their choice if they feel reasonably comfortable with an 8% risk of developing invasive breast cancers at 10 years,” he stated.

Confusion Over DCIS “People get confused about ductal carcinoma in situ. It is not a cancer by strict definition but a precancerous lesion because it has not yet spread outside the milk duct and does not spread to other parts of the body at that early stage,” said C. Kent Osborne, MD, Director of the Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston.

“There have been many discussions about this, and some people want to remove the word ‘cancer’ from the classification. This study is one of the first steps we need to take to start backing off of treating patients at low risk of tumor recurrence. The next step is to integrate the DCIS Score with known risk factors such as age and family history,” he added. Dr. Osborne moderated a press conference where these data were discussed. He said that it is a “no-brainer” that the test would be reimbursed, because it can save money by not overtreating low-risk patients. “The assay only provides estimates of risk of tumor recurrence, but it gives no data on outcomes if patients are treated according to their risk level,” he noted. n Disclosure: Drs. Anderson and Osborne reported no potential conflicts of interst.

ASCOPost.com | JANUARY 25, 2015

PAGE 85

San Antonio Breast Cancer Symposium Breast Cancer

Nab-Paclitaxel Boosts Pathologic Complete Response in High-Risk Breast Cancer By Alice Goodman

ab-paclitaxel (Abraxane) achieved superior results compared with conventional solvent-based paclitaxel in patients with early-stage high-risk breast cancer in the large phase III GeparSepto trial from the German Breast Group (GBG).1 The study, presented at the 2014 San Antonio Breast Cancer Symposium, showed a clinically meaningful and statistically significant absolute 9% improvement in pathologic complete response with neoadjuvant nab-paclitaxel compared with conventional paclitaxel, both followed by epirubicin/cyclophosphamide. With strict criteria, pathologic complete response was 38% with nab-paclitaxel vs 29% with conventional paclitaxel (P < .01). Since pathologic complete response after neoadjuvant therapy is a surrogate marker for long-term efficacy, these results suggest that using nabpaclitaxel instead of conventional paclitaxel may improve outcomes. “This head-to-head comparison of weekly nab-paclitaxel vs conventional paclitaxel followed by epirubicin/cyclophosphamide showed superiority of

Michael Untch, MD

nab-paclitaxel in achieving pathologic complete response in early-stage highrisk breast cancer,” said lead author Michael Untch, MD, Chief Physician at Helios Hospital Berlin-Buch, Berlin. “Long-term follow-up will be needed to determine the effect on outcomes.”

Triple-Negative Disease Subgroup analysis of pathologic complete response showed a consistent and significant benefit in favor of

nab-paclitaxel, irrespective of biologic subtypes. The effect of nab-paclitaxel was especially robust in triple-negative breast cancer in this trial, with an almost doubling of pathologic complete response in this specific high-risk subtype (48% vs 25%). Triple-negative disease was a major driver,” he said. “The odds ratio for pathologic complete response in favor of nab-paclitaxel was 1.53, which was even better than expected. In triplenegative breast cancer, the odds ratio was 2.69,” Dr. Untch told listeners. The finding in triple-negative breast cancer is especially important, as pathologic complete response is thought to be the most prognostic for outcome in this subtype, which comprises about 15% of all breast cancers.

EXPERT POINT OF VIEW

ommenting on the GeparSepto study presented at the San Antonio Breast Cancer Symposium, Lajos Pusztai, MD, Yale University School of Medicine, New Haven, Connecticut, said, “This study, along with a smaller SWOG study, establishes nab-paclitaxel as a legitimate treatment option for triple-negative breast cancer in the neoadjuvant/adjuvant setting.” “Although more peripheral neuropathy was seen with nab-paclitaxel, it is a classic conundrum for oncologists that more effective cancer therapies are also frequently more toxic,” he noted.

This study, along with a smaller SWOG study, establishes nabpaclitaxel as a legitimate option for triple-negative breast cancer in the neoadjuvant/adjuvant setting.

Study Details Nab-paclitaxel is engineered to encapsulate paclitaxel in near nanoseized albumin protein shells. This formulation enables delivery of higher dose intensity to the tumor bed compared with conventional paclitaxel, with similar tolerability. Studies have shown that this drug is superior to standard paclitaxel in the metastatic setting.2,3 More than 1,200 patients were treated with four cycles of chemotherapy on two different schedules: nab-paclitaxel for 12 weeks or conventional paclitaxel. In a window-of-opportunity study, patients with HER2-positive tumors (n = 71) received 6 weeks of pertuzumab (Perjeta) vs trastuzumab (Herceptin) or both drugs instead of conventional chemotherapy. To enter the trial, patients could have unilateral or bilateral or operable or inoperable breast cancer. Tissue samples were obtained for central testing of HER2, hormone receptor status, Ki67, and SPARC testing. Demographic and disease characteristics were well balanced for the two arms of the trial. The median age was 50 years, the

GeparSepto Trial Results With Nab-Paclitaxel ■■ In early-stage high-risk breast cancer, nab-paclitaxel achieved superior pathologic complete response rates compared with conventional solventbased paclitaxel. All patients received epirubicin/cyclophosphamide, except for a small cohort of HER2-positive patients. ■■ The benefit of nab-paclitaxel on pathologic complete response was especially evident in triple-negative breast cancer. ■■ Longer follow-up is needed to determine whether superior pathologic complete response translates to improved outcomes.

—Lajos Pusztai, MD

When making individual treatment decisions, Dr. Pusztai said there are two concerns: Should you trade more toxicity for greater efficacy, or should you use nab-paclitaxel at a lower dose? In this instance, lowering the dose may provide a reasonable alternative, he said. Dr. Pusztai is coauthor of a SWOG study, also presented at SABCS this year, showing that a lower dose of nab-paclitaxel (100 mg/m2 weekly) has fewer side effects while its efficacy seems to be preserved.1 “Also, peripheral neuropathy is cumulative. This toxicity and others can be managed by dose reduction of nab-paclitaxel,” he stated. n Disclosure: Dr. Pusztai reported no potential conflicts of interest.

Reference 1. Nahleh ZA, et al: 2014 San Antonio Breast Cancer Symposium. Poster P3-1116. Presented December 11, 2014.

median tumor size was 3 cm, two-thirds of patients were HER2-negative, and about 20% of patients were Ki67-positive.

A Glimpse at Toxicity Therapy as planned was possible in 79% of the nab-paclitaxel group and 86% of the paclitaxel group. No major differences in hematologic toxicities were observed between the two arms, with the exception of more neutropenia in the nab-paclitaxel arm. Febrile neutropenia was reported in about 4% of both arms. Sensory peripheral neuropathy was also increased in the nab-paclitaxel arm. Since this was a late-breaking abstract, the recovery from peripheral neuropathy had not yet been analyzed. “The literature suggests that peripheral neuropathy resolves more quickly after nab-paclitaxel compared to paclitaxel,” Dr. Untch noted.

“This study met the primary endpoint of increased pathologic complete response, and the effect of nab-paclitaxel was seen across all subgroups, especially triple-negative breast cancer. Longer term follow-up is needed to see whether increased pathologic complete response translates to improved overall survival,” he said. “It is possible that lower doses could reduce peripheral neuropathy.” n

Disclosure: This study was sponsored by Roche and Celgene. Dr. Untch reported no potential conflicts of interest.

References 1. Untch M, et al: 2014 San Antonio Breast Cancer Symposium. Abstract S2-07. Presented December 10, 2014. 2. Gradishar WJ, et al: J Clin Oncol 27:3611-3619, 2009. 3. Gradishar WJ, et al: J Clin Oncol 23:7794-7803, 2005.

XOFIGO® IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

Give your patient’s standard EARLIEST ONSET OF SYMPTOMSa

30%

BEST STANDARD OF CARE

• In ALSYMPCA, best standard of care was defined as local EBRT, treatment with glucocorticoids, ketoconazole, or antihormonal agents2 • Xofigo is not recommended in combination with chemotherapy1

REDUCED RISK OF DEATH vs PLACEBO PLUS BEST STANDARD OF CARE1

START NOW

WITH 6 INJECTIONS OF

EBRT=external beam radiation therapy; OTC=over-the-counter. Not an actual doctor. Model used for illustrative purposes only. a

In the ALSYMPCA trial, symptomatic was defined as regular analgesic use, including OTC, or use of EBRT to treat bone pain.

Important Safety Information • Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

Monitor patients with evidence of compromised bone • Bone Marrow Suppression: In the randomized trial, marrow reserve closely and provide supportive care 2% of patients in the Xofigo arm experienced bone measures when clinically indicated. Discontinue Xofigo marrow failure or ongoing pancytopenia, compared to in patients who experience life-threatening complications no patients treated with placebo. There were two deaths despite supportive care for bone marrow failure due to bone marrow failure. For 7 of 13 patients treated • Hematological Evaluation: Monitor blood counts at with Xofigo bone marrow failure was ongoing at the time baseline and prior to every dose of Xofigo. Prior to first of death. Among the 13 patients who experienced bone administering Xofigo, the absolute neutrophil count (ANC) marrow failure, 54% required blood transfusions. Four should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, percent (4%) of patients in the Xofigo arm and 2% in and hemoglobin ≥10 g/dL. Prior to subsequent the placebo arm permanently discontinued therapy due administrations, the ANC should be ≥1 × 109/L and to bone marrow suppression. In the randomized trial, the platelet count ≥50 × 109/L. Discontinue Xofigo if deaths related to vascular hemorrhage in association hematologic values do not recover within 6 to 8 weeks with myelosuppression were observed in 1% of Xofigoafter the last administration despite receiving treated patients compared to 0.3% of patients treated with supportive care placebo. The incidence of infection-related deaths (2%), • Concomitant Use With Chemotherapy: Safety and efficacy serious infections (10%), and febrile neutropenia (<1%) of concomitant chemotherapy with Xofigo have not been was similar for patients treated with Xofigo and placebo. established. Outside of a clinical trial, concomitant use Myelosuppression—notably thrombocytopenia,

PP-600-US-0474

09/14

Printed in USA

of care a survival boost

Median Overall Survival (OS) Was Extended1b 100

Xofigoc (n=614) Placeboc (n=307)

Probability of survival (%)

HR=0.695 (95% CI: 0.581-0.832)

Xofigo median OS: 14.9 months (95% CI: 13.9-16.1)

70 60

THE XOFIGO BOOST

3.6 month increase in

50 40

median overall survival1

Placebo median OS: 11.3 months (95% CI: 10.4-12.8)

30 20 10 0

Xofigo 614 Placebo 307

578 288

504 228

369 157

277 104

178 67

105 39

60 24

41 14

18 7

7 4

1 2

0 1

0 0

Time (months)

An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1 c Plus best standard of care.1

• In a prespecified interim analysis, median overall survival was 14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1 — P=0.00185; 95% CI: 0.552-0.875; HR=0.6951

of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations • Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated

patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see following pages for brief summary of full Prescribing Information.

To learn more, visit www.xofigo-us.com

Xoﬁgo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE Because clinical trials are conducted under widely varying conditions, adverse reaction rates Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of symptomatic bone metastases and no known visceral metastatic disease. another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with 2 DOSAGE AND ADMINISTRATION bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) 2.3 Instructions for Use/Handling of Xofigo and best standard of care and 301 patients received placebo and best standard of care General warning once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, organization. vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% Xofigo should be handled by the user in a manner which satisfies both radiation safety and of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, Treatment discontinuations due to adverse events occurred in 17% of patients who received caregivers and patient’s household members) from radiation or contamination from spills of bodily Xofigo and 21% of patients who received placebo. The most common hematologic laboratory fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). accordance with national and local regulations. Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal Xofigo exceeds the incidence for placebo. precautions for handling and administration such as gloves and barrier gowns when handling Table 3: Adverse Reactions in the Randomized Trial blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected System/Organ Class Xofigo (n=600) Placebo (n=301) area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 safety officer should be contacted immediately to initiate the necessary measurements and required % % % % procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamineBlood and lymphatic system disorders tetraacetic acid (EDTA) solution is recommended to remove contamination. Pancytopenia 2 1 0 0 For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times Gastrointestinal disorders after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect Nausea 36 2 35 2 caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly Diarrhea 25 2 15 2 and separately from other clothing. 19 2 14 2 Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. Vomiting The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. General disorders and administration site conditions The external radiation exposure associated with handling of patient doses is expected to be low, Peripheral edema 13 2 10 1 because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is Renal and urinary disorders recommended to minimize the time spent in radiation areas, to maximize the distance to radiation Renal failure and impairment 3 1 1 1 sources, and to use adequate shielding. Any unused product or materials used in connection with Laboratory Abnormalities the preparation or administration are to be treated as radioactive waste and should be disposed of Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which in accordance with local regulations. the incidence for Xofigo exceeds the incidence for placebo. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Table 4: Hematologic Laboratory Abnormalities 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

Hematologic Laboratory Abnormalities

Xofigo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel. Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo. Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. 3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹ CHANNELÂŹ blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XoďŹ go. 8.3 Nursing Mothers XoďŹ go is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from XoďŹ go, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efďŹ cacy of XoďŹ go in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with XoďŹ go in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ RADIUM ÂŹ ISÂŹ neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data. 8.7 Patients with Renal Impairment No dedicated renal impairment trial for XoďŹ go has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)]. 8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with XoďŹ go. Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies. There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGO ÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGO ÂŹ &OLLOWÂŹ good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily ďŹ&#x201A;uids to avoid contamination. When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹPOTENTIALÂŹ to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. ÂŠ 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: 05/2013 "3

The ASCO Post | JANUARY 25, 2015

PAGE 90

San Antonio Breast Cancer Symposium Breast Cancer

Ultrasonography Detects Mammographically Occult Invasive Cancers By Alice Goodman

ammograms often miss occult breast cancers concealed in dense breasts. Women with dense breasts represent about 40% to 50% of women who undergo mammography screening. In some states and centers in the United States, women with dense breasts are routinely offered ultrasonography following a negative mammography, and four states have laws including a phrase regarding the availability of “supplemental screening options, that may include ultrasound or magnetic

Data from 4 years of screening ultrasound were retrospectively reviewed, after Connecticut passed the first law that mandated informing patients whether or not they have dense breast tissue on mammogram and that mammography may miss some cancers. “We may need a new paradigm for screening. We have to deal with risk assessment in a simpler way. Low-risk women with no dense breast tissue should get mammography beginning at age 40. Women with a 25% or greater

We found all types and grades of breast cancers. They are exactly the kinds of cancers we hope to find on mammography, but it took ultrasonography to find them. —Jean M. Weigert, MD

There are no published head-tohead studies comparing supplemental screening ultrasonography vs digital tomosynthesis. Both technologies increase the rate of cancer detection, but the false-positive rate is about four times greater with ultrasound than with mammography and 30% to 40% lower with tomosynthesis. —Jafi A. Lipson, MD

resonance imaging [MRI]” for these women. Laws enacted in 19 states require that radiologists notify patients of their breast density in the “lay letter” that provides screening mammography results. Moreover, four states have mandatory insurance coverage of supplemental breast ultrasound screening, although two of those four states do not yet have notification laws. A large, retrospective, “real-world” study from five different radiology sites that are part of the Hospital of Central Connecticut confirmed that screening breast ultrasonography detects occult malignancy in women with dense breasts and that these cancers were not detected by mammography.1 Women with dense breasts were offered ultrasonography after negative mammography screening.

risk of breast cancer should get mammography and magnetic resonance imaging (MRI). Middle-of-the-road women with dense breast tissue and maybe one or two family members with breast cancer should be offered screening mammography and ultrasonography for early detection of breast cancer,”

said lead author Jean M. Weigert, MD, of the Hospitals of Central Connecticut, New Britain, Connecticut. Noting that digital tomosynthesis could be a big improvement over ultrasonography for detecting occult cancers, she said it would not be readily available to a majority of women for a number of years. “I’m from the real world, where everyone has ultrasound.”

Positive Predictive Value Increased Over Time About 31,000 mammograms were performed each year, and about 3,000 ultrasonographic exams were performed each year in women with dense breasts. The numbers of cancers detected per 1,000 women remained constant throughout the study. In year 1, 2,706 women underwent breast ultrasonography for dense breasts, and 11 cancers were detected. In year 4, 3,331 women were offered ultrasonography, and 11 cancers were detected. “Over time and with experience, we were able to identify lesions that needed to be biopsied,” said Dr. Weigert. Since false-positives are a downside of both mammography and ultrasonography, this is good news, she said, in an interview with The ASCO Post. When she reviewed the first 2 years and the last 2 years separately, the numbers of biopsies dropped with experience, yet the cancer detection rate remained the same. “We found all types and grades of cancers, including lobular, invasive ductal, combined ductal carcinoma in situ and lobular, ductal carcinoma in situ, and also atypical hyperplasia, which is a risk factor for breast cancer. They were predominantly estrogen receptor–positive and progesterone receptor–positive breast cancers in these women, with very few risk factors other than dense breast tissue. They are exactly the kinds of cancers we hope to find on mammography, but it took ultrasonography

Detecting Occult Invasive Breast Cancers With Ultrasonography ■■ Ultrasonography is a widely available screening modality that can detect occult invasive breast cancers not found on mammography in women with dense breasts. ■■ With experience, it is possible to reduce the rate of false-positive results with ultrasonography, which require unnecessary biopsy. ■■ Digital tomosynthesis can identify cancers in dense breasts and has a much lower false-positive rate than ultrasonography, but this technique is available only at a few centers, whereas ultrasonography is widely available.

to find them,” she stated. Because many of the same patients were coming in for yearly screening, the cancers detected in year 4 were smaller, she added. By year 4, most of the detected lesions were smaller than 1 cm, with no sentinel lymph node involvement. Although ultrasonography would add to the cost of screening, “there is no free lunch,” Dr. Weigert said. “Finding a cancer that is easier to treat would certainly have the potential to reduce costs of treating a more advanced cancer,” she stated.

Academic Center Perspective Discussant of this study, Jafi A. Lipson, MD, of Stanford University School of Medicine, Palo Alto, California, reviewed Dr. W eigert’s study from the perspective of experience at a radiology center with the latest technology—digital tomosynthesis (threedimensional digital mammography)— which is currently not widely available in community centers. “Density is a qualitative assessment that we make on the basis of a mammogram. There are four types of density, and density is an independent risk factor for breast cancer,” she said. “Density reduces the sensitivity of mammography and masks cancers, driving the search for a better modality to detect these cancers.” Breast cancer advocacy groups have been working toward having radiologists report breast density as part of screening information, and 20 states now have notification laws. Insurance coverage for supplemental screening of dense breasts is mandated in four states in the United States, and federal legislation is pending, Dr. Lipson said. Supplemental screening options include MRI for women who have more than a 25% lifetime risk of developing breast cancer, digital tomosynthesis, and ultrasonography. “All of these modalities have a range of benefits and harms. The benefit-to-harm ratio is determined by the prior probability of disease and the value placed on increased cancer detection given the risk of falsepositive exams,” she said. Dr. Lipson agreed that ultrasonography can detect mammographically occult cancers, but she had several issues with this study. “Because of the lack of a control group and no long-term follow-up, the true clinical impact of finding these cancers is unknown. It is not

when it’s time for

first-line Cll treAtment

indication GAZYVA® (obinutuzumab), in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). Boxed WArninGs: HePAtitis B VirUs reACtiVAtiOn AnD PrOGressiVe MUltifOCAl leUKOenCePHAlOPAtHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation Progressive Multifocal leukoencephalopathy (PMl) including fatal PMl, can occur in patients • receiving GAZYVA

For the first-line treatment of CLL in combination with chlorambucil1 ®

stArt with GAZYVA

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) include obinutuzumab (GAZYVA®) + chlorambucil as a preferred first-line regimen for CLL patients with comorbidities, without del(17p) 2,a,b a

NCCN treatment suggestions for patients with del(17p) are not segmented by age or comorbidities. Obinutuzumab (GAZYVA) + chlorambucil is included as a suggested treatment for this patient population. Suggested treatment regimens are listed in alphabetical order. Obinutuzumab (GAZYVA) + chlorambucil is listed first as a suggested treatment regimen for this patient population. Treatment regimens are listed in order of preference. Note: All recommendations are category 2A unless otherwise indicated.

iMPOrtAnt sAfetY infOrMAtiOn Hepatitis B Virus reactivation

• Hepatitis B virus (HBV) reactivation, in some cases

•

resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies including GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive) HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level, or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death

• Screen all patients for HBV infection by measuring HBsAg

• •

and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation

neArLY A 1-YeAr imProVement in meDiAn Pfs (23.0 months Vs 11.1 months; hr=0.16; 95% Ci, 0.11-0.24; P<0.0001)1 siGnifiCAntlY sUPeriOr Pfs: GAZYVA in combination with Clb more than doubled median Pfs vs Clb monotherapy1 1.0 Hr=0.16; 95% CI, 0.11-0.24; P<0.0001

0.9 0.8

84% risk reduction

0.7

Pfs

0.6 0.5 0.4 0.3

11.1

0.2 GAZYVA + chlorambucil (n=238) Chlorambucil (n=118)

0.1

23.0

0.0

GAZYVA + chlorambucil Chlorambucil

0 n at risk

time (months)

238

208

201

146

111

118

PFS, progression-free survival; Clb, chlorambucil; HR, hazard ratio; CI, confidence interval. Cll-11 trial Design1: GAZYVA, in combination with chlorambucil, was evaluated in a Phase III, open-label, multicenter, 3-arm, randomized, parallel-group comparative study in patients with previously untreated CD20+ chronic lymphocytic leukemia and coexisting medical conditions and/or reduced renal function. Patients with creatinine clearance <30 mL/min or inadequate liver function were excluded. The primary endpoint was progression-free survival. Overall response rate and complete response rate were secondary endpoints.

enhanced response rates1 • GAZYVA + Clb more than doubled response rates vs Clb monotherapy (75.9% vs 32.1%, respectively) • More than 1 in 4 patients receiving GAZYVA + Clb achieved a complete response (27.8% vs 0.9%, respectively) the most common Grade 3-4 adverse reactions were infusion reactions, neutropenia, and thrombocytopenia1 • The most common adverse reactions were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders

iMPOrtAnt sAfetY infOrMAtiOn (COnt’D) Progressive Multifocal leukoencephalopathy (PMl)

wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new • Premedicate patients with acetaminophen, antihistamine, onset or changes to preexisting neurologic manifestations. and a glucocorticoid. Institute medical management Evaluation of PML includes, but is not limited to, for infusion reactions as needed. Closely monitor patients consultation with a neurologist, brain MRI, and lumbar during the entire infusion. Infusion reactions within 24 puncture. Discontinue GAZYVA therapy and consider hours of receiving GAZYVA have occurred discontinuation or reduction of any concomitant • For patients with any Grade 4 infusion reactions, including chemotherapy or immunosuppressive therapy in patients but not limited to anaphylaxis, acute life-threatening who develop PML respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently infusion reactions discontinue GAZYVA therapy • GAZYVA can cause severe and life-threatening infusion reactions. Two-thirds of patients experienced a reaction to the first 1000 mgs infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (eg, bronchospasm, larynx and throat irritation,

• JC virus infection resulting in PML, which can be fatal, was

Please see the following pages for additional important safety information and brief summary of full Prescribing information, including Boxed WArninGs.

iMPOrtAnt sAfetY infOrMAtiOn (COnt’D) infusion reactions (cont’d)

• For patients with Grade 1, 2, or 3 infusion reactions: •

Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to and during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their hypertensive medication

thrombocytopenia (cont’d)

Fatal hemorrhagic events during Cycle 1 have also been reported. Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (ie, platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle

immunization

• The safety and efficacy of immunization with live or

attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery

tumor lysis syndrome (tls)

• Acute renal failure, hyperkalemia, hypocalcemia,

hyperuricemia, and/or hyperphosphatemia from TLS can occur within 12-24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (>25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12-24 hours prior to the infusion of GAZYVA. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis, as indicated

Pregnancy: Category C

• Women of childbearing potential should use effective

contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Geriatric Use

• Two hundred and forty previously untreated CLL patients

received GAZYVA in combination with chlorambucil. Of the 109 patients ≥75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients <75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) experienced an adverse event leading to death. Similar rates were observed in the comparator arm

infections

• Serious bacterial, fungal, and new or reactivated viral

infections can occur during and following GAZYVA therapy. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection

neutropenia

• GAZYVA, in combination with chlorambucil, caused Grade

• •

3 or 4 neutropenia in 34% of patients. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days) Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered

thrombocytopenia

• GAZYVA, in combination with chlorambucil, caused Grade 3 or 4 thrombocytopenia in 11% of patients in the trial. In 5% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion.

Visit GAZYVA.com for more information

Additional important safety information

• The most common adverse reactions (≥10%) were: infusion •

reactions (69%), neutropenia (40%), thrombocytopenia (15%), anemia (12%), pyrexia (10%), cough (10%), and musculoskeletal disorders (17%) Grade 3/4 adverse reactions were: infusion reactions (21%), neutropenia (34%), thrombocytopenia (11%), anemia (4%), leukopenia (5%), and pyrexia (<1%)

You are encouraged to report side effects to Genentech and the fDA. You may contact Genentech by calling 1-888-835-2555. You may contact the fDA by visiting www.fda.gov/medwatch, or calling 1-800-fDA-1088. references: 1. GAZYVA full Prescribing information. south san francisco, CA: Genentech UsA, inc.; June 2014. 2. referenced with permission from the nCCn Clinical Practice Guidelines in oncology (nCCn Guidelines®) for non-hodgkin’s Lymphomas V.1.2014. © national Comprehensive Cancer network, inc. 2014. All rights reserved. Accessed march 31, 2014. to view the most recent and complete version of the guideline, go online to www. nccn.org. nAtionAL ComPrehensiVe CAnCer networK®, nCCn®, nCCn GUiDeLines®, and all other nCCn Content are trademarks owned by the national Comprehensive Cancer network, inc.

Please see the following pages for brief summary of full Prescribing information, including Boxed WArninGs.

ASCOPost.com | JANUARY 25, 2015

PAGE 91

San Antonio Breast Cancer Symposium known if these cancers would have been detected by the next mammography screening. Also, the impact on mortality is unknown.” Turning to the harms of screening, she said that ultrasonography has a much higher rate of false-positives than mammography and digital tomosynthesis. “Many more biopsies are gener-

ated by screening ultrasonography than mammography, and most are false-positives,” she stated.

Cost Considerations A recent study found that 4 breast cancer deaths would be averted for every 10,000 women screened by ultrasonography and that 1.7 quality-adjusted

GAZYVA® (obinutuzumab) Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information. WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)]. • Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy. In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation. 5.2 Progressive Multifocal Leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to pre-existing neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two-thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

life years would be gained with ultrasonographic screening of women with dense breasts.2 Ultrasonography would lead to 354 biopsies for false-positive results per 1,000 women compared with mammography. The cost per year of quality-adjusted life years gained would be $325,000, and assuming a threshold of $50,000 to $60,000 per

Premedicate patients with acetaminophen, anti-histamine, and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)]. For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy. For patients with Grade 1, 2, or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)]. For patients with pre-existing cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their hypertensive medication as is suggested here. 5.4 Tumor Lysis Syndrome Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function, and fluid balance, and administer supportive care, including dialysis as indicated.

quality-adjusted life year, would not be considered cost-effective, she noted. When only women with extremely dense breasts were considered, the cost per quality-adjusted life year gained would be $246,000, which is still unacceptable. “These authors concluded that ulcontinued on page 92

• Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)] The most common adverse reactions (incidence ≥ 10%) were: infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in Tables 3 and 4 below are based on a total of 356 previously untreated patients with CLL during treatment with GAZYVA in combination with chlorambucil or with chlorambucil alone. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 45 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA based therapy. Table 3 Summary of Adverse Reactions Reported with ≥ 5% Incidence and ≥ 2% Greater in the GAZYVA Treated Arm

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days). Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered. 5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 11% of patients in the trial. In 5% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA. Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle. 5.8 Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)]

Chlorambucil n = 116

All Grades All Grades Grades % 3–4b % Grades % 3–4b % Injury, Poisoning and Procedural Complications Infusion related reactions

Blood and lymphatic system disordersc

5.5 Infections Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection. 5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 34% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

GAZYVA + Chlorambucil n = 240

Adverse Reactions (MedDRAa) System Organ Class

Neutropenia

Thrombocytopenia

16 3

Anemia

Leukopenia

General disorders and administration site conditions Pyrexia

Respiratory, thoracic and mediastinal disorders Cough

a MedDRA coded adverse reactions as reported by investigators. b c

No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms. Adverse events reported under ‘Blood and lymphatic system disorders’ reflect those reported by investigator as clinically significant. Table 4 Post-Baseline Laboratory Abnormalities by CTCAE Grade with ≥ 5% Incidence and ≥ 2% Greater in the GAZYVA Treated Arm GAZYVA + Chlorambucil n = 240

Investigations

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia Lymphopenia Leukopenia Thrombocytopenia Chemistry Hypocalcemia Hyperkalemia Hyponatremia AST (SGOT increased) Creatinine increased ALT (SGPT increased) Hypoalbuminemia Alkaline Phosphatase increased Hypokalemia

77 80 84 47

46 40 36 14

53 9 12 50

27 2 <1 11

22 16

<1 0

14 11

<1 0

The ASCO Post | JANUARY 25, 2015

PAGE 92

San Antonio Breast Cancer Symposium Ultrasonography continued from page 91

trasonography substantially increases costs while producing only small benefits,” she stated.

Challenge of Filtering the Data “By contrast, digital tomosynthesis reduces false-positives by 15% to 30%

Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused. Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, anti-histamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and < 2% thereafter [see Dosage and Administration (2)]. Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm. Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3–4 and none were fatal. Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). The number of fatal hemorrhagic events was similar between the treatment arms, with 4 in the GAZYVA treated arm. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1. Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm. Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%). 6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. Neutralizing activity of anti-GAZYVA antibodies has not been assessed. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known. 6.3 Additional Clinical Trial Experience Progressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)]. Worsening of pre-existing cardiac conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

and increases cancer detection by 30% to 50%, according to multiple prospective national and international studies,”3 Dr. Lipson continued. Currently, there are no published head-to-head studies comparing supplemental screening ultrasonography vs digital tomosynthesis. Both technologies increase the rate of cancer detec-

Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth. 8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established. 8.5 Geriatric Use Of 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients < 75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)]. 8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) > 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr < 30 mL/min [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment. 10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy. 17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. • Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. • Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]. • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)]. • New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)]. Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6 and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)]. • Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

tion, but the false-positive rate is about four times greater with ultrasound than with mammography and 30% to 40% lower with tomosynthesis, she said. “It can be challenging for women and their physicians to filter all of this information. There are now multiple new screening technologies, with no long-term outcome data regarding their

GAZYVA® [obinutuzumab] Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

true clinical impact. Most states with notification laws do not have insurance for these tests,” she said. She directed listeners to www. breastdensity.info for more information on this issue. This website is not beholden to any commercial sponsor and is a joint effort created by a working group of breast radiologists and breast cancer risk specialists, representing academic and community-based practices across California, formed to assist patients, referring doctors, and radiologists in responding to new legislation mandating that radiologists report breast density to patients. n

Disclosure: Dr. Weigert is a consultant for Tractus Inc. Dr. Lipson reported no potential conflicts of interest.

References 1. Weigert JM: The Connecticut experiment: 4 years of screening women with dense breasts with bilateral ultrasound. 2014 San Antonio Breast Cancer Symposium. Abstract S5-01. Presented December 12, 2014. 2. Sprague BL, Stout NK, Schechter C, et al: Benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts. Ann Intern Med. December 9, 2014 (early release online). 3. Friedewald SM, Rafferty EA, Rose SL, et al: Breast cancer screening using tomosynthesis in combination with digital mammography. JAMA 311:2499-2507, 2014.

The ASCO Post

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Journal Spotlight Melanoma

Nivolumab Improves Outcomes vs Dacarbazine in Previously Untreated Advanced Melanoma Without a BRAF Mutation By Matthew Stenger

n a phase III trial reported in The New England Journal of Medicine, Robert and colleagues found that the programmed cell death protein-1 (PD-1) immune-checkpoint–inhibitor antibody nivolumab (Opdivo) significantly increased overall survival, progression-free survival, and objective response rate compared with dacarbazine in patients with previously untreated metastatic melanoma without a BRAF mutation.1 Victoria Atkinson, MD, of Princess Alexandra Hospital and Gallipoli Medical Research Foundation, Queensland, and Paolo A. Ascierto, MD, of Istituto Nazionale Tumori Fondazione Pascale, Naples, contributed equally to The New England Journal of Medicine article.

31% and 30%), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 70% and 58%, 1 in 29% and 40%), metastasis stage (M1c in 61% in both; M0, M1a, or M1b in 39% in both), lactate dehydrogenase (LDH) level (> upper limit of normal in 38% and 36%, > two times upper limit of normal in 10% and 11%), his-

The median overall survival was not reached in the nivolumab group vs 10.8 months (95% confidence interval [CI] = 9.3–12.1 months) in the dacarbazine group, and overall survival at 1 year was 72.9% (95% CI = 65.5%–78.9%) vs 42.1% (95% CI = 33.0%–50.9%), yielding a hazard ratio (HR) of 0.42 (99.79%

Nivolumab was associated with a significant improvement in overall survival and progression-free survival, as compared with dacarbazine, with a low risk of high-grade toxic effects.

Study Details In this double-blind trial, 418 patients from 80 centers in Europe, Israel, Australia, Canada, and South America with previously untreated stage III or IV melanoma without a BRAF mutation were randomized between January 2013 and February 2014 to receive nivolumab at 3 mg/kg every 3 weeks plus dacarbazineplacebo every 2 weeks (n = 210) or dacarbazine at 1,000 mg/m2 every 3 weeks plus nivolumab-placebo every 2 weeks (n = 208). Patients had to have availability of tumor tissue from a metastatic or unresectable site for programmed death ligand-1 (PD-L1) biomarker analysis. Patients could have received prior adjuvant therapy. Treatment was continued until disease progression or unacceptable toxicity; treatment after disease progression was permitted in patients with clinical benefit and no substantial adverse events from study treatment. The primary endpoint was overall survival. The nivolumab and dacarbazine groups were generally balanced for age (median, 64 and 66 years), sex (58% and 60% male), geographic region (Europe or Canada for 69% and 70%; Israel, Australia, or South America for

Survival Data

—Victoria Atkinson, MD, Paolo A. Ascierto, MD, and colleagues

tory of brain metastases (3% and 4%), positive PD-L1 status (35% and 36%), and prior systemic therapy (adjuvant in 15% and 17%, neoadjuvant in 0.5% in both).

Follow-up and Subsequent Treatment All randomized patients were followed for up to 16.7 months at the time of database lock, which occurred at 5.2 months after the first visit of the last randomized patient. After discontinuation of study treatment, 63 patients in the nivolumab group (30%) and 114 in the dacarbazine group (55%) received systemic therapy, including ipilimumab (Yervoy) in 45 (21% of all patients) and 79 (38% of all patients), respectively.

Nivolumab for Advanced Melanoma ■■ Nivolumab was associated with significantly prolonged overall survival, including among patients with positive and negative/indeterminate PD-L1 status. ■■ Nivolumab was associated with a significantly prolonged progression-free survival and a significantly higher objective response rate compared with dacarbazine.

CI = 0.25–0.73, P < .001). Overall survival was significantly improved with nivolumab among both patients with positive PD-L1 status (median not reached vs 12.4 months; unadjusted HR = 0.30; 95% CI = 0.15–0.60) and those with negative or indeterminate status (median not reached vs 10.2 months; unadjusted HR = 0.48; 95% CI = 0.32–0.71). The survival benefit with nivolumab was also observed across subgroups for age, sex, metastasis stage, ECOG performance status, history of brain metastases, baseline LDH level, and geographic region. The median progression-free survival was 5.1 vs 2.2 months (HR = 0.43, P < .001).

Response Rates Responses were evaluated according to RECIST version 1.1. Of note, 8% of patients in the nivolumab arm responded after the occurrence of new lesions and treatment beyond progression. These are “uncommon” responses, or responses assessed according to immune-related response criteria, noted Dr. Ascierto. This finding suggests that we should consider both RECIST and immune-related response criteria in the assessment of pa-

tients treated with nivolumab. The objective response rate was 40.0% vs 13.9% (odds ratio [OR] = 4.06, P < .001), including 52.7% vs 10.8% in patients with positive PD-L1 status and 33.1% vs 15.7% in patients with negative or indeterminate status. Complete response was observed in 7.6% vs 1.0% of patients. Among responding patients, the median duration of response was not reached vs 6.0 months. The median time to response was 2.1 months in both groups. Reduction of ≥ 30% in tumor burden in the target lesion was achieved or maintained in 17 of 54 nivolumab patients (31%) treated beyond disease progression, compared with 8 of 49 dacarbazine patients (16%) treated beyond disease progression.

Adverse Events The most common treatment-related adverse events of any grade in the nivolumab and dacarbazine groups were nausea (16.5% vs 41.5%), fatigue (19.9% vs 14.6%), pruritus (17.0% vs 5.4%), and diarrhea (16.0% vs 15.6%). Treatmentrelated grade 3 or 4 adverse events occurred in 11.7% vs 17.6%, with the most common being diarrhea in the nivolumab group (1% vs 0.5%) and thrombocytopenia (0% vs 4.9%) and neutropenia (0% vs 4.4%) in the dacarbazine group. Treatment-related serious adverse events occurred in 5.8% vs 5.9%, and adverse events led to discontinuation of study treatment in 6.8% vs 11.7%. No deaths were attributed to study drug toxicity. The study authors concluded: “[N]ivolumab was associated with a significant improvement in overall survival and progression-free survival, as compared with dacarbazine. Nivolu mab was associated with a low risk of high-grade toxic effects.” n

Disclosure: The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. November 6, 2014 (early release online).

See commentary by Michael A. Postow, MD, and Jedd D. Wolchok, MD, PhD, on page 94.

The ASCO Post | JANUARY 25, 2015

PAGE 94

Perspective Melanoma

Survival Benefits of Front-Line Treatment With Nivolumab for Advanced Melanoma Confirmed, Yet Questions Remain By Michael A. Postow, MD, and Jedd D. Wolchok, MD, PhD

s reported in this issue of The ASCO Post, Robert and colleagues recently published a phase III study comparing the anti–programmed death 1 (PD-1) antibody nivolumab with the standard melanoma chemotherapy dacarbazine in the front-line treatment of patients with advanced BRAF wild-type melanoma.1 In this study, nivolumab was shown to be superior to dacarbazine in improving overall survival, progression-free survival, and objective response rate. Nivolumab was also associated with a lower rate of highgrade side effects than dacarbazine. Of importance, this study is the first to demonstrate that nivolumab, and any anti–PD-1 antibody, improves overall survival compared with a standard comparator in a large, well-conducted, randomized, placebo-controlled phase III study. The high response rate and favorable toxicity profile of nivolumab and pembrolizumab (Keytruda), another anti–PD-1 antibody, in patients with melanoma have been well known from large, previously published, early-phase studies.2-5 Yet how these anti–PD-1 antibodies perform in randomized studies against standard chemotherapy (dacarbazine or carboplatin/paclitaxel) has only recently begun to emerge. As reported by Drs. Jeffrey Weber and Sandra D’Angelo at the 2014 European Society for Medical Oncology (ESMO) meeting, nivolumab demonstrated a superior response rate compared with chemotherapy for patients with melanoma that had progressed after treatment with ipilimumab (Yervoy).6 In a similar patient population, pembrolizumab resulted in improved progression-free survival compared with chemotherapy, as demonstrated by results presented by Dr. Antoni Ribas at the Society for Melanoma Research meeting.7 The overall survival effects of nivolumab and pembrolizumab for patients with ipilimumabrefractory melanoma in randomized studies are not yet known, but reDrs. Postow and Wolchok are medical oncologists at Memorial Sloan Kettering Cancer Center, New York.

sults are eagerly expected, once the length of follow-up is more mature. Nivolumab and pembrolizumab are believed to be similarly effective. The study by Robert and colleagues is the first formally reported randomized study of an anti–PD-1 agent in the front-line setting. The study involved only melanoma patients who did not have a BRAF mutation. We expect that the favorable results for nivolumab over dacarbazine would be similar in patients with BRAF-mutant melanoma. In other studies, both

to select patients for nivolumab. PDL1 expression can be heterogeneous, even within individual patients,10 further complicating ongoing research in this area.

Questions Remain Despite the tremendous advance this study provides for our patients with melanoma, several essential questions remain about the best use of nivolumab and other anti–PD-1 antibodies. First, whether nivolumab or pembrolizumab improves overall

We expect that therapeutic regimens containing an anti–PD-1 antibody may ultimately be the first treatment considered in patients with advanced melanoma. —Michael A. Postow, MD, and Jedd D. Wolchok, MD, PhD

nivolumab and pembrolizumab have demonstrated efficacy in patients with BRAF-mutant melanoma.2,6 Other immune checkpoint antibodies, such as ipilimumab, have similarly shown equal response rates in patients with melanoma, with and without BRAF mutations.8 Anti–PD-1 antibodies should be considered for patients regardless of their BRAF status. Expression of PD-L1, one of the ligands for PD-1, on tumor cells has been associated with favorable response rates in prior, early-phase studies of nivolumab.9 In this study, however, patients with tumors classified as PD-L1–negative/indeterminate also had improved overall survival with nivolumab compared with dacarbazine. PD-L1 was therefore not found to be a predictive biomarker for overall survival, and the results do not support using tumor PD-L1 status

survival compared with ipilimumab remains unknown. Second, combining nivolumab with ipilimumab has shown high response rates in patients with melanoma, but whether it will ultimately be preferable to administer nivolumab in combination with ipilimumab or in a particular sequence remains to be determined. An ongoing randomized phase III study (Checkmate 67) comparing nivolumab, ipilimumab, and the combination of both completed accrual earlier in 2014 and should help to address this question. Third, since PD-L1 as a single biomarker was not found to be predictive for overall survival with nivolumab, additional investigations into biomarkers that may be more predictive remain of great interest. It is possible that a model incorporating many immunologic factors, including the presence of infiltrating CD8-positive T cells in a tumor,

may better capture the complexities of the tumor microenvironment relevant to benefit with PD-1 blockade.11 The presence of mutations in the tumor that produce immunogenic neoantigens may also be important, as was recently found in patients treated with ipilimumab.12 Finally, we are encouraged by the low rate of toxicity of nivolumab in this study and the lack of cumulative side effects with it in other, longer-term studies.5 As treatment with nivolumab and other anti–PD-1 antibodies is continuous every several weeks, however, the optimal duration of treatment remains unknown. Many patients who respond to anti–PD-1 antibodies and discontinue treatment due to side effects continue to respond to treatment. We should investigate whether treatment can be safely discontinued in other patients, particularly to ease the logistical challenges many patients face and to be mindful of the current environment of escalating health-care costs. In summary, the expectation that nivolumab would improve overall survival based upon its high durable response rate was confirmed in a frontline phase III study compared with dacarbazine. As anti–PD-1 antibodies have already demonstrated superiority to dacarbazine in randomized studies of ipilimumab-refractory patients— and have now demonstrated success for the first time in a randomized, controlled, front-line setting—we expect that therapeutic regimens containing an anti–PD-1 antibody may ultimately be the first treatment considered in patients with advanced melanoma. n Disclosure: Dr. Postow has received a research grant from Bristol-Myers Squibb. Dr. Wolchok is a paid consultant and has received research funding from Bristol-Myers Squibb and Merck.

References 1. Robert C, Long GV, Brady B, et al: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. November 6, 2014 (early release online). 2. Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109-1117, 2014.

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In the Clinic

Lanreotide in Gastroenteropancreatic Neuroendocrine Tumors By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n December 16, 2014, lanreotide (Somatuline depot injection) was approved for the treatment of patients with unresectable, well or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors to improve progression-free survival.1,2

Supporting Study Approval of lanreotide was based on findings in an international doubleblind trial in which 204 patients with unresectable, well or moderately differentiated, locally advanced or metastatic, nonfunctioning gastroenteropancreatic neuroendocrine tumors were randomized to receive subcutaneous lanreotide (120 mg) or placebo every 28 days.2,3 Neuroendocrine tumors arose outside the pancreas in 55% of patients. Patients had a median age of 63 years (range, 30 to 92 years), 53% were male, 95% were white, 4.4% had disease progression in the 6 months prior to study enrollment, 14% had received prior chemotherapy, and 69% had grade 1 tumors; more pa-

OF NOTE Lanreotide carries warnings/precautions for gallstones, glucose metabolism (hypoglycemia and hyperglycemia), and cardiac function (decreased heart rate).

Michael A. Postow, MD Jedd D. Wolchok, MD, PhD continued from page 94

3. Hamid O, Robert C, Daud A, et al: Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134-144, 2013. 4. Weber JS, Kudchadkar RR, Yu B, et al: Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumabrefractory or -naive melanoma. J Clin Oncol 31:4311-4318, 2013. 5. Topalian SL, Sznol M, McDermott DF, et al: Survival, durable tumor remis-

tients in the lanreotide group had greater than 25% hepatic tumor involvement (39% vs 27%). Progression-free survival was significantly prolonged with lanreotide (median not reached vs 16.6 months, hazard ratio = 0.47, P < .001). The median progression-free survival in the lanreotide group exceeds 22 months.

How It Works Lanreotide is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin in inhibiting various endocrine, neuroendocrine, exocrine, and paracrine functions.

How It Is Given The recommended dose of lanreotide is 120 mg every 4 weeks by deep subcutaneous injection. Treatment

OF NOTE The mechanism of action of lanreotide, an octapeptide analog of natural somatostatin, is believed to be similar to that of natural somatostatin in inhibiting various endocrine, neuroendocrine, exocrine, and paracrine functions.

lized by CYP enzymes, due to suppression of growth hormone. Drugs mainly metabolized by CYP3A4 that have a low therapeutic index should be coadministered with caution. Lanreotide may cause a reduced heart rate and should be used with caution in at-risk patients.

Safety Profile In the supporting trial, the most common adverse events of any grade in the lanreotide group were abdominal pain (34% vs 24% in the placebo

Lanreotide for Locally Advanced or Metastatic Gastroenteropancreatic Neuroendocrine Tumors ■■ Lanreotide was approved for the treatment of patients with unresectable, well or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors. ■■ The recommended dose of lanreotide is 120 mg every 4 weeks by deep subcutaneous injection.

should continue until disease progression or unacceptable toxicity. There is no recommended dose adjustment for mild or moderate renal impairment. Data are insufficient to recommend a dose in patients with severe renal impairment or hepatic impairment of any severity. Somatostatin analogs may decrease metabolic clearance of drugs metabo-

sion, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020-1030, 2014. 6. Weber JS, Minor DD, D’Angelo, S, et al: A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS936558; ONO-4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy. 2014 ESMO Congress. Abstract LBA3. 7. Ribas A, Pzanov I, Dummer R, et al: A randomized controlled comparison of pembrolizumab and chemotherapy in pa-

group), musculoskeletal pain (19% vs 13%), vomiting (19% vs 9%), headache (16% vs 11%), injection-site reaction (15% vs 7%), hyperglycemia (14% vs 5%), hypertension (14% vs 5%), and cholelithiasis (14% vs 7%). The most common severe adverse events were abdominal pain (6% vs 4%), musculoskeletal pain (2% vs 2%), and vomiting (2% vs 2%). The most common serious ad-

tients with ipilimumab-refractory (IPI-R) melanoma (MEL). Society for Melanoma Research 2014 Congress. Presented November 16, 2014. 8. Shahabi V, Whitney G, Hamid O, et al: Assessment of association between BRAFV600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother 61:733-737, 2012. 9. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012. 10. Madore J, Vilain R, Menzies AM,

verse event was vomiting (4%). Treatment was discontinued due to adverse events in 5% of lanreotide patients and 3% of placebo patients. Lanreotide carries warnings/precautions for gallstones, glucose metabolism (hypoglycemia and hyperglycemia), and cardiac function (decreased heart rate). Periodic patient monitoring for gallstones should be considered. Glucose monitoring is recommended. n References 1. US FDA Press Release: Approved drugs. Lanreotide. Available at http://www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm427065.htm. Accessed January 7, 2015. 2. Somatuline depot (lanreotide) injection prescribing information, Ipsen Biopharmaceuticals, Inc, December 2014. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022074s011lbl. pdf. Accessed January 7, 2015. 3. Caplin ME, Pavel M, Ćwikła JB, et al: Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371:224-233, 2014.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

et al: PD-L1 expression in melanoma shows marked heterogeneity within and between patients: Implications for antiPD-1/PD-L1 clinical trials. Pigment Cell Melanoma Res. December 5, 2014 (early release online). 11. Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-571, 2014. 12. Snyder A, Makarov V, Merghoub T, et al: Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189-2199, 2014.

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PAGE 98

Journal Spotlight

Coupling Head and Neck Cancer Screening and Lung Cancer Scans Could Improve Early Detection, Survival

dding head and neck cancer screenings to recommended lung cancer screenings would likely improve early detection and survival, according to a multidisciplinary team led by scientists af-

filiated with the University of Pittsburgh Cancer Institute (UPCI), a partner with the University of Pittsburgh Medical Center (UPMC) Cancer Center. In an analysis published in the jour-

nal Cancer1 and funded by the National Institutes of Health (NIH), the team provided a rationale for a national clinical trial to assess the effectiveness of adding examination of the head and neck to

lung cancer screening programs. People most at risk for lung cancer are also those most at risk for head and neck cancer. “When caught early, the 5-year survival rate for head and neck cancer is

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Journal Spotlight

over 83%,” said senior author Brenda Diergaarde, PhD, Assistant Professor of Epidemiology at the University of Pittsburgh’s Graduate School of Public Health and a member of the UPCI. “However, the majority of cases are diagnosed later, when survival rates generally shrink to below 50%. There is a strong need to develop strategies that

will result in identification of the cancer when it can still be successfully treated.” Head and neck cancer is the world’s sixth most common type of cancer. Worldwide every year, 600,000 people are diagnosed with it and about 350,000 die. Tobacco use and alcohol consumption are the major risk factors for developing this type of cancer.

The early symptoms are typically a lump or sore in the mouth or throat, trouble swallowing, or a voice change, which are often brushed off as a cold or something that will heal. Treatment, particularly in later stages, can be disfiguring and can change the way a person talks or eats. Dr. Diergaarde and her team analyzed the records of 3,587 people en-

Patients at risk for lung cancer whom we would refer for the newly recommended annual screening are the same patients who our study shows also likely would benefit from regular head and neck cancer screenings. —David O. Wilson, MD, MPH, Brenda Diergaarde, Phd, and colleagues

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rolled in the Pittsburgh Lung Screening Study (PLuSS), which consists of current and ex-smokers aged 50 and older, to see if they had a higher chance of developing head and neck cancer. In the general U.S. population, fewer than 43 per 100,000 people would be expected to develop head and neck cancer annually among those 50 and older. Among the PLuSS participants, the rate was 71.4 cases annually per 100,000 people. Recently, the U.S. Preventive Services Task Force, as well as the American Cancer Society and several other organizations, recommended annual screening for lung cancer with low-dose computed tomography in people 55 to 74 years old with a smoking history averaging at least a pack a day for a total of 30 years. The recommendation came after a national clinical trial showed that such screening reduces lung cancer mortality. “Head and neck cancer is relatively rare, and screening the general population would be impractical,” said coauthor David O. Wilson, MD, MPH, Associate Director of UPMC’s Lung Cancer Center. “However, the patients at risk for lung cancer whom we would refer for the newly recommended annual screening are the same patients who our study shows also likely would benefit from regular head and neck cancer screenings. If such screening reduces mortality in these at-risk patients, that would be a convenient way to increase early detection and save lives.” Dr. Diergaarde’s team is collaborating with otolaryngologists to design a national trial that would determine if regular head and neck cancer screenings for people referred for lung cancer screenings would indeed reduce mortality. n Reference 1. Dixit R, Weissfeld JL, Wilson DO, et al: Incidence of head and neck squamous cell carcinoma among subjects at high risk of lung cancer: Results from the Pittsburgh Lung Screening Study. Cancer. January 5, 2015 (early release online).

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Perspective Thoracic Oncology

Crizotinib in ROS1-Positive NSCLC: A Next Step Forward By Jacek Jassem, MD, PhD, and Rafał Dziadziuszko, MD, PhD

dvances in the molecular characterization of non–small cell lung cancer (NSCLC) have led to the identification of molecularly defined distinct subsets of patients who derive benefit from targeted therapies. Currently, two such groups of agents have moved widely into clinical practice: epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors—erlotinib, gefitinib (Iressa), and afatinib (Gilotrif)—in patients with NSCLCs harboring activating mutations within the kinase domain of the EGFR gene; and crizotinib (Xalkori), an inhibitor of oncogenic anaplastic lymphoma kinase (ALK) in tumors with the rearranged ALK gene. In both subsets of patients, new therapeutics have proved more effective than standard chemotherapy and are currently considered treatments of choice. Further research on mechanisms of resistance to these agents is likely to lead to even larger clinical benefit of respective patient groups, as exemplified by the promising activity of third-generation EGFR inhibitors.

duration of response (17.6 months) were far above those seen with conventional chemotherapy, even though ROS1-rearranged tumors seem to be particularly sensitive to pemetrexed (Alimta).5 Similar results have been recently reported in the European Trial on Crizotinib in the ROS1 Translocated Lung Cancer (EUCROSS) study.6 Interestingly, crizotinib also seems to be more effective in ROS1,

The group of new potential therapeutic targets in NSCLC, particularly in adenocarcinoma, is growing, … and clinical trials assessing such targets are underway. These therapies provide new opportunities for treating NSCLC and will hopefully change the current grim landscape in this malignancy. —Jacek Jassem, MD, PhD, and Rafał Dziadziuszko, MD, PhD

ROS1 Rearrangement Identification of c-Ros 1 (ROS1) oncogene rearrangement was initially reported in glioblastomas, and the rearrangement was subsequently found in other tumor types, including NSCLC. The ROS1 gene is partially homologous to ALK, and is a potent oncogenic driver with a physiologic role in postnatal maturation of epididymis epithelium. As demonstrated by in vitro studies, crizotinib—an ALK inhibitor—may also inhibit ROS1 kinase. Activity of crizotinib in patients with tumors harboring ROS1 rearrangement has been heralded in case reports1-3 and has now been confirmed in a large clinical study reported by Shaw and colleagues4 and recently reviewed in The ASCO Post (December 15, 2014). The efficacy of crizotinib has proved to be unprecedented—both response rate (72%) and the estimated Dr. Jassem is Head of the Department of Oncology and Radiotherapy, Medical University of Gdańsk. Dr. Dziadziuszko is Assistant Professor in the Department of Oncology and Radiotherapy, Medical University of Gdańsk, Poland.

to “triple-negative” NSCLCs—ie, those that lack the three above-mentioned genetic abnormalities. Reverse transcriptase–polymerase chain reaction (RT-PCR) is also an option, but this method requires multiple primer sets and may miss rare rearrangements. Most recently, widely available and less-expensive immunohistochemistry staining has been shown to serve as a reliable method

compared to ALK fusion-positive tumors. Hence, ROS1-positive NSCLC represents a novel patient subset that derives apparent clinical benefit from crizotinib therapy. Fusion-positive ROS1 tumors constitute only around 1% to 2% of all NSCLC cases and occur almost exclusively in adenocarcinomas. However, they affect specifically a growing population of nonsmoking patients and may show aggressive clinical behavior.7,8

Diagnostic Process Similarly to ALK, ROS1 rearrangements are routinely indentified with break-apart fluorescence in situ hybridization (FISH), a cumbersome and relatively expensive method, and this may hamper the widespread diagnostic process. Despite similar clinicopathologic features, ROS1 rearrangements are mutually exclusive from KRAS and EGFR mutations and ALK rearrangements. Hence, to increase the yield, a search for ROS1 changes has been frequently confined

of screening for ALK and ROS1 rearrangements9,10 and, after standardization and validation, may possibly replace FISH as a routine primary assay. Next-generation sequencing of selected multi-oncogene panels is rapidly entering clinical application, with hopes of providing clinically relevant information on all targetable molecular aberrations, including ROS1 rearrangement, with acceptable turnover time.

Ongoing Research Although crizotinib provides impressive responses in ROS1 fusion– positive patients, most patients will eventually develop progression owing to the acquisition of resistant mutations in the kinase domain of ROS1 or activation of other signaling pathways. Ongoing research has identified specific molecular resistance mechanisms to ROS1 inhibitors and has led to the development of next-generation compounds, such as cabozantinib (Cometriq) and the investigational agent foretinib, which may overcome

the resistance.11,12 Other molecules, such as RXDX-101, which shares ALK, ROS1, and pan-TRK inhibitory activity, are being developed in earlyphase clinical trials exclusively in molecularly defined subsets of patients. In summary, we are witnessing an important step in the development of targeted therapies for NSCLC. Similarly to EGFR mutations and ALK rearrangements, ROS1 fusions constitute a driving oncogenic genetic alteration with rationally designed and effective targeted therapy. These three mutations combined account for about 20% of all NSCLCs. Furthermore, the group of new potential therapeutic targets in NSCLC, particularly in adenocarcinoma, is growing (eg, RET, MET, HER2, and BRAF), and clinical trials assessing such targets are underway. These therapies provide new opportunities for treating NSCLC and will hopefully change the current grim landscape in this malignancy. n

Disclosure: Dr. Jassem reported no potential conflicts of interest. Dr. Dziadziuszko is on the advisory boards of Pfizer, Novartis, and Clovis.

References 1. Bergethon K, Shaw AT, Ou SH, et al: J Clin Oncol 30:863-870, 2012. 2. Ou S-HI, Bang Y-J, Camidge DR, et al: 2013 ASCO Annual Meeting. Abstract 8032. 3. Chiari R, Buttitta F, Iacono D, et al: Clin Lung Cancer 15:470-474, 2014. 4. Shaw AT, Ou S-HI, Bang Y-J, et al: N Engl J Med 371:1963-1971, 2014. 5. Kim HR, Lim SM, Kim HJ, et al: Ann Oncol 24:2364-2370, 2013. 6. Mazieres J, Zalcman G, Crino L, et al: 2014 ASCO Annual Meeting. Abstract 11035. Presented June 2, 2014. 7. Li C, Fang R, Sun Y, et al: PLoS One 6:e28204, 2011. 8. Kim MH, Shim HS, Kang DR, et al: Lung Cancer 83:389-395, 2014. 9. Cha YJ, Lee JS, Kim HR, et al: PLoS One 9:e103333, 2014. 10. Boyle TA, Masago K, Ellison KE, et al: Clin Lung Cancer. October 24, 2014 (early release online). 11. Katayama R, Kobayashi Y, Friboulet L, et al: Clin Cancer Res. Oct 28, 2014 (early release online). 12. Davare MA, Saborowski A, Eide CA, et al: Proc Natl Acad Sci USA 110:19519-19524, 2013.

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Announcements

Daniel F. Hayes, MD, FASCO, Elected ASCO President for 2016–2017 Term

aniel F. Hayes, MD, FASCO, has been elected President of the American Society of Clinical Oncology (ASCO) for the term beginning in June 2016. He will take office as PresidentElect during the ASCO Annual Meeting in Chicago in June 2015. “I’m honored to be elected incoming president of ASCO, which has had such a major influence on my professional career,” said Dr. Hayes. “I look forward to working with ASCO leadership and staff on the critical

Daniel F. Hayes, MD, FASCO

initiatives within the oncology community, including new strategies for health-care reform; the development of CancerLinQTM; efforts to improve value in cancer care; personalized cancer care; and reducing global disparities in cancer treatment. ASCO is uniquely positioned to tackle these issues head-on, and I look forward to being part of this exciting time in the life of the Society.” Dr. Hayes, a breast cancer specialist, is Professor of Internal Medicine, Stuart B. Padnos Professor in Breast Cancer, and Clinical Director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center. An ASCO member since 1986, Dr. Hayes served on the ASCO Board of Directors from 2011 to 2014, the Conquer Cancer Foundation Grants Selection Committee, as Chair of the Scientific Program Committee, and on the Editorial Board of the Journal of Clinical Oncology. Watch future issues of The ASCO Post for an interview with Dr. Hayes regarding his upcoming term.

Newly Elected ASCO Board Members Four new members were elected to the ASCO Board of Directors and two new members were elected to the ASCO Nominating Committee (see page 127). ASCO’s Board of Directors comprises oncology leaders who are elected to positions reflecting various specialties within the oncology field. The

following physicians will begin 4-year terms as members of ASCO’s Board of Directors starting in June 2015: • Craig R. Nichols, MD, has been elected as Treasurer. Dr. Nichols is the Co-Director of the Testicular Cancer Multidisciplinary Clinic at

Virginia Mason Medical Center in Seattle. He serves as co–primary investigator on the recently funded Northwest National Cancer Institute Community Oncology Research Program and is Executive Officer of Cancer Control and Prevention

Research for the Southwest Oncology Group. An ASCO member since 1986, Dr. Nichols serves as Co-Chair of the Management of Testicular Cancer Committee and as a member of the Practice Guidelines Implecontinued on page 102

The ASCO Post | JANUARY 25, 2015

PAGE 102

Announcements Daniel F. Hayes, MD, FASCO, Elected ASCO President continued from page 101

mentation Network. Previously, Dr. Nichols served as a member of the Genitourinary Cancers Symposium Program Committee and Health Services Committee and as Chair of the Nominating Committee.

• J. Chris Nunnink, MD, FASCO, has been elected to a Community Oncologist seat. Dr. Nunnink is Attending Physician in Medical Oncology at Fletcher Allen Health Care and Associate Professor at the Vermont Cancer Center and the College of Medicine at the University of Vermont, where he is devel-

oping a network for oncology care in rural upstate New York and Vermont. An ASCO member since 1986, he currently serves on the Clinical Practice Committee and has served on the State Affiliate Council. Dr. Nunnink has served as an

Craig R. Nichols, MD

J. Chris Nunnink, MD, FASCO

ASCO delegate to the American Medical Association (AMA) since 2010 and was the ASCO advisor to the AMA’s Relative Value Scale Update Committee. • Stephen B. Edge, MD, FACS, FASCO, has been elected to a Surgical Oncologist seat. Dr. Edge is Director of the Baptist Cancer Center and

Stephen B. Edge, MD, FACS, FASCO

Adjunct Professor of Surgery at the Vanderbilt University School of Medicine. Since joining ASCO in 1988, he has co-chaired the Guideline Panel for Postmastectomy Radiation and served on the Health Services Research Committee. He is currently a member of the Technology Assessment Panel for Sentinel Node Biopsy in Breast Cancer. He was on the ASCO/National Comprehensive Cancer Network (NCCN) Quality Measure Panel and is currently on an ASCO Measure Development Task Force. He has been on the Editorial Boards of Cancer.Net, the Journal of Clinical Oncology, and the Journal of Oncology Practice. • Jedd D. Wolchok, MD, PhD, has been elected to an Undesignated

Jedd D. Wolchok, MD, PhD

Specialty seat. Dr. Wolchok is Chief of the Melanoma and Immunotherapeutics Service in the Department continued on page 103

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PAGE 103

Journal Spotlight Breast Cancer

No Benefit of Adding Lapatinib to Fulvestrant in Hormone Receptor–Positive Advanced Breast Cancer By Matthew Stenger

n a phase III trial (Cancer and Leukemia Group B [CALGB] 40302/ Alliance) reported in Journal of Clinical Oncology, Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues found that the addition of the dual EGFR-HER2 inhibitor lapatinib (Tykerb) to endocrine therapy with fulvestrant (Faslodex) did not improve progression-free survival or overall survival and worsened toxicity in postmenopausal

tor–positive tumors, any HER2 status, and prior aromatase inhibitor treatment were randomly assigned to receive fulvestrant at 500 mg intramuscularly on day 1 followed by 250 mg on days 15 and 28 and then every 4 weeks and either daily lapatinib at 1,500 mg (n = 146) or placebo (n = 145). The primary endpoint was progression-free survival. The study planned to accrue 324 patients and was powered to detect a 50%

Adding lapatinib to fulvestrant does not improve progression-free survival or overall survival in advanced ER-positive breast cancer and is more toxic. —Harold J. Burstein, MD, PhD, and colleagues

women with hormone receptor–positive advanced breast cancer.1 Some data suggest that resistance to endocrine agents is associated with acquired overexpression of EGFR or HER2, and there is some evidence indicating that exposure to EGFR- and HER2-targeting agents can resensitize breast cancers to antiestrogen therapies and endocrine treatments. Given the availability of effective, well-tolerated antiestrogen and dual kinase inhibitor therapies, CALGB 40302 tested the hypothesis that targeting of both estrogen receptor and HER2 signaling would improve outcomes in advanced breast cancer.

Study Details In this double-blind trial, 295 patients with stage III or IV estrogen receptor–positive or progesterone recep-

Daniel F. Hayes, MD, FASCO Elected ASCO President continued from page 102

of Medicine and Associate Director of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center. He

improvement in progression-free survival with lapatinib from 5 to 7.5 months. The study was activated in September 2006. A third planned interim analysis in June 2010 showed a hazard ratio (HR) for progression-free survival of 0.98 (95% confidence interval [CI] = 0.73–1.33), which crossed the futility boundary such that the predicted probability of finding that lapatinib was superior to placebo with continued accrual and follow-up was < 1%. The trial was closed to new accrual in July 2010. The lapatinib and placebo groups were genrally balanced for age distribution (eg, 34% and 37% 50–59 years, 28% and 32% 60–69 years), race (87% and 91% white), prior tamoxifen (57% in both), bone disease only (31% and 30%), Eastern Cooperative Oncology Group performance status (0 in 59% is Associate Professor in the Immunology and Microbial Pathogenesis Program at Weill Cornell Graduate School of Medical Sciences of Cornell University and Associate Professor of Medicine at Weill Cornell Medical College. He is an Associ-

and 72%, 1 in 39% and 27%), prior aromatase inhibitor therapy (97% in both), prior trastuzumab (Herceptin, 2% and 3%), estrogen receptor–positive status (99% and 97%), progesterone receptor–positive status (73% and 68%), HER2-positive status (16% and 21%), number of metastatic sites (1 in 37% and 43%, 2 in 34% in both, 3 in 20% and 14%), prior chemotherapy for metastatic breast cancer (16% and 17%), and disease-free interval (> 2 years in 48% and 53%).

No Progression-Free Survival Benefit Median follow-up for surviving patients was 2.8 years. At final analysis, median progression-free survival was 4.7 months in the lapatinib group vs 3.8 months in the placebo group (HR for placebo vs lapatinib = 1.04, P = .37). Median overall survival was 30 vs 26.4 months (HR = 0.91, P = .25). Median progression-free survival was 4.1 vs 3.8 months (HR for placebo vs lapatinib = 1.00, 95% CI = 0.76– 1.30) among patients with HER2-negative tumors and 5.9 vs 3.3 months (HR for placebo vs lapatinib = 1.23, 95% CI = 0.69–2.18) among those with HER2positive tumors; the differential treatment effect by HER2 status was not significant (P = .53).

Objective Response Among the 70% of patients with measurable disease, objective response was observed in 20% vs 9% (P = .048). Complete response was observed in 2% of patients in each group. Response was observed in 13% vs 23% of patients with HER2-negative disease and 38% vs 17% with HER2-positive ate Member in the Ludwig Institute for Cancer Research. Dr. Wolchok joined ASCO in 1998 and has served as Chair of the Scientific Program Committee and the Best of ASCO® Planning Committee. He has been a member of the Editorial Board of the

disease, but the interaction between treatment and HER2 status was not significant (P = .53).

Adverse Events No grade ≥ 4 adverse events were reported. Lapatinib patients had a higher rate of grade 3 events (19% vs 5%, P < .001), including diarrhea (8% vs 0%), acneiform rash (3% vs 0%), fatigue (3% vs 0%), and increased alanine transaminase or aspartate transaminase (4% vs 1%). Treatment was discontinued due to adverse events in 12% vs 2% of patients (P < .001), mostly due to diarrhea, fatigue, and rash. No grade 3 cardiac toxicity was reported. The investigators concluded: “Adding lapatinib to fulvestrant does not improve progression-free survival or overall survival in advanced ER-positive breast cancer and is more toxic…. Given the importance of multiple lines of endocrine therapy in the palliation of advanced breast cancer and the opportunities for improving outcomes in the adjuvant setting, other approaches to overcome clinical endocrine resistance are needed.” n

Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. Burstein HJ, Cirrincione CT, Barry WT, et al: Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2. J Clin Oncol. October 27, 2014 (early release online).

See commentary by Ruth O’Regan, MD, on page 106.

Journal of Clinical Oncology, the Cancer Education Committee, and the Conquer Cancer Foundation Grants Selection Committee. See page 127 for information about newly elected members of the ASCO Nominating Committee. n

Visit The ASCO Post website at ASCOPost.com

Exploring the PD-L1 pathway as a new direction in cancer immunotherapy research Emerging research is directing focus on programmed death-ligand 1 (PD-L1) expressed on and around tumors Cancer can evade immune destruction by upregulating the inhibitory ligand PD-L1 on tumor cells and tumor-infiltrating immune cells, such as macrophages and dendritic cells.1,2 PD-L1 binds to B7.1 and PD-1 on cytotoxic T cells, disabling the anticancer immune response.1-3 Discover the PD-L1 pathway, a focus of investigation and cancer immunotherapy research by visiting

www.ResearchPDL1.com

Macrophage

PD-L1 expression

B7.1

PD-L1 PD-1

Inactive T cell

PD-L1

Tumor cell Dendritic cell

References: 1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. 2. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapyâ&#x20AC;&#x201C;â&#x20AC;&#x201C;inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587. 3. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.

The ASCO Post | JANUARY 25, 2015

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Perspective

Complexities of Targeting HER2 in Estrogen Receptor–Positive Breast Cancers By Ruth O’Regan, MD

he interactions between the estrogen receptor (ER) and HER2 pathways in breast cancers are clearly complex and remain incompletely understood. Historically, cancers that express both ER and HER2 were thought to be intrinsically resistant to endocrine therapy, likely due to HER2 being the dominant pathway. However, recent genomic analyses of ER-positive, HER2-positive breast cancers suggest the existence of a subtype that may be driven by ER and consequently sensitive to endocrine agents.1 In fact, inhibition of HER2 alone in ER-positive, HER2-positive breast cancers may allow ER to act as an escape pathway resulting in resistance to HER2-directed agents.2,3 Likewise, there is evidence to suggest a role for HER2 signaling in resistance to endocrine therapy.4,5 Given the known crosstalk between the ER and HER2 pathways, both in the HER2-positive and HER2-normal settings, a dual approach in which both pathways are inhibited concomitantly may represent an optimal therapeutic approach to overcome the potential resistance associated with targeting either pathway alone.

ER-Positive, HER2-Positive Breast Cancer Johnston et al6 evaluated the addition of lapatinib (Tykerb), a tyrosine kinase inhibitor that targets both EGFR and HER2, to letrozole in patients with ER-positive advanced breast cancer. In the 200 patients accrued to the trial with ER-positive, HER2-positive disease, there was a significant improvement in progression-free survival of 5 months among patients who were randomly assigned to receive lapatinib, which led to U.S. Food and Drug Administration approval of this regimen. Similarly, the addition of trastuzumab (Herceptin) to anastrozole sigDr. O’Regan is Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology and Chief of Hematology and Medical Oncology, Georgia Cancer Center for Excellence at Grady Memorial Hospital.

nificantly improved progression-free survival by 2 months in patients with advanced ER-positive, HER2-positive breast cancer.7 In the Cancer and Leukemia Group B (CALGB) trial recently reported by Burstein et al8 —reviewed in this issue of The ASCO Post—progression-free survival was improved by 2.5 months for patients with ERpositive, HER2-positive breast cancer treated with lapatinib and fulvestrant (Faslodex) compared to fulvestrant alone, but this difference was not significant, likely due to the small numbers of patients in this analysis. Given emerging data demonstrating considerable heterogeneity in cancers

cers remain poorly understood, but enhanced signaling through growth factor pathways, including members of the epidermal growth factor receptor (EGFR) family, has been demonstrated in preclinical2 and clinical studies.3 The improved outcome noted in recent trials9,10 with inhibition of mTOR in patients with ERpositive, HER2-normal breast cancer supports the importance of these pathways in resistance to endocrine agents. The CALGB trial reported by Burstein et al8 demonstrated no benefit for the addition of lapatinib to fulvestrant in patients with ER-positive,

As Burstein et al concluded, there are currently no conclusive data to support the addition of agents targeting the EGFR/HER2 pathway in ER-positive, HER2-normal cancer, particularly with the significant increase in toxicity. —Ruth O’Regan, MD

that express both hormone receptors (HR) and HER2,1 including the surprising finding that almost one-third of these cancers have a luminal A phenotype using intrinsic subtyping, future studies should stratify based on genomic subtypes to identify which HRpositive, HER2-positive cancers can be successfully treated with combined ER and HER2 blockade, potentially avoiding unnecessary chemotherapy. In the meantime, the results of the CALGB trial,8 though not statistically significant, are in keeping with other trials, 6,7 and combined HER2 blockade with lapatinib and ER blockade with letrozole remains a viable treatment option for selected patients with ER-positive, HER2-positive advanced breast cancer.

ER-Positive, HER2-Normal Breast Cancer The mechanisms underlying resistance to endocrine agents in ERpositive, HER2-normal breast can-

HER2-normal cancers. Likewise, Johnston et al6 noted no difference in progression-free survival with the addition of lapatinib to letrozole in patients with ER-positive, HER2normal breast cancer. However, a preplanned analysis of this trial6 noted a nonsignificant improvement in progression-free survival of 5 months for the approximately 200 patients with endocrine-resistant cancers who received lapatinib plus letrozole compared to letrozole alone, supporting a potential role for the EGFR/HER2 pathways in these resistant cancers. This hypothesis is not, however, supported by the CALGB trial.8 Progression-free survival in the control arm was only 3 months, suggesting that the majority of patients enrolled had endocrine-resistant cancers, but no benefit for the addition of lapatinib to fulvestrant was noted. Furthermore, a phase II trial11 failed to note a benefit for the addition of trastuzu mab to endocrine

therapy specifically in patients with endocrine-resistant metastatic breast cancer. As Burstein et al concluded, there are currently no conclusive data to support the addition of agents targeting the EGFR/HER2 pathway in ERpositive, HER2-normal cancer, particularly with the significant increase in toxicity. The fact that inhibition of a single growth factor receptor has now been demonstrated to be ineffective in several trials,6,8,12 while inhibition of mTOR,9,10 a final common protein downstream of these growth factor receptors, appears effective, suggests the possibility of compensatory signaling through other growth factors, which may be worth evaluating in metastatic specimens from prior and ongoing trials. n

Disclosure: Dr. O’Regan reported no potential conflicts of interest.

References 1. Carey LA, Barry WT, Pitcher B, et al: Gene expression signatures in pre- and post-therapy specimens from CALGB 40601, a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2positive breast cancer. 2014 ASCO Annual Meeting. Abstract 506. Presented May 31, 2014. 2. Xia W, Bacus S, Hegde P, et al: A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci USA 103:7795-7800, 2006. 3. Paplomata E, Nahta R, O’Regan RM: Systemic therapy for early stage breast cancer: Time for a less-is-more approach. Cancer. October 24, 2014 (early release online). 4. Schafer JM, Bentrem DJ, Takei H, et al: A mechanism of drug resistance to tamoxifen in breast cancer. J Steroid Biochem Mol Biol 83:75-83, 2002. 5. Kaklamani VG, Cianfrocca M, Ciccone J, et al: Increased HER2/neu expression in recurrent hormone receptor-positive breast cancer. Biomarkers 15:191-193, 2010. 6. Johnston S, Pippen J Jr, Pivot X, et al: Lapatinib combined with letrozole versus letrozole and placebo as first-line continued on page 107

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Announcements

Appointments and Awards Announced at The Johns Hopkins Kimmel Cancer Center

he Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore recently announced new appointments and awards given to faculty.

New Director of Thoracic Oncology Julie Brahmer, MD, a medical oncologist with expertise in the use of immunotherapies to treat lung cancer, has been named Director of the Tho-

Julie Brahmer, MD

racic Oncology Program at The Johns Hopkins Kimmel Cancer Center. Dr. Brahmer will lead a multidisciplinary team of physicians, nurses, researchers, and fellows developing new treatments for lung and esophageal cancers and mesothelioma. She will also oversee a $35 million investment in the program and the opening of the new Thoracic Center of Excellence at Johns Hopkins Bayview Medical Center, as well as laboratory research and clinical trials. “Dr. Brahmer has established herself as an international leader in the field of immunotherapy for lung cancer,” says William Nelson, MD, PhD, Director of the Kimmel Cancer Center. “She is poised to lead an impressive group of cancer care professionals dedicated to bringing the most innovative treatments to patients.” Dr. Brahmer has been a faculty

Targeting HER2 continued from page 106

therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27:5538-5546, 2009. 7. Kaufman B, Mackey JR, Clemens MR, et al: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: Results from the randomized phase III TAnDEM study. J Clin

member at Johns Hopkins since 2001 and is the author of more than 90 scholarly articles and book chapters. The Thoracic Oncology Program at the Kimmel Cancer Center offers a comprehensive one-day clinic, where lung cancer patients receive a complete treatment plan at the time of their visits. The clinic is located at Johns Hopkins Bayview and is led by radiation oncologist Russell Hales, MD. “The Johns Hopkins Kimmel Cancer Center is a special place, with committed experts dedicated to bringing the best treatments to patients through research and clinical trials. I am honored to be part of this team and to help lead us into the next phase of cancer medicine,” says Dr. Brahmer. Dr. Brahmer is an active leader in national efforts to drive and support better research and treatment for lung cancer. She is a member of ASCO and the Eastern Cooperative Oncology Group’s Thoracic Committee and Cancer Prevention Steering Committee. A founding board member of the National Lung Cancer Partnership, now known as Free to Breathe, she currently serves as a member of its Scientific Executive Committee. Dr. Brahmer earned her medical degree from the University of Nebraska, completed her residency in internal medicine at the University of Utah, and finished her training with a fellowship in medical oncology at Johns Hopkins. She is board-certified in medical oncology.

Massachusetts General Hospital’s Warren Prize Johns Hopkins oncologist Bert Vogelstein, MD, received the Warren Triennial Prize of Massachusetts General Hospital. The Warren Prize

Oncol 27:5529-5537, 2009. 8. Burstein HJ, Cirrincione CT, Barry WT, et al: Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: A randomized, doubleblind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancerCALGB 40302 (Alliance). J Clin Oncol 32:3959-3966, 2014. 9. Baselga J, Campone M, Piccart M,

honors scientists who have made outstanding contributions in fields related to medicine and includes a cash award of $50,000. The award, created in 1871, is given every 3 years and is named for John Collins Warren, a cofounder of Massachusetts General Hospital who played a leading role in Elizabeth Montgomery, MD

Bert Vogelstein, MD

establishing The New England Journal of Medicine. Dr. Vogelstein’s research focuses on determining the molecular basis of a common human cancer. He and his colleagues were the first to map cancer genomes and use genomewide sequencing to identify the basis of hereditary diseases. They also determined the genetic landscapes of more than a dozen tumor types and have provided the conceptual basis for what is now called personalized medicine.

research examines the power of the immune system’s ability to fight cancer. A molecule on tumor cells, called PD-L1, controls a “stop” signal to immune cells, which might otherwise have the capacity to kill tumor cells. Blocking PD-L1 has shown promise in early clinical trials involving melanoma and lung cancer. Dr. Montgomery will be studying PDL1 expression in esophageal cancers

Robert Anders, MD, PhD

Researcher Awarded Funding to Study Esophageal Cancer The Esophageal Cancer Awareness Association has awarded Elizabeth Montgomery, MD, Professor of Pathology and Oncology and a member of The Johns Hopkins Kimmel Cancer Center, a research grant totaling $16,000 for her collaborative research with Robert Anders, MD, PhD, and Elizabeth Thompson, MD, PhD, titled “Evaluation of PD-L1 Expression in Esophageal Adenocarcinoma.” Her

et al: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520-529, 2012. 10. Bachelot T, Bourgier C, Cropet C, et al: Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptorpositive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. J Clin Oncol 30:2718-2724, 2012. 11. Zelnak AB, Paplomata E, Mu-

Elizabeth Thompson, MD, PhD

to determine whether PD-L1–blocking therapies could offer a new type of therapy for this disease. n

rali S, et al: Phase 2 trial of trastuzumab and/or everolimus in hormone-resistant HER2-negative metastatic breast cancer. 2014 ASCO Annual Meeting. Abstract 576. Presented June 2, 2014. 12. Martin M, Loibl S, von Minckwitz G, et al: Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: First efficacy results from the LEA study. 2012 San Antonio Breast Cancer Symposium. Abstract S1-7. Presented December 5, 2012.

Continue treatment.* 1-4 Extend survival. For patients with advanced nonsquamous† NSCLC Median Overall Survival: 13.9 months with ALIMTA single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02 * Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent. After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA continuation maintenance showed extended overall survival with a safety profile consistent with previously reported ALIMTA single-agent trials

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.

Select Important Safety Information Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. Warnings and Precautions Premedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

Why consider maintenance therapy*? After completion of first-line therapy, several studies have shown that 50% of patients with advanced NSCLC off active treatment will experience rapid disease progression (within 3 months)‡2,5-8 You may have patients* with advanced nonsquamous† NSCLC who are eligible for continuation maintenance with single-agent ALIMTA

57%% 57

57% (n=539) of patients in the PARAMOUNT trial were eligible for continuation maintenance therapy (ALIMTA or placebo) from the 939 patients who received ALIMTA/cisplatin induction therapy1,4

PARAMOUNT PARAMOUNT PARAMOUNT PARAMOUNT

SAFETY SAFETY PP rr oo ff ii ll ee

The safety profile of ALIMTA continuation maintenance in patients with advanced nonsquamous NSCLC was consistent with the safety profile of single-agent ALIMTA in previously reported phase III trials1-4

of patients patients of

2.9 2.9

months months months months

Median OS OS Median

2.9 months’ median overall survival advantage was demonstrated with single-agent ALIMTA following induction with ALIMTA/cisplatin compared with placebo in patients* with advanced nonsquamous NSCLC1,4 Median overall survival (months) (95% CI): ALIMTA + BSC (n=359): 13.9 (12.8-16.0); Placebo + BSC (n=180): 11.0 (10.0-12.5); Unadjusted HRa,b: 0.78 (95% CI: 0.64-0.96); P=0.02

NCCN NCCN Guidelines®®®® Guidelines

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC Category 1§: NCCN Guidelines® recommend continuation of pemetrexed for injection (ALIMTA) after 4-6 cycles of cisplatin and pemetrexed chemotherapy in the absence of disease progression for patients with advanced or metastatic nonsquamous NSCLC9

‡ The median PFS for the referenced studies was less than 3 months. § Based upon high-level evidence, there is uniform National Comprehensive Cancer Network® (NCCN®) consensus that the intervention is appropriate. a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy. b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Select Important Safety Information

Common Terminology Criteria for Adverse Events Drug-related Toxicities (Version 3.0) Adverse Reactions: Grades 3-4 In the PARAMOUNT trial, grades 3-4 adverse reactions occurring more frequently (≥2%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (4.8% vs 0.6%), neutropenia (3.9% vs 0%), and fatigue (4.5% vs 0.6%). Adverse Reactions: All Grades In the PARAMOUNT trial, adverse reactions of any severity (all grades) occurring more frequently (≥5%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (15% vs 4.8%), neutropenia (9% vs 0.6%), fatigue (18% vs 11%), nausea (12% vs 2.4%), vomiting (6% vs 1.8%), mucositis/stomatitis (5% vs 2.4%), and edema (5% vs 3.6%).

See the complete data at ALIMTAhcp.com/data See the Important Safety Information and Brief Summary for ALIMTA on the following pages. References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597. 4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Fidias PM, et al. J Clin Oncol. 2009;27(4):591-598. 6. Paz-Ares L, et al. Lancet Oncol. 2012;13(3):247-255. 7. Cappuzzo F, et al. Lancet Oncol. 2010;11(6):521-529. 8. Zhang L, et al. Lancet Oncol. 2012;13(5):466-475. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed August 18, 2014. To view the most recent and complete version of the guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Indications for ALIMTA ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Important Safety Information for ALIMTA Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy. Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. Warnings and Precautions Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities. Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment. ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities. ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function. Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC) The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%). Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%). Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%). Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/ desquamation (10% vs 3%). Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%). Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Brief Summary of Prescribing Information on the adjacent page.

Drug Interactions See Warnings and Precautions for specific information regarding NSAID administration in patients with renal insufficiency.

PM_HCP_ISI_NSCLC1M_17OCT2012

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother. Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea. Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

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Journal Spotlight

Physical Activity Improves Survival for Men With Localized Prostate Cancer

mong a large group of men with localized prostate cancer, those who engaged in higher levels of physical activity had lower rates of overall mortality and lower rates of prostate cancer-specific mortality, according to a study published in Cancer Epidemiol-

ogy, Biomarkers & Prevention.1 “Our results extend the known benefits of physical activity to include prostate cancer–specific survival,” said Stephanie Bonn, MSc, a doctoral candidate in the Department of Medical Epidemiology and Biostatistics at the

ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information. 1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer — Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information]. 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information. 2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. 2.3 Premedication Regimen and Concurrent Medications Vitamin Supplementation Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)]. Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)]. Corticosteroids Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)]. 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)]. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin. Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3.

75% of previous dose (pemetrexed and cisplatin). Nadir platelets <50,000/mm3 without bleeding 75% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin). Nadir platelets <50,000/mm3 with bleedinga, 50% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin). a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding. If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2. Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b Dose of ALIMTA Dose of Cisplatin (mg/m2) (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous 75% of previous dose dose Any diarrhea requiring hospitalization (irrespective 75% of previous 75% of previous of Grade) or Grade 3 or 4 diarrhea dose dose ALIMTA® (pemetrexed for injection)

PV 8927 AMP

Karolinska Institutet in Stockholm. “However, it is important to remember that our results are on a group level. An individual’s survival depends on many factors, but physical activity is one factor that individuals can modify. Hopefully, our study can motivate men to be

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.) Grade 3 or 4 mucositis

50% of previous dose

100% of previous dose

NCI Common Toxicity Criteria (CTC). Excluding neurotoxicity (see Table 3). In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity b

Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/ Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)]. 3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed. 4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. 5 WARNINGS AND PRECAUTIONS 5.1 Requirement for Premedication and Concomitant Medication to Reduce Toxicity Vitamin Supplementation Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0]. Corticosteroids Administer dexamethasone the day before, the day of, and the day after ALIMTA administration [see Dosage and Administration (2.3)]. 5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)]. 5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)]. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. 5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)]. 5.5 Required Laboratory Monitoring Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the ALIMTA® (pemetrexed for injection)

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physically active even after a prostate cancer diagnosis.” Men with localized prostate cancer who walked or cycled for 20 or more minutes a day had a 30% decreased risk of death from any cause (overall mortalcontinued on page 112

The ASCO Post | JANUARY 25, 2015

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Journal Spotlight Physical Activity in Men With Prostate Cancer continued from page 111

ity) and a 39% decreased risk of death as a result of their disease (prostate cancer-specific mortality) compared with those who walked or cycled less. For those who engaged in one or more hours of exercise per week, overall and

prostate cancer-specific mortality rates were decreased by 26% and 32%, respectively, compared with less active counterparts. Bonn and colleagues generated these results after analyzing data from 4,623 men diagnosed with localized prostate cancer from 1997 to 2002 and followed until 2012. Participants in

An individual’s survival depends on many factors, but physical activity is one factor that individuals can modify. Hopefully, our study can motivate men to be physically active even after a prostate cancer diagnosis. —Stephanie Bonn, MsC

3 3 platelet count is ≥100,000 cells/mm platelet , and count creatinine is ≥100,000 cells/mm clearance is ≥45 mL/min , and creatinine [see Dosage clearance is ≥45 mL/min Incidence [see1% Dosage to 5% Incidence 1% to 5% Body as a Whole — febrile neutropenia, Body as ainfection, Whole —pyrexia febrile neutropenia, infection, pyrexia and Administration (2.4)]. and Administration (2.4)]. lacrimati General Disorders — dehydration General Disorders — dehydration In 5.6 Pregnancy Category D 5.6 Pregnancy Category D Metabolism and Nutrition — increased AST,and increased Metabolism NutritionALT— increased AST, increased ALT Based on its mechanism of action, Based ALIMTA on itscan mechanism cause fetal of action, harm when ALIMTA administered can cause fetal harm when administered Renal — creatinine renal failureclearance decrease, renal failure Renal — creatinine to a pregnant woman. Pemetrexed to a pregnant administered woman.intraperitoneally Pemetrexed administered to mice during intraperitoneally to mice during clearance decrease, Special organogenesis was embryotoxic, organogenesis fetotoxic andwas teratogenic embryotoxic, in mice fetotoxic at greater and than teratogenic 1/833rdin mice at greater thanSenses 1/833rd— conjunctivitisSpecial Senses — conjunctivitis than 1% Incidence Less than 1% the recommended human dose. the Ifrecommended ALIMTA is used human during dose. pregnancy, If ALIMTAor isif used the patient during pregnancy,Incidence or if theLess patient becomes pregnant while takingbecomes this drug,pregnant the patient whileshould takingbethis apprised drug, the of the patient potential should be apprisedCardiovascular of the potential— arrhythmia Cardiovascular — arrhythmia Disorders — chest painGeneral Disorders — chest pain C hazard to the fetus. Women of childbearing hazard to thepotential fetus. Women shouldofbechildbearing advised to avoid potential becoming should be advised toGeneral avoid becoming Metabolism and Nutrition — increased GGTand Nutrition — increased GGT Metabolism In pregnant. Women should be advised pregnant. to use Women effective shouldcontraceptive be advised to measures use effective to prevent contraceptive measures to prevent Neurology — motor neuropathyNeurology — motor neuropathy Ta pregnancy during treatment with pregnancy ALIMTA [see during Usetreatment in Specificwith Populations ALIMTA [see (8.1)]. Use in Specific Populations (8.1)]. Non-Small Cell Lung Cancer (NSCLC) – Maintenance Non-Small Cell Lung Cancer (NSCLC) – Maintenance of the 50 6 ADVERSE REACTIONS 6 ADVERSE REACTIONS ALIMTA Maintenance FollowingALIMTA Non-ALIMTA Containing, Platinum-Based Maintenance Following Non-ALIMTAInduction Containing, Platinum-Based In maintena Therapy Therapy T 6.1 Clinical Trials Experience 6.1 Clinical Trials Experience Table 5 provides the frequency Table 5 and severity of adverse reactions of reactions reported provides the frequency andreported severityinof>5% adverse doses in of Because clinical trials are conducted Because under clinicalwidely trials varying are conducted conditions, underadverse widely varying conditions, adverse the 438trials patients ALIMTA the 218 patients with the received 438 patients withmaintenance NSCLC who and received ALIMTA maintenance and the 218 patie reduction reactions rates cannot be directly reactions compared rates tocannot rates be in other directlyclinical compared trials toandrates mayinnot other clinical andwith mayNSCLC not who NSCLC who received placebo following a platinum-based induction therapy. NSCLC who received placebo following a platinum-based induction therapy. the place reflect the rates observed in clinical reflectpractice. the rates observed in clinical practice. All patients immediately following cycles of platinum-based All patients received study4therapy immediately following 4 cycles ofarm platinum and In clinical trials, the most common In clinical adverse trials,reactions the most(incidence common ≥20%) adverseduring reactions (incidence ≥20%)received during study therapy for locally advanced or metastatic NSCLC.advanced Patients inorboth study arms were fully in both studyacid treatment for locally metastatic NSCLC. Patients armsandw therapy with ALIMTA as a single-agent therapy with were ALIMTA fatigue, as nausea, a single-agent and anorexia. were fatigue, Additional nausea,treatment and anorexia. Additional supplemented withused folic in acid and vitamin B12. with folic acid and vitamin B12. supplemented common adverse reactions (incidence common≥20%) adverseduring reactions therapy (incidence with ALIMTA ≥20%)when during used therapy in with ALIMTA when Tabl combination with cisplatin included combination vomiting,with neutropenia, cisplatin included leukopenia, vomiting, anemia, neutropenia, stomatitis/leukopenia, Table anemia, stomatitis/Reactions inTable 5: Adverse Patients 5: Adverse Receiving Reactions ALIMTAinversus Patients Placebo Receiving ALIMTA versusALIMTA Placeb a a pharyngitis, thrombocytopenia, pharyngitis, and constipation. thrombocytopenia, and constipation. in NSCLC Following Platinum-Based in NSCLCInduction Following Therapy Platinum-Based Induction Therapy Non-Small Cell Lung Cancer (NSCLC) Non-Small – ALIMTA Cell Lung in Combination Cancer (NSCLC) with Cisplatin – ALIMTA in Combination with Cisplatin ALIMTA Placebo ALIMTA Placebo Advers Table 4 provides the frequencyTable and 4severity provides of the adverse frequency reactions and that severity haveofbeen adverse reactions that have been (N=438) (N=438) (N=218) (N=218)Sys Reactionb Reactionb reported in >5% of 839 patients reported with NSCLC in >5% who of were 839 patients randomized with toNSCLC studywho and were received randomized to study and received ALIMTA plus cisplatin and 830ALIMTA patientsplus withcisplatin NSCLC and who830 werepatients randomized with NSCLC to studywho andwere randomized to study and All Grades Grade 3-4 All Grades Grade 3-4 All Grades Grad received gemcitabine plus cisplatin. received All patients gemcitabine received plus study cisplatin. therapy All patients as initialreceived treatment study therapy as initial treatment Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) AllToxic Adv for locally advanced or metastatic for locally NSCLCadvanced and patients or metastatic in both treatment NSCLC and groups patients were infully both treatment groups were fully All Adverse Reactions All66 Adverse Reactions 16 37 66 16 4 37 Labora supplemented with folic acid and supplemented vitamin B12. with folic acid and vitamin B12. Laboratory Laboratory Hema Table 4: Adverse Reactions inTable Fully 4:Supplemented Adverse Reactions in Fully Supplemented Hematologic Hematologic Anem a a Patients Receiving ALIMTA plus Patients Cisplatin Receiving in NSCLC ALIMTA plus Cisplatin in NSCLC 13 6 6 3 15 15 Anemia Anemia Neut 03 06 0 3 6 Neutropenia Neutropenia ALIMTA/cisplatin Gemcitabine/cisplatin ALIMTA/cisplatin Gemcitabine/cisplatin Clinica 1 1 1 2 2 6 6 Leukopenia Leukopenia (N=839) (N=839) (N=830) (N=830) Reactionb Reactionb Const Hepatic Grade 3-4 Hepatic Symp All Grades Grade 3-4 All Grades Grade 3-4 All Grades Increased ALT Increased 10 ALT 0 10 4 0 4 Fatig Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Increased AST Increased 8 AST 0 48 0 4 Gastr All Adverse Reactions All90 Adverse Reactions 37 91 90 53 37 91 53 Clinical Clinical Naus Laboratory Laboratory Constitutional Constitutional Vom Hematologic Hematologic Symptoms Symptoms Muco 10 10 46 46 6 6 33 33 Anemia Anemia Fatigue Fatigue 25 5 11 25 15 11 Gener 27 27 38 38 15 15 29 29 Neutropenia Neutropenia Gastrointestinal Gastrointestinal Edem 85 8 21 21 5 18 18 Leukopenia Leukopenia 1 6 6 1 19 19 Nausea Nausea a 13 13 27 27 4 4 10 10 Thrombocytopenia Thrombocytopenia Adverse 02 5 5 2 19 19 Anorexia Anorexia adverse Renal Renal 0 19 1 0 9 Vomiting Vomiting to those Creatinine elevation Creatinine 10 elevation 1 10 7 1 7 1 01 27 2 1 7 Mucositis/stomatitis Mucositis/stomatitis b NCI CT 01 35 3 1 5 Diarrhea Diarrhea Clinical Clinical A Constitutional Constitutional Infection Infection 5 2 25 02 2 erythropo Symptoms Symptoms Neurology Neurology factors (6 Fatigue Fatigue 43 7 45 43 57 45 5 Neuropathy-sensory Neuropathy-sensory 9 1 49 01 4 T Gastrointestinal Gastrointestinal frequent Dermatology/Skin Dermatology/Skin 47 4 53 53 7 56 56 Nausea Nausea In Rash/Desquamation Rash/Desquamation 10 0 10 3 0 3 6 6 36 36 6 40 40 Vomiting Vomiting a 24 12 1 this table aacut 24 2 27 27 Anorexia Anorexia For the purpose of Foroff theofpurpose 5% wasofused this for table inclusion a cut offofofall5% events was where used fortheinclusion of all events w 01 0 a possible relationship 20 20 1 21 21 Constipation Constipation reporter considered reporter considered to ALIMTA. a possible relationship to ALIMTA. In b 12 b 01 0 Criteria version 12 1 14 14 Stomatitis/Pharyngitis Stomatitis/Pharyngitis Refer to NCI CTCAE Refer3.0 to NCI for each CTCAE Grade Criteria of toxicity. version 3.0 for each Grade of toxicity. 21 13 13 No clinically2 relevant differencesNoin clinically 1 12 12 Diarrhea Diarrhea Grade 3/4relevant adversedifferences reactions were in Grade seen3/4 in patients adverse reactions were seen in 0 0 ethnic origin, 65 6 on age, gender, 0 5 Dyspepsia/Heartburn Dyspepsia/Heartburn based based or on histology age, gender, except ethnic a higher origin,incidence or histology of Grade except3/4 a higher incidence of Gr fatigue for Caucasian patients compared fatigue fortoCaucasian non-Caucasian patientspatients compared (6.5% to versus non-Caucasian 0.6%). patients (6.5% versus 0 Neurology Neurology Safetyforwas patients assessed who by received exposure at least for patients one dosewho of received at least one Neuropathy-sensory Neuropathy-sensory 9 0 9 01 12 12 Safety was1 assessed by exposure ALIMTA (N=438).0cThe incidence ALIMTA of adverse (N=438). reactions The incidence was evaluated of adverse for patients reactionswho was evaluated for patien Taste disturbance Taste 8 disturbance0c 89 0c 9 received ≤6 cycles of ALIMTA, and received compared ≤6 cycles to patients of ALIMTA, who received and compared >6 cycles to patients of ALIMTA. who received >6 cycles of N Dermatology/Skin Dermatology/Skin Increases in adverse Increases grades)inwere adverse observed reactions with(all longer grades) exposure; were observed however no with longer exposure; how c reactions (all Alopecia Alopecia 12 0c 12 21 10c 21 1 clinically relevant differences inclinically Grade 3/4 relevant adverse differences reactions inwere Grade seen. 3/4 adverse reactions were seen. increase Rash/Desquamation Rash/Desquamation 7 0 87 01 8 Consistent 1with the higher incidence Consistent of anemia with the (allhigher grades)incidence on the ALIMTA of anemia arm,(all usegrades) on the ALIMTAAa Se a For the purpose of this table aacut Foroff theofpurpose 5% wasofused this for table inclusion a cut offofofall5% events was where used fortheinclusion of all events (mainly where the of transfusions RBC) and of transfusions erythropoiesis (mainly stimulating RBC) and agents erythropoiesis (ESAs; erythropoietin stimulating agents (ESAs; erythr reporter considered a possible relationship reporter considered to ALIMTA. a possible relationship to ALIMTA. and darbepoetin) were higher inand thedarbepoetin) ALIMTA arm compared were highertointhetheplacebo ALIMTAarm arm(transfusions compared to the placebo arm (tranE b b Refer to NCI CTC Criteria version Refer 2.0 for to NCI eachCTC Grade Criteria of toxicity. version 2.0 for each Grade of toxicity. 9.5% versus 3.2%, ESAs 5.9% 9.5% 6.2 P versusversus 1.8%).3.2%, ESAs 5.9% versus 1.8%). c c T According to NCI CTC Criteria version According 2.0, to thisNCIadverse CTC Criteria event term version should 2.0, this onlyadverse be reported event term should be reported Theonly following additional adverseThe reactions following were additional observed adverse in patients reactions with were non-small observed in patients with no ALIMTA. as Grade 1 or 2. as Grade 1 or 2. cell lung cancer who received ALIMTA. cell lung cancer who received ALIMTA. size, it i No clinically relevant differences Noinclinically adverserelevant reactionsdifferences were seenininadverse patientsreactions based were seenIncidence in patients1%based to 5% Incidence 1% to 5% relations on histology. on histology. Dermatology/Skin — alopecia, Dermatology/Skin pruritus/itching — alopecia, pruritus/itching Gastrointestinal T In addition to the lower incidence In addition of hematologic to the lower toxicityincidence on the ALIMTA of hematologic and cisplatin toxicity on the ALIMTA and cisplatin— constipationGastrointestinal — constipation General General (in the Disorders absence—ofedema, neutropenia) fever (in the absence of neutropenia) combina arm, use of transfusions (RBC and arm,platelet) use of transfusions and hematopoietic (RBC and growth platelet) factors andwas hematopoietic lower in growth factors was Disorders lower in — edema, fever Hematologic — thrombocytopenia Hematologic — thrombocytopenia B the ALIMTA and cisplatin arm compared the ALIMTA to and the gemcitabine cisplatin armand compared cisplatintoarm. the gemcitabine and cisplatin arm. — decreased creatinine Renalclearance, — decreased increased creatinine creatinine, clearance, decreased increased creatinine, de G The following additional adverseThe reactions following were additional observed adverse in patients reactions with were non-small observed in patientsRenal with non-small glomerular filtration rate glomerular filtration rate G cell lung cancer randomly assigned cell lung to receive cancerALIMTA randomly plusassigned cisplatin.to receive ALIMTA plus cisplatin.

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Journal Spotlight

the study were all men in the National Prostate Cancer Register of Sweden Follow-up Study, a retrospective, nationwide cohort study of men with localized prostate cancer who were alive in 2007. Data on physical activity were obtained through paper- and web-based questionnaires about lifestyle. Infor-

mation about cause and date of death was obtained from the Swedish Causeof-Death Registry. “Nearly all men in Sweden who were diagnosed with localized prostate cancer from Jan. 1, 1997, to Dec. 31, 2002, were included in the National Prostate Cancer Register of Sweden Follow-up Study,” said Bonn. “This means our re-

sults are generalizable on the population level. However, our data came only from men who were still alive in 2007, which most likely excludes men with more aggressive disease. Our results are, therefore, most applicable to men with less aggressive disease.” n Disclosure: The study was supported by the Swedish Cancer Society and the Swedish

Injury, poisoning, Injury,complications poisoning, and — procedural Radiation recall complications has been— Radiation recall has been Special Senses — ocular surface Special disease Senses(including — ocular conjunctivitis), surface disease increased (including conjunctivitis), increasedand procedural reported in patients who have previously reported inreceived patientsradiotherapy. who have previously received radiotherapy. ion lacrimation Respiratory — interstitial pneumonitis Respiratory — interstitial pneumonitis ncidence Less than 1% Incidence Less than 1% Skin — Bullous conditions, including Skin — Stevens-Johnson Bullous conditions, syndrome including andStevens-Johnson toxic epidermal syndrome and toxic epidermal Cardiovascular — supraventricular Cardiovascular arrhythmia— supraventricular arrhythmia necrolysis. Some cases were fatal. necrolysis. Some cases were fatal. Dermatology/Skin — erythemaDermatology/Skin multiforme — erythema multiforme General Disorders — febrile neutropenia, General Disorders allergic — reaction/hypersensitivity febrile neutropenia, allergic reaction/hypersensitivity 7 DRUG INTERACTIONS 7 DRUG INTERACTIONS Neurology — motor neuropathyNeurology — motor neuropathy 7.1 Non-Steroidal Anti-Inflammatory 7.1 Non-Steroidal Drugs (NSAIDs) Anti-Inflammatory Drugs (NSAIDs) Renal — renal failure Renal — renal failure Although four timesibuprofen a day) can (400 decrease mg four the times clearance a day) ofcan decrease the clearance of Continuation of ALIMTA as Continuation Maintenance ofFollowing ALIMTA ALIMTA as Maintenance Plus Platinum Following ALIMTA Plus ibuprofen Platinum (400 mg Although pemetrexed, it can be administered pemetrexed, with ALIMTA it can be in patients administered with normal with ALIMTA renal infunction patients with normal renal function nduction Therapy Induction Therapy (creatinine clearance ≥80 mL/min). (creatinine No doseclearance adjustment ≥80 mL/min). of ALIMTA isNo needed dose adjustment with concomitant of ALIMTA is needed with concomitant Table 6 provides the frequencyTable 6 and severity provides of adverse the frequency reactions andreported severity inof >5% adverse reactions reported in >5% NSAIDs in patients with normal renal NSAIDs function in patients [see Clinical with normal Pharmacology renal function (12.3)]. [see Clinical Pharmacology (12.3)]. 00 patients with non-squamous of the 500NSCLC patients whowith received non-squamous at least one NSCLC cyclewho of ALIMTA received at least one cycle of ALIMTA Caution should be used whenCaution administering should be NSAIDs used concurrently when administering with ALIMTA NSAIDs concurrently with ALIMTA nduction ance (n=333) or placebo maintenance (n=167) on(n=333) the continuation or placebo maintenance (n=167) ontrial. the continuation maintenance trial. to patients with mild to moderate to patients renal insufficiency with mild to (creatinine moderate renal clearance insufficiency from 45(creatinine to clearance from 45 to The median of maintenance cycles The median administered of maintenance to patientscycles receiving administered one or more to patients receiving one or more 79 mL/min). 79 mL/min). nf >5% of maintenance therapydoses was 4ofonmaintenance both the pemetrexed therapy was and4 placebo on both arms. the pemetrexed Dose and placebo arms. Dose NSAIDs with short eliminationNSAIDs half-lives with(e.g., shortdiclofenac, eliminationindomethacin) half-lives (e.g., should diclofenac, indomethacin) should ents ns forwith adverse events occurred reductions in for 3.3% adverse of patients eventsinoccurred the ALIMTA in 3.3% arm and of patients 0.6% inin thebe avoided ALIMTA armforand 0.6% in a period of 2 days be avoided before, the for aday period of, and of 2 days 2 days before, following theadministration day of, and 2 days following administration ebo arm. Dose delays for theadverse placeboevents arm. Dose occurred delays in 22% for adverse of patients events in the occurred ALIMTAin 22%ofofALIMTA. patients in the ALIMTA of ALIMTA. dm-based 16% in the placebo arm. armPatients and 16% in both in thestudy placebo armsarm. werePatients supplemented in both study with folic arms were supplemented withoffolic In the absence data regardingInpotential the absence interaction of databetween regarding ALIMTA potential andinteraction NSAIDs withbetween ALIMTA and NSAIDs with were fully 12. d vitamin B acid and vitamin B12. longer half-lives (e.g., meloxicam, longer nabumetone), half-lives patients (e.g., meloxicam, taking these nabumetone), NSAIDs should patients interrupt taking these NSAIDs should interrupt a b a b dosing for atReceiving least 5 days before, dosing the day for at of, least and 2 days 5 days following before, theALIMTA day of,administration. and 2 days following If ALIMTA administration. If le 6: Selected Adverse Reactions Table 6: Selected OccurringAdverse in ≥5% Reactions of Patients Occurring Receiving in ≥5% of Patients concomitant administration concomitant is necessary, administration patientsofshould NSAIDsbeismonitored necessary,closely patients for should be monitored closely for Aboin Nonsquamous NSCLC ALIMTA Following in Nonsquamous ALIMTA PlusNSCLC Cisplatin Following Induction ALIMTA Therapy Plus Cisplatin Induction Therapy of NSAIDs toxicity, especially myelosuppression, toxicity,renal, especially and gastrointestinal myelosuppression, toxicity. renal, and gastrointestinal toxicity. ALIMTA Placebo ALIMTA Placebo 7.2 Nephrotoxic Drugs 7.2 Nephrotoxic Drugs (N=333) (N=167) (N=333) (N=167) se Reaction Organ Adverse Reaction Organ ALIMTA is primarily eliminated ALIMTA unchanged is primarily renally aseliminated a result ofunchanged glomerularrenally filtration as a result of glomerular filtration a and Term a stem and Term System All Grades Grade 3-4 All Gradesa Grades Grade 3-4 3-4aa All Gradesa Grades 3-4a and tubular secretion. Concomitant and tubular administration secretion.ofConcomitant nephrotoxic administration drugs could result of nephrotoxic in drugs could result in de 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) delayed clearance of ALIMTA.delayed Concomitant clearance administration of ALIMTA.ofConcomitant substances administration that are also of substances that are also city (%) verse Reactions All53 Adverse Reactions 17 34 53 4.8 17 34 tubularly secreted4.8 (e.g., probenecid) tubularly couldsecreted potentially (e.g.,result probenecid) in delayed could clearance potentially of ALIMTA. result in delayed clearance of ALIMTA. 4 atory Laboratory 8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS atologic Hematologic 8.1 Pregnancy 8.1 Pregnancy mia Anemia 15 4.8 4.8 15 0.6 4.8 4.8 0.6 Teratogenic Effects - PregnancyTeratogenic Category DEffects [see Warnings - Pregnancy and Precautions Category D [see (5.6)].Warnings and Precautions (5.6)]. 1 tropenia Neutropenia 9 3.9 0.6 9 3.9 0 0.6 0 Based on its mechanism of action, Based ALIMTA on itscan mechanism cause fetal of action, harm when ALIMTA administered can cause fetal harm when administered 0 al1 Clinical to a pregnant woman. There are to anopregnant adequatewoman. and well There controlled are no studies adequateof and ALIMTA well incontrolled studies of ALIMTA in titutional Constitutional pregnant women. Pemetrexedpregnant was embryotoxic, women. Pemetrexed fetotoxic, and wasteratogenic embryotoxic, in mice. fetotoxic, In and teratogenic in mice. In ptoms Symptoms mice, repeated intraperitonealmice, dosesrepeated of pemetrexed intraperitoneal when given dosesduring of pemetrexed organogenesis when given during organogenesis 0 gue Fatigue 18 4.5 11 18 0.6 4.5 11 fetal malformations 0.6 caused (incomplete caused fetal ossification malformations of talus(incomplete and skull bone; ossification about 1/833rd of talus and skull bone; about 1/833rd 0 2 the recommended intravenousthe human recommended dose on a intravenous mg/m2 basis), human on a mg/m and dose cleft palate (1/33rd basis), and cleft palate (1/33rd rointestinal Gastrointestinal the recommended dose on intravenous a mg/m2 basis). humanEmbryotoxicity dose on a mg/m was 2 basis). Embryotoxicity was 0 2.4 2.4recommended0 intravenousthehuman 0.3 0.3 12 12 sea Nausea characterized by increased embryo-fetal characterized deaths by increased and reduced embryo-fetal litter sizes.deaths If ALIMTA andisreduced used litter sizes. If ALIMTA is used 0 0 1.8 1.8 0 6 6 miting Vomiting during duringbecomes pregnancy, pregnant or if the while patient takingbecomes this drug, pregnant the patient while taking this drug, the patient 0 2.4 2.4 pregnancy,0or if the patient 0.3 0.3 5 5 ositis/stomatitis Mucositis/stomatitis 1 should be apprised of the potential shouldhazard be apprised to the fetus. of the Women potentialofhazard childbearing to the potential fetus. Women of childbearing potential ral Disorders General Disorders should be advised to use effective should contraceptive be advisedmeasures to use effective to prevent contraceptive pregnancymeasures during theto prevent pregnancy during the ma Edema 5 0 3.6 5 0 3.6 0 treatment with ALIMTA. treatment with ALIMTA. 1 a e0reactions of any severity Adverse (all grades) reactions occurring of anymore severity frequently (all grades) (≥5%)occurring or Grademore 3-4 frequently (≥5%) or Mothers Grade 3-4 8.3 Nursing 8.3 Nursing Mothers e0 reactions occurring more adverse frequently reactions (≥2%) occurring in ALIMTA-treated more frequently patients (≥2%) compared in ALIMTA-treated Itpatients is notcompared known whether ALIMTA It is not or its known metabolites whether are ALIMTA excreted or itsin metabolites human are excreted in human e0 receiving placebo to those receiving placebo milk. Because many drugs aremilk. Because excreted in human many milk, drugsand arebecause excretedofinthe human potential milk,for and because of the potential for b TCAE 0 Criteria version 3.0 NCI CTCAE Criteria version 3.0 serious adverse reactions in nursing seriousinfants adversefrom reactions ALIMTA,in anursing decisioninfants shouldfrom be ALIMTA, made to a decision should be made to Administration of RBC (13% versus Administration 4.8%) and platelet of RBC(1.5% (13% versus 4.8%) 0.6%) and transfusions, platelet (1.5%discontinue versus 0.6%)nursing transfusions, or discontinue discontinue the drug,nursing taking or intodiscontinue account thetheimportance drug, taking of into the drug account the importance of the drug 0 oiesis stimulating agents erythropoiesis (12% versus stimulating 7%), andagents granulocyte (12% colony versus stimulating 7%), and granulocyte colony stimulating for the mother. for the mother. 6% versus 0) were higher factors in the(6% ALIMTA versus arm0) compared were higher to inthetheplacebo ALIMTAarm. arm compared to the placebo arm. 8.4 Pediatric Use 8.4 Pediatric Use 0 following additional GradeThe3 following The or 4 adverse additional reactions Gradewere 3 orobserved 4 adverse morereactions were observed more Efficacy of ALIMTA in pediatricEfficacy patientsofhas ALIMTA not been in pediatric demonstrated. patientsALIMTA has notwas been demonstrated. ALIMTA was tly in the ALIMTA arm. frequently in the ALIMTA arm. administered as an intravenousadministered infusion overas10anminutes intravenous on Day infusion 1 of aover 21 10 dayminutes cycle toon Day 1 of a 21 day cycle to ncidence 1% to 5% Incidence 1% to 5% 0 pediatric patients with recurrentpediatric solid tumors patients in awith Phase recurrent 1 studysolid (32 patients) tumors inand a Phase a Phase 1 study (32 patients) and a Phase Blood/Bone Marrow — thrombocytopenia Blood/Bone Marrow — thrombocytopenia 2 study (72 patients). All patients 2 study received (72 patients). pretreatment All patients with vitamin received B12 pretreatment and folic acidwith vitamin B12 and folic acid where the General Disorders — febrile neutropenia General Disorders — febrile neutropenia supplementation and dexamethasone. supplementation The dose escalation and dexamethasone. in the PhaseThe 1 study dose escalation determinedin the Phase 1 study determined ncidence Less than 1% Incidence Less than 1% 2 the maximum tolerated dose was the maximum 1910 mg/m tolerated dose was(or1910 mg/m2forandpatients and this dose 60 mg/kg this dose (or 60 mg/kg for patients Cardiovascular — ventricular tachycardia, Cardiovascular syncope — ventricular tachycardia, syncope <12 months old) was evaluated<12 months in the Phaseold) 2 study was evaluated of patientsinwith the relapsed Phase 2 study or refractory of patients with relapsed or refractory n patients General Disorders — pain General Disorders — pain osteosarcoma, Ewing sarcoma/peripheral osteosarcoma,PNET, Ewingrhabdomyosarcoma, sarcoma/peripheral neuroblastoma, PNET, rhabdomyosarcoma, neuroblastoma, rade 3/4 Gastrointestinal — gastrointestinal Gastrointestinal obstruction — gastrointestinal obstruction ependymoma, medulloblastoma/supratentorial ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade PNET,glioma. or nonbrainstem high grade glioma. 0.6%). Neurologic — depression Neurologic — depression No responses were observed among No responses the 72 patients were observed in this Phase among 2 trial. the 72 Thepatients most common in this Phase 2 trial. The most common dose of Renal Renal — renal failure toxicities reported were hematological toxicities(leukopenia, reported were neutropenia/granulocytopenia, hematological (leukopenia, anemia, neutropenia/granulocytopenia, anemia, nts who— renal failure Vascular — pulmonary embolism Vascular — pulmonary embolism thrombocytopenia, and lymphopenia), thrombocytopenia, liver function and abnormalities lymphopenia),(increased liver function ALT/AST), abnormalities (increased ALT/AST), ALIMTA. No relevant No relevant due to effect genderfororALIMTA race was safety identified, due to except genderan or racefatigue, was identified, except an fatigue, and nausea. and nausea. wever no effect for ALIMTA safety ed incidence of rash in men (24%) increased incidence comparedoftorash women (16%). in men (24%) compared to women (16%). The single dose pharmacokinetics The single of ALIMTA dose pharmacokinetics administered in doses of ALIMTA ranging administered in doses ranging Additional Additional TrialsExperience Across Clinical Trials from 400 to 2480 mg/m2 werefrom 400 to mg/m12 were evaluated in2480 the Phase trial inevaluated 22 patients in the (13Phase males1and trial in 22 patients (13 males and arm, use Experience Across Clinical epsis, which in some cases was Sepsis, fatal, which occurred in some in approximately cases was fatal, 1% of occurred patients. in approximately 1% of patients. 9 females) aged 4 to 18 years9 (average females) age aged124 years). to 18 years Pemetrexed (averageexposure age 12 (AUC years).andPemetrexed exposure (AUC and ropoietin Esophagitis Esophagitis 1% of patients. occurred in less than 1% of patients. Cmax) appeared to increase proportionally Cmax) appeared withtodose. increase The average proportionally pemetrexed with dose. clearance The average pemetrexed clearance nsfusions occurred in less than 2 2 (2.30 L/h/m ) and half-life (2.3(2.30 L/h/m hours) in pediatric ) and half-life patients (2.3were hours) comparable in pediatric to values patients were comparable to values Postmarketing Experience 6.2 Postmarketing Experience reported in adults. use of reported in adults. The following adverse reactionsThehave following been identified adverse reactions during post-approval have been identified use of during post-approval on-small Because these reactions ALIMTA. are reported Becausevoluntarily these reactions from aare population reported ofvoluntarily uncertainfrom 8.5 a population of Use uncertain 8.5 Geriatric Use Geriatric is not always possible size, to reliably it is not estimate alwaystheir possible frequency to reliably or establish estimatea their causalfrequency or ALIMTA establishis known a causalto be substantially ALIMTA excreted is known by to thebekidney, substantially and theexcreted risk of adverse by the kidney, and the risk of adverse ship to drug exposure. relationship to drug exposure. reactions to this drug may be greater reactions in patients to this drug with may impaired be greater renal function. in patients Renal withfunction impaired renal function. Renal function These reactions occurred with These ALIMTA reactions when occurred used as with a single-agent ALIMTA when and used in asmonitoring a single-agent and in with is recommended monitoring administration is recommended of ALIMTA. with No dose administration reductions ofother ALIMTA. than No dose reductions other than ation therapies. combination therapies. those recommended for all patients thoseare recommended necessary forforpatients all patients 65 years are necessary of age or older for patients [see 65 years of age or older [see Dosage and Administration (2.4)]. Dosage and Administration (2.4)]. Blood and Lymphatic System –Blood Immune-mediated and Lymphatichemolytic System –anemia Immune-mediated hemolytic anemia ecreased Of 3,946 patients (34.0% ≥65)Ofstudied 3,946 patients across the (34.0% five clinical ≥65) studied trials [see across Clinical the five clinical trials [see Clinical Gastrointestinal — colitis, pancreatitis Gastrointestinal — colitis, pancreatitis Studies (14.1, 14.2, 14.3, and 14.4)], Studiesthe(14.1, effect14.2, of ALIMTA 14.3, and on survival 14.4)], the waseffect similar of ALIMTA in patients on survival was similar in patients General Disorders and Administration GeneralSite Disorders Conditions and — Administration edema Site Conditions — edema

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Research Council for Health, Working Life, and Welfare. Bonn declares no conflicts of interest.

Reference 1. Bonn SE, Sjölander A, Lagerros YT, et al: Physical activity and survival among men diagnosed with prostate cancer. Cancer Epidemiol Biomarkers Prev. December 19, 2014 (early release online).

The ASCO Post | JANUARY 25, 2015

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FDA Update

FDA Approves Companion Diagnostic for the Detection of BRCA1/2 Mutations in Ovarian Cancer

he recent U.S. Food and Drug Administration (FDA) of olaparib (Lynparza) occurred concurrently with that of a companion diagnostic, BRACAnalysis CDx. This genetic

test is designed to detect the presence of mutations in the BRCA genes in blood samples from patients with ovarian cancer. The BRCA genes are involved with repairing damaged

DNA and normally work to suppress tumor growth. Women with BRCA mutations are more likely to get ovarian cancer, and it is estimated that 10% to 15% of all ovarian cancer is as-

<65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia. 8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment. 8.8 Gender Of 3,946 patients (Male 70.5% ) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients. 8.9 Race Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients. 10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days. The ability of ALIMTA to be dialyzed is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (PPI) Instruct patients to read the patient package insert before initiating ALIMTA. • Instruct patients on the need for folic acid and vitamin B12 supplementation to reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. • Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia. • Instruct patients to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear. • Instruct patients to inform their physician of all concomitant prescription or over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)]. To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch. Additional information can be found at www.AlimtaHCP.com

PV 8927 AMP

019517_elalns_PM92674_OT_fa.indd 4

ALIMTA PM HCP BS NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5

sociated with these hereditary BRCA mutations. The FDA evaluated the BRACAnalysis CDx’s safety and efficacy under the agency’s premarket approval pathway used for high-risk medical devices. Until now, Myriad Genetics had been marketing this test, although not specifically for use as a companion diagnostic, without FDA approval as a laboratory-developed test, which is a test that is designed, manufactured, and used in a single laboratory. The new test is approved as a companion diagnostic, specifically to identify patients with advanced ovarian cancer who may be candidates for treatment with olaparib. “The approval of safe and effective companion diagnostic tests and drugs continue to be important developments in oncology,” said Alberto Gutierrez, PhD, Director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health. “We are very excited that the BRACAnalysis CDx is the FDA’s first

approval of an laboratory-developed test under a premarket approval application and is the first approval of an laboratory-developed test companion diagnostic. The use of companion diagnostics helps bring to market safe and effective treatments specific to a patient’s needs.” The FDA’s approval of the BRACAnalysis CDx is based on data from the clinical study used to support approval of olaparib. Blood samples from clinical trial participants were tested to validate the test’s use for detecting BRCA mutations in this population. BRACAnalysis CDx’s application was reviewed under the FDA’s priority review program for devices, which provides for priority review of devices that meet certain criteria, including that the devices are intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition and, if approved, would offer significant, clinically meaningful advantages compared to marketed products. n 9/26/14 1:32 PM

PRINTER VERSION 4 OF 4

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PAGE 115

Expert’s Corner Breast Cancer

Breast Health Global Initiative Tackles Third-World Health Care A Conversation With Benjamin O. Anderson, MD By Alice Goodman

Benjamin O. Anderson, MD

enjamin O. Anderson, MD, is the Director of the Breast Health Global Initiative (BHGI) and surgical oncologist and Director of the Breast Health Clinic at the University of Washington in Seattle. The ASCO Post recently spoke with Dr. Anderson about the conceptual framework of the risk-stratification program developed by BHGI, the challenges presented by cultural obstacles, and the power of advocacy worldwide.

A Conceptual Framework What motivated you to try to improve health-care delivery for breast cancer in the developing world? In the late 1990s, I was invited to participate in a breast cancer–related project in the Ukraine run by PATH [the global health nonprofit headquartered in Seattle]. It quickly became evident that the National Comprehensive Cancer Network (NCCN) guidelines we use in the United States do not apply to countries that lack fundamental resources and infrastructure. Like cancer guidelines from other high-income countries, the NCCN guidelines assume that all the necessary tools are available and can be deployed to optimize disease management. The BHGI has developed a conceptual framework that addresses management of breast cancer globally and can be applied in individual countries with few health-care resources by Western standards, adjusting for local cultural and political realities. Our risk-stratification program prioritizes available tools for managing breast cancer diagnosis and treatment according to the best evidence available. Keep in mind that the evidence comes from wealthier countries. We defined four levels for allocation of resources: basic, limited, enhanced, and maximal. Surgery would be considered essential for survival. Chemotherapy is

an example of a limited resource, not necessarily essential but would provide a major improvement in survival. Enhanced resources might not improve survival but would improve treatment options. Maximal resources, such as PET or MRI imaging, are not appropriate or relevant for low- and middle-income patients, since these modalities add significantly to infrastructure cost and complexity but do not directly improve survival. The guidelines are now comprehensive, covering early detection, diagnosis, treatment by stage, health-care systems and supportive and palliative care. We are focusing on implementing what we have learned. The real value of our conceptual framework is that it allows people to think through problems that otherwise seem vast and insurmountable.

Resource Stratification What projects have emanated from the work on risk-stratification? Many countries are involved in the BHGI. In 2009, Lancet Oncology published our report on the Asian Oncology Summit, which used our framework to develop five guidelines for Asia.1 I am really excited about the upcoming third edition of Disease Control Priorities (DCP3), coordinated by the University of Washington Department of Global Health, funded by the Bill and Melinda Gates Foundation, and published by the World Bank. This evaluation tool provides an economic framework for health management in low and middle income countries. DCP3 will be launched to coincide with World Cancer Day on February 15, 2015. For the first time, DCP3 will include a full volume focused on cancer, using a modified version of the BHGI resource-stratification framework, characterizing resources as basic, limited, and augmented. The concept of resource stratification is taking off, and the next step is how to implement it.

Cultural Understanding Is Key What factors are key to its success? Guidelines and interventions must be relevant to the countries you are trying to help. For some countries, they are trying to figure out how to get patients to come for medical care before they develop ulcerating breast masses. Late detection of breast cancer is the major problem in the developing world, not overtreatment of breast cancer, as commonly discussed in the United States.

Cultural understanding is another key factor. The BHGI framework needs to be implemented in the context of social and cultural norms within a given environment.

Cultural Obstacles What obstacles have you encountered related to cultural beliefs? Cancer fatalism is a huge obstacle. Some people believe that God has created cancer as an irreversible punishment, or that witchcraft has delivered the disease as a curse. If you believe that cancer is invariably fatal, why would you participate in a program aimed at early detection? Other obstacles include fear of stigmatization. In some Sub-Saharan African countries, it is common that a husband would divorce a wife with cancer, stripping her of any claim to her home or marital property. This is a huge disincentive toward early breast cancer detection.

Power of Advocacy Can advocacy play an important role? Powerful advocates can change awareness and influence policy. Survivors can become advocates, so we have to produce survivors by focusing on early cancer detection, diagnosis, and treatment. Advocacy may be the single most powerful tool in addressing breast cancer globally. It is not an add-on; it’s a core feature.

Focus on Radiation Therapy How is radiation therapy being approached in countries with few resources? In the poorest regions of the world, radiation therapy is absent or so limited that it is not available, according to a recent International Atomic Energy Agency (IAEA) report. Radiation oncologists are lobbying to bring radiation therapy to these countries. Radiation therapy can be important for palliative care, as well as curative, and it is one of the few effective treatments for painful bone metastasis. This is important in countries where cancers are discovered at advanced stages. Also, cancer is the only disease for which radiation is a treatment. A first step in low-resource countries is to develop a center for excellence with an infrastructure, which becomes a magnet for multidisciplinary treatment and training. Radiation therapy is often the beginning of that cancer center, because it attracts other specialists like surgeons and medical oncologists involved in both curative and palliative care.

Appropriate Tools What are some of the issues in bringing radiation therapy to the developing world? What we consider the best solutions may not be implementable in developing countries. However, tools we consider no longer appropriate may, in fact, be the only way to bring radiation therapy to these environments. One of the simplest approaches is to use cobalt as a radioactive source, because it is renewable and does not require running water and electricity grids like linear accelerators do. However, many governments do not like cobalt, because it can be used in dirty bombs.

Developing Radiation Centers Has anyone quantified the actual need for radiation therapy in developing countries with limited resources? Two groups are working on this. Mary Gospodarowicz, MD, of Princess Margaret Hospital, Toronto, Canada, recently convened a Global Task Force for Radiotherapy in Cancer Control. And the IAEA is attempting to quantify the need and costs in different countries—one at a time. The goal is to develop radiation centers in these countries. The IAEA is interested in providing linear accelerators and related infrastructure to make radiation treatment practical and available.

Stepwise Progress Are any of these countries interested in developing radiation centers? A number of countries have recognized the importance of developing radiation centers, and their health-care ministries are trying to address this goal. A key concept is that our job is not to go into countries and fix cancer, but rather to provide the tools so people can address problems in their own countries in sustainable ways. The IAEA is driving efforts on the ground, including its PACT [Program Action for Cancer Therapy] initiative. I feel positive about this work and other efforts by the IAEA. It is a very exciting time. I think we are making stepwise progress in the delivery of cancer care, and radiation therapy is a component of that. Rome was not built in a day! n

Disclosure: Dr. Anderson reported no potential conflicts of interest.

Reference 1. Consensus statements from the Asian Oncology Summit 2009. Lancet Oncol 10:1075-1127, 2009.

The ASCO Post | JANUARY 25, 2015

PAGE 116

ASH Annual Meeting Hematology

Venetoclax Gaining Ground in Two Types of Leukemia By Alice Goodman

enetoclax, formerly known as ABT-199, is moving forward into phase III development in acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL), based on encouraging data from separate phase Ib and II trials presented at the 56th Annual Meeting and Exposition of the American Society of Hematology (ASH). Venetoclax is being studied in combination with other drugs used to treat AML and CLL. It is also being studied in non-Hodgkin lymphoma. Venetoclax is an inhibitor of the B-cell lymphoma–2 (BCL-2) protein, which interferes with cell death and is expressed in cancers of the lymph nodes, spleen, and other organs of the immune system. Venetoclax “cuts off” BCL-2, thereby restoring apoptosis of cancer cells.

Acute Myelogenous Leukemia Encouraging results were reported from a phase II trial evaluating singleagent venetoclax in patients with relapsed/refractory AML and as frontline therapy in AML patients unfit for intensive chemotherapy.1 “AML is an aggressive cancer with low survival rates, and there is a high need for new, effective treatment options. The results of this trial of venetoclax are encouraging and warrant additional study in patients with AML,” said Marina Konopleva, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston. The study included 32 patients. Venetoclax achieved an overall response rate of 15.5%; one patient had a complete response, and four patients had a complete response with incomplete platelet recovery. Isocitrate dehydrogenase (IDH) mutations are currently of interest in AML and are thought to be a potential target in this malignancy. Three of the patients who had complete responses and incomplete platelet recovery had IDH mutations; two of the IDH-positive patients achieved minimal residual disease negativity, with complete abolishing of leukemic cells. Venetoclax was successful in reducing the bone marrow blast count. In evaluable patients who received venetoclax, the median blast count was reduced by 36%; six patients (19%) had at least a 50% reduction in blasts. Adverse events occurring in up to 25% of patients included nausea, diarrhea, fatigue, neutropenia, and vomit-

ing. Grade 3 and 4 adverse events occurring in up to three patients were febrile neutropenia, anemia, and pneumonia.

Chronic Lymphocytic Leukemia A phase Ib study of the combination of venetoclax plus rituximab (Rituxan) demonstrated encouraging safety and excellent activity in patients with CLL.2 Venetoclax will move on to a phase III study, which will compare it in combination with rituximab vs bendamustine (Treanda) and rituximab in previously treated CLL. “Venetoclax plus rituximab is highly active in relapsed/refractory CLL, achieving an overall response rate of 88% and a complete response rate of 31%. The results suggest that rituximab adds to the efficacy of venetoclax,” said lead author Andrew Roberts, MD, of Royal Melbourne Hospital, Parkville, Australia. “Seventeen patients became minimal residual disease–negative on treatment, which is impressive bone marrow clearance,” he noted. Venetoclax as a single agent induced rapid responses in about 80% of patients with relapsed/refractory CLL. Preclinical models showed synergy between venetoclax and rituximab, one of the backbones of treatment of CLL. The phase Ib study was undertaken to determine whether the addition of rituximab would improve the efficacy of venetoclax. The phase Ib study was designed to identify a maximal tolerated dose of

EXPERT POINT OF VIEW

“T

hese studies are interesting, with provocative and compelling findings,” said Timothy Graubert, MD, the Hagler Family Chair in Oncology and Director of the Hematologic Malignancy Program at Massachusetts General Hospital in Boston. “Bcl-2 proteins regulate cell survival or promote cell death. They can be aberrantly expressed, and the imbalance of these factors can contribute to leukemia initiation and therapeutic resistance. ABT-199 Timothy Graubert, MD [venetoclax] tips the balance toward cell death,” Dr. Graubert explained. The study in AML included 40% of patients with secondary AML and 40% who had had three or more prior therapies. “These are bad actors resistant to therapy and high-risk refractory diseases—the worst of the worst,” he stated. Tumor lysis syndrome has been a concern with this agent. Adjusting the dose downward and monitoring for tumor lysis syndrome seemed to have decreased the risk, he continued. “Thus, this improved safety and tolerability in this study,” Dr. Graubert noted. The gastrointestinal side effects were manageable and did not lead to treatment discontinuation. The AML patients with IDH mutations had higher response rates. This unexpected result may turn out to be important, and this observation needs to be studied further, he said. n Disclosure: Dr. Graubert reported no potential conflicts of interest.

increasing in increments weekly to the recommended dose. Rituximab was given every 4 weeks for six doses. “The new schedule overcomes tumor lysis syndrome,” Dr. Roberts said. Venetoclax was generally well tolerated, with mild gastrointestinal toxicity and grade 3 or 4 myelosuppression: neutropenia, 47%; thrombocytopenia,

The results of this trial of venetoclax are encouraging and warrant additional study in patients with AML. —Marina Konopleva, MD, PhD

venetoclax as well as the optimal schedule of giving the drug with rituximab. The study enrolled 49 patients with relapsed/refractory CLL, with a maximum of three previous myelosuppressive regimens and no previous transplant. Treatment discontinuation was reported in 10 patients, one after the occurrence of tumor lysis syndrome. This adverse reaction led to modifications of the initial dosing regimen for venetoclax, starting at 20 mg daily and

16%; and anemia, 14%. The overall response rate was 88%; 31% had a complete response or a complete response with incomplete platelet recovery; 45% had a partial response; and 12% had an unconfirmed partial response. Similar rates of responses were also seen in the subset of patients with 17p deletion. Nine of the 15 complete responders tested negative for minimal residual disease on flow cytometry, and an ad-

ditional responder tested negative for minimal residual disease at 14 months. Eight of the partial responders tested negative for minimal residual disease. None of the five complete responders who discontinued therapy had disease progression up to 26 weeks. The study failed to identify a maximum tolerated dose; 400 mg is the currently recommended phase II dose based on toxicity and efficacy data. Higher doses were associated with slightly more neutropenia, gastrointestinal toxicity, and dose reductions. n

Disclosure: Drs. Konopleva and Roberts have received research funding from AbbVie and Genentech. Dr. Roberts is employed by the Walter and Eliza Hall Institute of Medical Research, which receives milestone payments for the development of ABT-199.

References 1. Konopleva M, Pollyea DA, Potluri J, et al: A phase 2 study of ABT-199 in patients with acute myelogenous leukemia. 2014 ASH Annual Meeting. Abstract 118. Presented December 7, 2014. 2. Roberts AW, Ma S, Brander DM, et al: Determination of the recommended phase 2 dose of ABT-199 combined with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia. 2014 ASH Annual Meeting. Abstract 325. Presented December 8, 2014.

ASCOPost.com | JANUARY 25, 2015

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ASH Annual Meeting Hematology

Blinatumomab Achieves Complete Molecular Responses in Majority of B-Cell Leukemia Patients By Alice Goodman

esults from the international phase II BLAST study show that one cycle of blinatumomab (Blincyto) immunotherapy achieved complete minimal residual disease response in 78% of patients with acute lymphoblastic leukemia.1 Complete minimal residual disease response was achieved in 80% of patients across all cycles of blinatumomab. The study is unique in that it used minimal residual disease status as part of the inclusion criteria and minimal residual disease response as its primary endpoint. Minimal residual disease response is a measure of complete eradication of disease. Patients can achieve a complete hematologic remission by conventional measures, ie, less than 5% blasts, and still have minimal residual disease at the molecular level, explained lead author

of Hematology. “New approaches are needed to improve outcomes in patients with persistent or recurrent minimal residual disease.” Blinatumomab has recently been granted U.S. Food and Drug Administration approval for treatment of patients with Philadelphia-negative precursor B-cell acute lymphoblastic leukemia. It is the first in a novel class of drugs called bispecific T-cell engagers (BiTE), and it is designed to direct cytotoxic T cells to CD19-expressing cancer cells, found on the cell surface of B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma.

Study Details and Findings BLAST enrolled 116 adults from 46 centers in 11 counties; all patients had B-cell acute lymphoblastic leukemia in complete hematologic remis-

It is now possible to assess minimal residual disease by quantitative measurement of individual T-cell receptor and immunoglobulin rearrangements in more than 90% of acute lymphoblastic leukemia patients. Minimal residual disease is a strong prognostic factor for relapse and overall survival. —Nicola Goekbuget, MD

Nicola Goekbuget, MD, Goethe University Hospital, Frankfurt, Germany. “It is now possible to assess minimal residual disease by quantitative measurement of individual T-cell receptor and immunoglobulin rearrangements in more than 90% of acute lymphoblastic leukemia patients. Minimal residual disease is a strong prognostic factor for relapse and overall survival. Nearly all patients with persistent or recurrent minimal residual disease relapse despite continued chemotherapy, and minimal residual disease persistence indicates resistance to conventional chemotherapy,” she told listeners at a press conference during the 2014 Annual Meeting of the American Society

sion (< 5% blasts after three cycles of chemotherapy) but were minimal residual disease-positive (ie, level of ≥ 10-3). Central nervous system involvement was an exclusion criterion. No prior allogeneic hematopoietic

EXPERT POINT OF VIEW

“B

linatumomab is one of several approaches to harness the immune system, and these therapies will revolutionize the treatment of cancer, but we will have to balance the effects of ‘revving up’ the immune system with toxicity. Compared with CAR [chimeric antigen receptor] T cells [made from each patient’s T cells] genetically engineered to target the CD19

Blinatumomab is one of several approaches to harness the immune system, and these therapies will revolutionize the treatment of cancer. —Catherine Bollard, MD

antigen, blinatumomab is an ‘off the shelf ” treatment for all patients,” said Catherine Bollard, MD, a bone marrow transplant specialist at Children’s National Hospital and George Washington University, Washington, DC. n stem cell transplant was allowed. The median age was 45 years (range, 18 to 76 years). Two-thirds were in first relapse, and about one-third was in second relapse; 2% were in third relapse. All patients received at least one cycle of blinatumomab and were assessed for minimal residual disease in a reference lab. Patients continued on blinatumomab for up to three additional cycles, and transplant-eligible patients with a donor went on to hematopoietic stem cell transplant. They were followed for efficacy for 2 years. Patients treated with blinatumomab achieved minimal residual disease responses regardless of age, minimal residual disease level at baseline, or relapse history. No predictive factor for response was identified.

Blinatumomab for B-Cell Acute Lymphoblastic Leukemia ■■ The first bispecific T-cell engager (BiTE) agent to be approved by the FDA achieved molecular remissions in 78% of patients with B-cell acute lymphoblastic leukemia. ■■ The study is unique in that it used the presence of minimal residual disease as an inclusion criterion and minimal residual disease response as a primary endpoint. ■■ Responses were seen at all ages and in patients with a high minimal residual disease level at baseline.

Adverse events occurring in 20% or more of patents included immune reactions of pyrexia, fever, and chills; only 7% had grade 3 or higher fever. Gastrointestinal side effects occurred in about 22% of patients. Twenty-nine percent of patients had tremor, and 13% had aphasia. “Neurologic symptoms are clinically relevant, although most neurologic events on study were grade 1 or 2,” she said. “Blinatumomab is more easily applicable than CAR [chimeric antigen receptor] T cells. This drug makes the T cells do the job in vivo. The drug has just been approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia, and the question is whether it will find a role in front-line treatment,” she commented. n Disclosure: Dr. Goekbuget reported being a consultant and receiving honoraria and research funding from Amgen Inc.

Reference 1. Goekbuget N, Dombret H, Bonifacio M, et al: BLAST: A confirmatory, singlearm, phase 2 study of blinatumomab, a bispecific T-cell engager (BiTE) antibody construct, in patients with minimal residual disease B-precursor acute lymphoblastic leukemia. 2014 ASH Annual Meeting. Abstract 379. Presented December 8, 2014.

The ASCO Post | JANUARY 25, 2015

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ASH Annual Meeting Hematology

Victory for Pediatric Regimens in Adolescents and Young Adults With ALL By Alice Goodman

ong in the works, early results of the U.S. Intergroup C10403 trial clearly showed that treating acute lymphoblastic leukemia (ALL) in adolescents and young adults using a pediatric-inspired regimen improves event-free survival and overall survival and should be the backbone for future studies in this age group.1 Experts agreed that this finding represents a paradigm shift in how to treat adolescents and young adults with ALL. “This large North American trial validates that pediatric ALL regimens administered by adult hematologists/ oncologists improve survival in adolescents and young adults compared with adult regimens. The 2-year event-free survival of 66% and 2-year overall survival of 79% are major improvements compared with 34% and 39%, respectively, in historic controls. This is a clear opportunity to improve care in adolescents and young adults with ALL,” said lead author Wendy Stock, MD, of the University of Chicago Medical Center. Other important findings of this long-awaited study are that the presence of a BCR-ABL1–like signature and aberrant CRLF2 expression are associated with worse event-free survival and overall survival and represent high-risk characteristics. “Excellent event-free survival and overall survival were achieved if these features were not present,” Dr. Stock told the audience. “We can now focus additional research on evaluating novel treatment combinations to reduce minimal residual disease in these patients to further improve their duration of response and long-term survival.” The concept that pediatric regimens could improve outcomes for adolescents and young adults with ALL gained attention in the year 2000, when retrospective data showed that outcomes were dramatically different, “depending on the door through which these patients entered,” she said. At that time, Dr. Stock and colleagues reported that patients aged 16 to 20 years had

significantly better outcomes on pediatric protocols than on adult protocols, and this finding was subsequently confirmed by groups of investigators in multiple countries. The cooperative groups undertook the Intergroup C10403 trial in North America to evaluate treatment with a pediatric-intensive regimen by adult hematologists/oncologists. At the 2014 ASH Annual Meeting, Dr. Stock presented the main results of the trial. Findings on adherence and outcomes based on psychosocial factors will be presented separately in the future.

A Glimpse at Study Details The study enrolled 318 patients, aged 16 to 39 years old, with ALL; 22 patients withdrew from the study, many of whom had Philadelphia chromosome–positive disease, which was an exclusion criterion. From 2007 to 2013,

Pediatric Regimens in Adolescents and Young Adults With ALL ■■ A large cooperative group, prospective study validated the use of a pediatric-inspired regimen for the treatment of older adolescents and young adults with acute lymphoblastic leukemia (ALL). ■■ These results are long awaited and establish a protocol that represents a paradigm shift in the treatment of ALL in this age group. ■■ The pediatric-inspired regimen is a platform for future studies aimed at eradication of minimal residual disease in high-risk groups.

L-asparaginase (Oncaspar) and more maintenance therapy. “These are the essential ingredients. The drugs we intensified in the adult ALL world were myelosuppressive. This regimen goes back to nonmyelosuppressive regimens,” Dr. Stock explained at a press conference. The regimen consisted of induction, consolidation, interim maintenance, delayed intensification, and prolonged maintenance (2 years for girls and 3 years for boys).

Use of the pediatric regimen in C10403 will serve as a foundation for future studies in adolescents and young adults with ALL in U.S. Intergroup trials. This represents a shift in the approach to treatment of adolescents and young adults with ALL. —Wendy Stock, MD

296 patients were treated. The median age of study patients was 25 years, and most patients were between 20 and 29 years. Seventy-five percent were white, 10% were African American, and 15% were Hispanic/ Latino. About three-quarters had Bprecursor ALL and one-quarter, Tprecursor ALL. Interestingly, 31% had a body mass index > 30, and 7% were morbidly obese. The backbone of the pediatric-inspired regimen included intensified glucocorticoid, vincristine, and pegylated

Foundation for Future Studies Event-free survival analysis showed no difference according to age group or precursor B-cell or T-cell lineage. Overall survival was significantly worse in obese patients and significantly improved in patients with undetectable minimal residual disease, Dr. Stock said. In a multivariate analysis, the only significant risk factor for event-free survival and overall survival was aberrant expression of CRLF2. Dr. Stock noted that only 90 patients had sufficient data for inclusion in the multi-

variate analysis. The regimen still needs to be finetuned to optimize dose reductions in pegylated-L-asparaginase and still achieve adequate depletion of leukemic cells, she told the audience. “Use of the pediatric regimen in C10403 will serve as a foundation for future studies in adolescents and young adults with ALL in U.S. Intergroup trials. This represents a shift in the approach to treatment of adolescents and young adults with ALL,” Dr. Stock stated. Dr. Stock and colleagues are preparing a concept for the successor U.S. Intergroup trial, which should begin in 2015. The plans include use of the molecular signature of the disease to stratify patients and to add either a novel antibody or a targeted kinase inhibitor to eradicate minimal residual disease and improve outcomes. “Other groups around the world are also adopting the use of pediatric regimens for the treatment of the young adult with ALL,” Dr. Stock said in an e-mail. n

Disclosure: Dr. Stock has received research funding from Sigma-Tau and is a member of an entity’s Board of Directors or advisory committees.

Reference 1. Stock W, Luger SM, Advani AS, et al: Favorable outcomes for older adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL): Early results of U.S. Intergroup Trial C10403. 2014 ASH Annual Meeting. Abstract 796. Presented December 9, 2014.

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The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

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DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1,2

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

as a single agent

overall response rate1 overall response rate1

76 54%

% (95% CI: 62, 87)

median duration of response1

(95% CI: 40, 67)

median duration of response1

10.5 5.6

months

(95% CI: 7, 15)

months

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1 Major efficacy outcome: Investigator-assessed response rate1 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

50 40 30 20 10 0

Complete Response

Partial Response

TAFINLAR as a single agent (N=54)

Complete Response

TAFINLAR

150 mg twice daily

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1 Efficacy outcome: Investigator-assessed median duration of response1

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months Months TAFINLAR as a single agent (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

(dabrafenib) 50 mg, 75 mg capsules

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination. Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%). The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%). Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions. To learn more, visit TAFINLARMEKINISTHCP.com Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages. Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703. TAFINLARMEKINISTHCP.com TAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014

(dabrafenib) 50 mg, 75 mg capsules

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)]. 5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. 5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. 5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. 5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)]. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. 5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination. 5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. 5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white. Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent. In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination. Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades Adverse Reactions Gradesa 3 and 4 Gradesa General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders 45 0 43 Rashc Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute. Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness. Gastrointestinal Disorders: Stomatitis, pancreatitis. General Disorders and Administration Site Conditions: Asthenia. Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular. Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma. Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension. Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

All All All Grades Grades Grades Grades 3 and 4 Grades 3 and 4 Grades 3 and 4a Tests Hematology Leukopenia 62 5 46 4 21 0 Lymphopenia 55 22 59 19 40 6 Neutropenia 55 13 37 2 9 2 Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0 Liver Function Tests Increased AST 60 5 54 0 15 0 Increased alkaline 60 2 67 6 26 2 phosphatase Increased ALT 42 4 35 4 11 0 Hyperbilirubinemia 15 0 7 4 0 0 Chemistry Hyperglycemia 58 5 67 6 49 2 Increased GGT 56 11 54 17 38 2 Hyponatremia 55 11 48 15 36 2 Hypoalbuminemia 53 0 43 2 23 0 Hypophosphatemia 47 5 41 11 40 0 Hypokalemia 29 2 15 2 23 6 Increased creatinine 24 5 20 2 9 0 Hypomagnesemia 18 2 2 0 6 0 Hyperkalemia 18 0 22 0 15 4 Hypercalcemia 15 0 19 2 4 0 Hypocalcemia 13 0 20 0 9 0 a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase. QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent. 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. 7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)]. Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight. MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)]. Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss. In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals. 8.3 Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1. Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older. 8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)]. Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients. Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)]. MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)]. Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)]. Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)]. MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment. 8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated. • TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)]. • TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal. TAFINLAR is a registered trademark of GlaxoSmithKline. MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

ASCOPost.com | JANUARY 25, 2015

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Announcements

NIH Recruits Three Lasker Clinical Research Scholars

he National Institutes of Health (NIH) has selected three researchers as new Lasker Clinical Research Scholars as part of a joint initiative with the Albert and Mary Lasker Foundation to nurture the next generation of great clinical scientists. This highly competitive program provides talented early-stage researchers the opportunity to carry out in-

“Identifying talented and innovative scholars early in their careers is paramount to building a robust cadre of physician-researchers,” said NIH Director Francis S. Collins, MD, PhD. “We hope this continued effort with the Lasker Foundation leads to major scientific discoveries that impact human health.” “The Lasker Clinical Research

Identifying talented and innovative scholars early in their careers is paramount to building a robust cadre of physician-researchers. —Francis S. Collins, MD, PhD

dependent clinical and translational research for 5 to 7 years at the NIH campus in Bethesda, Maryland. Upon project review, the researchers also have the possibility of additional years of financial support, at the NIH or an NIH-funded research institution. The scholars are Hans Ackerman, MD, DPhil, Andrea Apolo, MD, and Falk Lohoff, MD. They join two NIH Lasker scholars hired previously.

Scholars is an innovative program that supports accomplished young clinician researchers as they work to discover new knowledge and develop therapies and cures,” added Lasker Foundation President Claire Pomeroy, MD, MBA. “Providing career pathways for the next generation of scientific investigators is crucial to carrying out the Lasker mission to improve health by accelerating support

of medical research. We are excited to continue growing this program and look forward to the breakthroughs that will be made by these talented individuals.”

Closer Look at the Scholars Dr. Ackerman is Chief of the Physiology Section in the Sickle Cell Branch at NIH’s National Heart, Lung, and Blood Institute. He is studying how metabolic and genetic factors affect blood flow in people with sickle cell disease, with a special emphasis on stroke and kidney injury in adults. He also is working with the Sickle Cell Research and Treatment Center in Bamako, Mali, to identify the major causes of death and disability in children with sickle cell disease. Dr. Apolo is Chief of the Bladder Cancer Section at NIH’s National Cancer Institute, where her research involves developing and designing clinical trials to test novel agents for the treatment of urologic cancers. Her primary research interest is in bladder cancer (urothelial carcinoma). In particular, she is working to develop new bladder cancer targeted therapies such as antiangiogenesis compounds, Met inhibitors, and immunotherapeutic combinations.

Dr. Lohoff is Chief of the Section on Clinical Genomics and Experimental Therapeutics in the Laboratory of Clinical and Translational Studies at NIH’s National Institute on Alcohol Abuse and Alcoholism. His research focuses on heritable and nonheritable genetic aspects that influence the onset, progression, and treatment of alcohol use disorders and addictions. Findings from these studies are translated into human clinical studies using diverse approaches, including molecular biomarkers, pharmacogenetics, epigenetics, and functional imaging genetics. The Lasker scholars have access to the NIH Clinical Center, one of the largest hospitals in the world devoted to clinical research. The Lasker Foundation will provide additional developmental support to the scholars while they are working at NIH by funding travel to scientific meetings and providing the opportunity to participate in selected Foundation activities. The Lasker Clinical Research Scholar program honors the contributions of Mary and Albert Lasker to the NIH and the overall biomedical community. Learn more about the program at http://www.nih.gov/science/ laskerscholar. n

Two Oncology Leaders Elected Members of ASCO Nominating Committee

SCO recently announced election of Lisa A. Carey, MD, and Primo N. Lara, Jr, MD, to serve a 3-year term on the ASCO Nominating Committee beginning in 2016 (see pages 101-102 for news on other ASCO elections). Lisa A. Carey, MD, is Chief of the Division of Hematology/Oncology and Physician-in-Chief of the North Carolina Cancer Hospital. She is the Jacobs Preyer Distinguished Professor in Breast Cancer Research and Associate Director for Clinical Research at

the University of North Carolina Lineberger Comprehensive Cancer Center. Dr. Carey joined ASCO in 1997 and has served as Subcommittee Chair of the Professional Development Committee and Track Leader of the Cancer Education Committee, as well as a member of the Breast Cancer Consensus Panel and the Editorial Board of the Journal of Clinical Oncology. She will serve as the Chair of the Nominating Committee in 2017–2018. Primo N. Lara, Jr, MD, is Professor of Medicine at the University of Cali-

fornia (UC) Davis School of Medicine and Associate Director for Translational Research at the UC Davis Comprehensive Cancer Center. Since joining ASCO in 1997, he has served on the Cancer Education Committee, including as Chair of its ConLisa A. Carey, MD Primo N. Lara, Jr, MD tinuing Medical Education Subcommittee and as Genitourinary Cancers track leader, and on Board of Directors for the Association the Editorial Board of the Journal of of Northern California Oncologists, Clinical Oncology. He has served on the an ASCO State Affiliate Society. n

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PAGE 128

ASH Annual Meeting Hematology

Cleveland Clinic Piloting ‘Adaptive Therapy’ Approach in Multiple Myeloma By Caroline Helwick

or newly diagnosed multiple myeloma patients, Cleveland Clinic specialists believe two drugs may suffice for most patients, bucking the trend toward using triplets for all patients and reserving them for patients with insufficient response to two. They described a pilot study of their “carepath” at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition.1 The carepath was described at the ASH meeting by two members of the Cleveland Clinic team: lead author Mayur Narkhede, MD, and senior investigator Frederic Reu, MD, who designed the algorithm.

Study Goals “VRD (bortezomib [Velcade]/ lenalidomide [Revlimid]/dexamethasone) is preferred by many centers due to higher response rates, although no survival advantage over Rd (lenalidomide/dexamethasone) has been shown. Since no test predicts who may experience harm from insufficient or

ease control with two drugs, and the majority ultimately achieved a very good partial response or better,” he said. “The problem with multiple myeloma research is that studies ignore the huge heterogeneity of this disease. No one adjusts the treatment plan according to anything that can be measured,” Dr. Reu noted. “Our pilot data show that this is generally safe and achieves disease control in all the patients tested so far.”

Carepath Details The response-adaptive carepath was developed for newly diagnosed symptomatic patients with measurable disease and without associated amyloidosis, who were ineligible for or uninterested in trial participation. The carepath advises initial treatment with Rd or bortezomib/dexamethasone (VD), with therapy adjusted depending on the initial early response endpoints. When patients fail to achieve reduction of M proteins to at least a minor response range after the first cycle or at

Maybe we don’t need three drugs in all cases. In more than 60% of patients, we achieved disease control with two drugs, and the majority ultimately achieved a very good partial response or better. —Frederic Reu, MD

excessive therapy, we designed a carepath that starts with two drugs but adapts treatment early to achieve uniform myeloma control,” Dr. Narkhede said. While an overall survival advantage has not yet been observed, a higher risk of side effects and higher costs have clearly been demonstrated, they noted. In cytogenetically high-risk patients, use of three drugs for induction actually reduced overall survival in a retrospective analysis from Moffitt Cancer Center, they added. Dr. Reu added, “Maybe we don’t need three drugs in all cases. In more than 60% of patients, we achieved dis-

least a partial response range after the second cycle of front-line treatment, clinicians add the other novel agent, then give another 1 to 2 cycles using the same parameters before stepwise addition of cyclophosphamide, and if these response endpoints are still not met after an additional 2 cycles, liposomal doxorubicin may also be given. The choice between Rd and VD is based on insurance coverage and status of the kidneys; patients with suspected cast nephropathy receive VD. Dr. Narkhede said an important component of this carepath is frequent assessments. “We assessed response after each cycle. Although we want to

Adaptive Therapy for Multiple Myeloma ■■ A treatment carepath in newly diagnosed symptomatic multiple myeloma patients starts with two drugs and adds a third (or more) only if an early partial response is not achieved. ■■ In a pilot study of 24 patients at the Cleveland Clinic, this response-adaptive design achieved disease control in all patients, including in 60% given only lenalidomide or bortezomib plus dexamethasone.

control multiple myeloma with two drugs if possible, we also want to avoid disease progression, since it can cause irreversible organ damage or death. This is generally avoided in partial remission, the first goal of induction, after which consolidation with autologous stem cell transplant is considered in eligible patients.” After transplant, patients entered maintenance with low-dose lenalidomide or every-other-week bortezomib. If they did not undergo transplant, either because they were thought to be ineligible or they decided against it, patients continued on the doublet that produced a partial response, and after 3 years, entered the single-agent maintenance phase. If three or more drugs were required for induction, patients continued for 1 year on that regimen, then switched to VRD for 2 years, then entered maintenance.

Initial Success With Doublet In a pilot study of 24 patients, 15 received induction with a doublet, 6 received a triplet, and 3 received four drugs. Among the 24 patients, 17 received Rd initially and 7 received VD. Of the 17 on Rd, partial responses or better were observed in 12. Of the seven VD-treated patients, three had at least a very good partial response. In this group, who were treated with doublets only, one patient who initially achieved a partial response had progressive disease after 6.5 months. Response-adapted therapy allowed disease control with the Rd or VD doublet in about 60% of patients after a median follow-up of almost 11 months. Subsequent triplets controlled disease in another 30%, while 10% required a fourth drug. “Disease was controlled predominant-

ly with a doublet,” Dr. Narkhede said. Response-adapted therapy also avoided disease progression during induction and, so far, also death during follow-up. “None of 24 patients progressed before reaching a partial remission, the main goal of response-adapted induction, after a median follow-up of 10 months,” he noted. Adverse events included hospitalization in one patient, below-the-knee deep-vein thrombosis in two patients, and peripheral neuropathy in two patients (one was grade 3 but transient). The authors concluded that compared to VRD for all patients, which is an emerging trend, doublets reduced the rate of peripheral neuropathy and the cost of treatment. They estimated that the savings for this small cohort exceeded $4,000 per cycle.

Looking Ahead Overall survival will be the ultimate assessment of the utility of this approach, but the response assessments to date support the ongoing use of the carepath, the authors concluded. Dr. Reu said he would not be surprised if the carepath suggested a survival advantage. “In the future we need to test if this might translate into better overall survival. Maybe we are not causing drug resistance as fast as if we start off with three drugs.” n

Disclosure: Dr. Reu has received research funding from Celgene, Novartis, and Millennium/Takeda, has been a consultant for Millennium/Takeda, and a member of the speakers bureau for Onyx. Dr. Narkhede reported no potential conflicts of interest.

Reference 1. Narkhede M, Valent J, Cummings C, et al: Results of an upfront myeloma carepath pilot with response-adapted therapy. 2014 ASH Annual Meeting. Abstract 2620. Presented December 7, 2014.

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ASH Annual Meeting Hematology

Will Checkpoint Inhibitors Be Winners in Hematologic Cancers, Too? By Caroline Helwick

“Featured Topic” session during the 56th American Society of Hematology (ASH) Annual Meeting and Exposition drew a standing-room-only crowd to hear two experts weigh in on checkpoint blockade in hematologic malignancies. While new to hematology, these drugs— the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitor ipilimumab (Yervoy) and the programmed cell death protein 1 (PD-1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda)—are already being incorporated into the treatment paradigm of solid tumors. Stephen Ansell, MD, PhD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota, described the immunologic state of the intratumoral environment in lymphoma and how

Stephen Ansell, MD, PhD

its manipulation can be beneficial. Ronald Levy, MD, Professor of Medicine at Stanford University, Palo Alto, California, reviewed studies of these agents presented at the ASH meeting and predicted how these drugs will be clinically applied in hematology. “I was disappointed that there were only four abstracts altogether in all of hematologic cancers, involving just 130 patients, so there’s still a paucity of data,” Dr. Levy said. “I suspect there will be many more papers at ASH next year.”

Powerful Immune Components “In lymphoma, there are immunologic barriers present in the intratumoral environment that damp down an effective immune response, and there are potential therapeutic targets to modulate immune function,” Dr. Ansell said. It has been known for some time that T cells are present in the intratumoral environment, but whether they are beneficial or harmful has not been clear. A greater percentage of CD8-positive T cells or CD4-positive T cells correlate with a lower proliferative rate. However, this does not result in clearance of the tumor. In fact, complete responses are seen in the absence of high T-cell counts. “Could we activate T cells and

produce a more effective immune response?” he asked. “To do so would require overcoming multiple immunologic barriers.” In short, the lymphoma B cell recruits T regulatory cells to the tumor and ulti-

Ronald Levy, MD

mately skews the microenvironment in favor of this phenotype. Also present are effector T cells, many of which become “exhausted” and have limited ability to eradicate the tumor. Additionally, many cells express immunosuppressive ligands on their surface. Intratumoral monocytes and follicular dendritic cells are also present. This composition supports the malignant environment, he explained. Such factors “stack the deck against an effective immune response,” he said. “Understanding these barriers gives opportunities for therapeutic intervention.” This is what is happening now with the checkpoint inhibitors, which are “taking the brakes off the immune system,” blocking these inhibitory signals and correcting the unfavorable environment for the effector T cells. By overcoming the immunosuppressive events that have limited their ability, the T cells can now target the tumor cell. Dr. Ansell pronounced immune therapy “the new frontier,” one that “holds real promise” and is “only the beginning of a new wave.”

Activity May Be Limited “Immunologists have provided us with a plethora of targets,” Dr. Levy agreed. “T cells are being stimulated or inhibited by a variety of interactions on targets against which we now have antibodies.… The future holds an amazing array of new drugs that will unleash the T-cell immune response that’s always been lurking there…. We are already seeing responses, dramatically so, in ways we could not have predicted.” But Dr. Levy questioned whether these drugs will be potent in hematologic malignancies in general, or whether their benefit may be reserved for a malignancy that is tailor-made for them, Hodgkin

lymphoma, where there is increased PD-1 ligand (PD-L1/2) expression. “Here, we have a perfect situation for PD-1 blockade to work,” he said. “We have a target that is overexpressed by the tumor cells. When we take the brakes off the interaction between the PD-L1 ligand and the T cells, amazing things happen.” While he called the findings for nivolumab and pembrolizumab in Hodgkin lymphoma “pretty amazing stuff,” he was underwhelmed with the activity of checkpoint blockade in several other hematologic cancers. For example, in a phase I study of ipilimumab in 13 patients who had disease progression after allogeneic transplant and a median of seven prior therapies, the clinical benefit rate was 36%.1 The one responder had Hodgkin lymphoma. Three with lymphoid malignancies achieved stable disease. The most impressive finding was the lack of acute graft-vs-host disease with this treatment, he said. “The drug was deemed tolerable and promising, but I don’t think many of us want to manage grade 3 diarrhea. I think ipilimumab is going to be too toxic for me,” he offered. Similarly, in a phase I study of the PD-1 blocker nivolumab in 54 patients with relapsed/refractory lymphoid malignancies, the overall response rate was 28% in B-cell lymphomas and 17% in T-cell lymphomas.2 There were no responses in multiple myeloma patients. “If we are looking for an efficacy signal, I don’t think we are blown away by this,” he suggested. “We anxiously await more data from an ongoing phase II study, but at the end of the day, if the phase II efficacy is about the same, this may be great news to the immunologists but not so great to hematologists. We have lots of agents with that degree of efficacy.” Dr. Ansell, however, seemed more optimistic. He described a study (not presented at ASH) on the PD-1 blocker pidilizumab in 68 patients with diffuse large B-cell lymphoma, progressing after autologous transplant. Disease progression at 16 months was reduced by 28%, meeting the primary endpoint.3 “What was interesting is that a number of high-risk patients had positive positronemission tomography (PET) scans after transplant, and even they did well (51% response rate), suggesting that blockade of this mechanism is important,” he said. In another study, pidilizumab was combined with rituximab (Rituxan) in

32 patients with relapsed follicular lymphoma, producing a 66% response rate, including complete responses in 55%.4 “These encouraging responses suggest this might be a very active agent to add to rituximab,” Dr. Ansell said.

Indisputable Activity The activity was indisputable, however, for nivolumab and pembrolizu mab in Hodgkin lymphoma. In a phase I trial of nivolumab in 23 relapsed/refractory Hodgkin lymphoma patients, the objective response rate was 87%, and 17% of them were complete responses.5 “Have you ever seen a waterfall plot where essentially all the water was falling? Contrast this with what we see in non-Hodgkin lymphoma.” The responses were durable; at 24 weeks, progression-free survival was 86%. Of 10 tumors examined for PDL1/2 expression, all were amplified. At this point, however, the measurement of ligand expression is imperfect. Whether this can be used to select patients remains unclear. A similar study of pembrolizumab in 15 patients confirmed the effectiveness of blocking this interaction,6 but Dr. Levy tempered his enthusiasm for the PD-1 inhibitors in Hodgkin lymphoma by pointing out, “If we use PD-1 blockers only in relapsed/refractory patients, that’s a small use of these drugs. How to move this very active regimen up front in competition with all our other treatments, in a disease that we already treat very successfully, will be an interesting challenge.” n Disclosure: Dr. Ansell received research funding from Seattle Genetics, Bristol Myers Squibb, and Celldex. Dr. Levy received research funding from Pfzer, Bristol-Myers Squibb, and Pharmacyclics, and is a consultant for Five Prime, Bullet Biotech, Kite Pharma, BeiGene, Immune Design, and Immunocellular Therapeutics.

References 1. Davids MS, et al: ASH Annual Meeting. Abstract 3964. Presented December 8, 2014. 2. Lesokhin AM, et al: ASH Annual Meeting. Abstract 291. Presented December 8, 2014. 3. Armand P, et al: J Clin Oncol 31:41994206, 2013. 4. Westin JR, et al: Lancet Oncol 15:6977, 2014. 5. Armand P, et al: ASH Annual Meeting. Abstract 289. Presented December 8, 2014. 6. Moskowitz CH, et al: ASH Annual Meeting. Abstract 290. Presented December 8, 2014.

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Journal Spotlight Cancer Genetics

Study Finds Whole-Genome Sequencing Is Successful in Identifying Patients’ Risk for Inherited Cancers By Jo Cavallo

study by researchers at The University of Texas Southwestern Medical Center in Dallas and The Ohio State University in Columbus of wholegenome sequencing on patients found to have BRCA1 or BRCA2 mutations as well as on those who were not carriers of a BRCA1/2 mutation has found cancer risk of potentially pathogenic variants in the non-BRCA patients. Although the study results, published online in EBioMedicine,1 highlight the potential for improving risk assessment in patients with a family history of cancer, they also raise concerns over how best to counsel them. “Right now, performing whole-genome sequencing in the cancer genetics clinic is inappropriate, but ultimately this is what is going to happen,” said Theodora Ross, MD, PhD, Professor of Internal Medicine and Director of the Cancer Genetics Program at The Univer-

Theodora Ross, MD, PhD

sity of Texas Southwestern Medical Center and corresponding author of the study. She emphasized, however, that since there is the potential to identify not only genetic risks for the patient’s primary diagnosis, but also risks for other conditions, “genetic counseling is so important” for patients.

Study Details The researchers recruited 258 individuals from the cancer genetics clinics of The University of Texas Southwestern Medical Center and The Ohio State University cancer genetics programs. The researchers took blood samples from the patients and performed whole-genome sequencing on members of two cohorts of patients: those with BRCA1 (n = 88) or BRCA2 (n = 88) mutations and those who were not carriers of a BRCA1/2 mutation (n = 82). The genomes of 176 unrelated BRCA carriers at high risk for breast and ovarian cancers were first investigated to determine whether whole-genome sequencing confirmed the clinically diagnosed mutations. In the BRCA1/2 cohort, the researchers found that whole-genome

sequencing correctly identified the majority of clinically diagnosed BRCA1 and BRCA2 mutations, detecting 89.3% of

the BRCA1 mutations and 88.6% of the BRCA2 mutations. Initial analysis of potentially pathogenic variants in 163 other

clinically relevant genes suggested that whole-genome sequencing would provide added useful clinical results.

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Journal Spotlight

Loss-of-function variants represented only a small fraction of potentially pathogenic variants. However, after the researchers expanded their analysis to 3,209 genes, whole-genome sequencing identified additional cancer risk, loss-of-function variants, and potentially pathogenic variants in patients with known BRCA1/2 mutations. This

finding also led to diagnoses of cancer risk in 21% of the non-BRCA patients. In total, reported the researchers, whole-genome sequencing provided likely genetic cancer risk of potentially pathogenic variants in 20.7% of the non-BRCA1/2 clinic patients. In contrast, according to the study abstract, “A recent report using targeted gene

panel testing provided similar cancer risk of potentially pathogenic variants in 10.6% of non-BRCA1/2 patients.” “There are other major challenges involved in translating whole-genome sequencing into the clinic, including questions of mutation penetrance, better understanding of the genes about which we understand little, and how to counsel

Whole-Genome Sequencing in Breast Cancer ■■ Whole-genome sequencing performed on the germlines of patients with BRCA1 or BRCA2 mutations as well as on those who were not carriers of BRCA1/2 mutations identified potentially pathogenic loss-of-function mutations in cancer genes other than BRCA1/2. ■■ In the BRCA1/2 cohort, sequencing identified the majority of clinically diagnosed BRCA1 and BRCA2 mutations, detecting 89.3% of BRCA1 and 88.6% of BRCA2 mutations.

We want to change the face of EGFR-targeted therapy Rash is caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2 In the treatment of EGFR mutation–positive non–small cell lung cancer (NSCLC), rash and other skin toxicities are wellestablished side effects of EGFR tyrosine kinase inhibitors.3,4

90% of patients treated with approved EGFR inhibitors experience rash3,4 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.3,4

Rash and its symptoms can negatively affect both patient quality of life and patient compliance, while its psychosocial impact contributes to the assessment of severity.5,6 Beyond the clinical symptom burden, rash visibility can cause significant patient distress even when it is not severe.5 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

Clovis Oncology is leading the fight

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals LLC; 2014. 4. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 5. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurse. 2011;15(1):88-96. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed August 26, 2014. Copyright © 2014 Clovis Oncology. DARO-101 8/14

■■ Whole-genome sequencing provided likely genetic cancer risk diagnoses in specific cancer genes in 20.7% of the nonBRCA1/2 clinic patients.

patients who test negative or positive for an identified familiar mutation in one of the less well understood genes (CHEK2, PALB2, and RAD51C are good examples of this),” wrote the study authors.

Next Steps The researchers are submitting their whole-genome sequencing data to the National Center for Biotechnology Information database of genotypes and phenotypes repository, so other investigators can do their own analyses and publish their findings, said Dr. Ross. She also hopes to perform parallel wholegenome sequencing on the more than 2,000 patients who come into The University of Texas Southwestern Medical Center’s cancer genetics clinic for testing each year. In addition, Dr. Ross plans to use whole-genome sequencing to evaluate “mystery” patients—those with cancer-susceptibility syndromes but no known genetic defect—to attempt to identify candidate cancer genes. Most important, said Dr. Ross, is to make the study of single genes a top research priority. “The problem is there is not enough basic science being done on the newly discovered genes in the genome. We are finding all of these broken open reading frames, and few are doing the basic and creative research needed to understand these ‘new’ gene products’ purposes in the normal cell,” she said. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Foley SB, Rios JJ, Mgbemena VE, et al: EBioMedicine (2014) http://dx.doi. org/10.1016/j.ebiom.2014.12.003.

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ASH Annual Meeting Issues in Oncology

Panelists Lambast, Explore the High Cost of Cancer Drugs By Caroline Helwick

t the 2014 American Society of Hematology Annual Meeting, a symposium on the high cost of cancer drugs proved provocative and a bit testy as panelists presented their various points of view.

‘Medical Darwinian System’ Already known for his outspoken views on the topic is Hagop M. Kantarjian, MD, Professor and Chair of Leukemia at the University of Texas MD Anderson Cancer Center, Hous-

ment—$1 billion—calling this “a myth propagated by pharmaceutical companies.” Actually, the most recent figure is $2.6 billion, published in November 2014 by the Tufts Center for the Study of Drug Development, which, according to Dr. Kantarjian, is funded by the pharmaceutical industry. [Tufts website states that it receives “unrestricted grants from pharmaceutical and biotechnology firms as well as companies that provide related services to the research-based industry (eg, contract

There is no escape in the discussion of drug prices. We need a situation where cancer drugs are affordable and patients can take them without the anxiety associated with lack of affordability. —Hagop M. Kantarjian, MD

ton. Dr. Kantarjian did not mince words, laying the blame squarely on the drug manufacturers. “Are cancer drug prices too high? Definitely yes. Are they harming our patients? Yes, they are,” he said. He noted that the cost of cancer drugs has skyrocketed from about $10,000 for a year’s treatment prior to 2000 to $100,000 a year, a 10-fold increase, despite an 8% reduction in the average household income. Out-of-pocket expenses are compromising the economic and emotional security of cancer patients, who are often forced to choose between treatment and the family’s financial health, he said. The end result, Dr. Kantarjian suggested, is a “medical Darwinian system,” in which “if you can pay, you live, and if you cannot, you may die of your disease.”

‘Price Does Not Accurately Reflect Benefit’ Dr. Kantarjian said he does not buy the arguments given in support of high costs: Price reflects the expense of cancer research and the cost/benefit ratio of the drugs, market forces will set prices at reasonable levels, and price control will stifle innovation. “None of these is true, morally justifiable, or defensible,” he maintained. He went further in his debunking of the oft-quoted figure for drug develop-

research, consulting, and technology firms).”] According to Dr. Kantarjian, this figure is inflated through the inclusions and exclusion of numerous components of the entire drug-development process. “A most objective estimate is that the cost of developing a cancer drug is 10% of the estimate,” he said. He further maintained that price does not accurately reflect benefit, as new drugs are all priced at more than $100,000 a year, regardless of the length of survival prolongation. And, he contended that market forces do not correct imbalances, since there is a “collective monopoly” of companies with a “tacit agreement” not to compete on the basis of cost. Additionally, Medicare legislation allows companies to be “the only decider on drug prices,” he said, and strategies are in place to prolong patent life. Innovation will continue, he predicted, “whether profits are reasonable or exorbitant,” since 85% of basic research is funded through taxpayer money. “There is no escape in the discussion of drug prices. We need a situation where cancer drugs are affordable and patients can take them without the anxiety associated with lack of affordability,” he emphasized. He asked physicians to be true to the Hippocratic Oath: “Protect patients against harm and injustice on the per-

sonal and social level.” High drug prices, when they are unaffordable, become harmful to the patient, he said. Dr. Kantarjian also stated that, while most experts emphasize the difficulties in finding solutions, he believes there are several practical and simple solutions that will improve market forces: (1) allow Medicare to negotiate drug prices, (2) allow importation of drugs for personal use, (3) develop, through professional societies (ASCO, ASH, ACS), pathways and guidelines that propose treatment or drug “value”, (4) allow organizations like PCORI to incorporate drug prices in their analyses of treatment benefit, (5) prevent strategies that delay availability of generics. He finally suggested that since patients are their only real own advocates, the only solution might be patient-based grass root movements that highlight and protest high cancer drug prices. Next up was Alex W. Bastian, MBA, Vice-President for Gf K Market Access, San Francisco, which provides strategic & commercial consulting services to pharmaceutical, biotechnology, medical device, and diagnostics industries. He asked the audience to “open its mind” to a few concepts that are “real world, practical and actual consider-

Alex W. Bastian, MBA

veloping drugs in this setting. Since 1998, there have been 249 “failed” drugs in the hematology pipeline. “I don’t know at what price, but it’s a lot, even at the price tag mentioned by Dr Kantarjian,” he said. “The number of approvals is much less in comparison to other cancers.” “This gets to the idea of unintended consequences,” he continued. The point is not that current treatments must be priced high to justify past investments, but that high prices and healthy margins justify the continued investment in future therapeutics, he indicated. The investment community is looking for a good return on its money, and profits are simply part of Americanstyle capitalism, he said. This gets trickier as tumors become more molecularly classified. Potential markets for drugs become smaller as ever more targeted

It’s important to recognize that some patients are at risk for financial toxicity. Our study highlights that patient-physician cost communication can reduce out-of-pocket costs, even in oncology. —S. Yousuf Zafar, MD

ations that take place—some related to structural characteristics and practices within our marketplace.” Discussions about the cost of drugs have been a “constant theme” over the past century, and the problem is not unique to America, according to Mr. Bastian, who suggested the focus be on “value” rather than cost. In hematology, value has clearly been proven by the doubling and even tripling in survival among various malignancies treated with the latest agents, he indicated. Nevertheless, the treatment armamentarium is much weaker for hematologic cancers than for solid tumors, which highlights the difficulties in de-

treatments are required. “For a population with very low prevalence rates and high mortality, to justify investment by tumor types and subtumor types, we are talking fractions and subfractions,” he said. “Developing drugs is difficult for these populations.” “If you are the investor, this is the real world—how to justify your investments. There are grave unintended consequences of advocating for hypertension-like drug prices for hematologic malignancies,” he said. “There’s an implicit agreement that financial rewards will be provided to the manufacturer” largely through patent protections, he said. But he predicted a

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ASH Annual Meeting major shift in the next few years. “The days when Gleevec will cost cents on the dollar are close,” he indicated. Meanwhile, he acknowledged, “We are front-loading cost, and the question is whether that’s right. I can’t answer that. A healthy discussion is important,” he said, and this discussion should examine total benefits as well as costs. This debate needs to include “a rounded view.”

Financial Toxicity S. Yousuf Zafar, MD, Associate Professor of Medicine at Duke University, Durham, North Carolina, talked about the need for physicians to integrate costs into clinical decision-making and to include patients in these discussions. “It’s important to recognize that some patients are at risk for financial toxicity,” he said. The average cancer patient spends about $5,000 out of pocket, and since 1999, the cost of insurance premiums has risen by 182%, and worker contributions to employee plans have gone up nearly 200%, he indicated. In prospective, studies of patients, Dr. Zafar and colleagues have found that 52% of patients want to discuss treatment-related out-of-pocket costs with their oncologists and 51% want

their oncologist to take costs into account when making treatment decisions, but only 19% have actually discussed these things with their doctors. For those who did discuss costs, 57% reported having lower out-of-pocket costs as a result. “Our study highlights that patientphysician cost communication can reduce out-of-pocket costs, even in oncology, where treatment options are often limited,” he said. “We have to involve patients. I do this in the clinic every day.”

to pay for a restricted indication, such as a certain stage of cancer,” he said. He conceded that cost-effectiveness calculations are “often messy,” as they usually lack validated surrogate markers of long-term clinical outcomes; nevertheless, they are important factors in decision-making in Canada.

Drug Reimbursement Decisions in Canada Canada might be able to teach the United States a thing or two about drug reimbursement, according to a talk by Andreas L aupacis, MD, a palliative care specialist at St. Michael’s Hospital in Toronto. Drug reimbursement in Canada is more restrictive, and decisions are largely based on cost-effectiveness, “an ethical though admittedly imperfect tool with which to make tough policy decisions,” Dr. Laupacis said. “In Canada, drug reimbursement committees decide whether to pay for a drug out of the public purse, not to pay because the drug is not cost-effective, or

Andreas Laupacis, MD

Prior to the past few years, decisions in Canada were made based on the price submitted for consideration by the manufacturer, with no avenue for negotiation between the companies and payers. “This meant we often suggested that drugs not be funded, because at the price they charged, the drugs were not cost-effective,” he said. “That changed recently, and if a drug is not felt to be cost-effective at the price submitted by the manufacturer, we have the ability to negotiate in an attempt to

find a price at which it becomes costeffective,” he indicated. Regardless of determining cost-effectiveness and negotiating with drug companies, prices are still “massively higher” than they used to be and “generally not massively better” than current best treatments, he maintained. “For the way forward, there are no easy solutions,” Dr. Laupacis concluded. His suggestions were to focus on obtaining high-quality information about effectiveness of drugs to accurately drive cost-effectiveness ratios, to negotiate prices aggressively based on cost-effectiveness, to use tools such as value-based discounts, and to involve patients in the dialogue. Following the talks by panelists, a question-and-answer session featured several physicians who also were cancer patients lauding current therapies, albeit expensive, for keeping them alive. n Disclosure: Dr. Kantarjian has received research funding from Novartis, BMS, Ariad, Amgen, Pfizer, Sanofi, and Astex. Mr. Bastian has worked with or provided professional consulting services to multiple pharmaceutical companies for which his company received payment. Dr. Zafar is a nonpaid consultant for Genentech. Dr. Laupacis is a data monitoring committee member of Novartis.

Visit The ASCO Post Newsreels at ASCOPost.com For important news and interviews with experts filmed live during the 2015 ASH Annual Congress in San Francisco and the San Antonio Breast Cancer Symposium, visit www.ASCOPost.com and select the “Newsreels” tab. Video interviews include but are not limited to: From ASH Richard M. Stone, MD, on the SAL-SORAML Trial and the UK NCRI AML 17 Trial Linda J. Burns, MD, on the BLAST Study and CAR T-cell Therapy in ALL Bertrand Coiffier, MD, PhD, on the RO-CHOP Study Alan F. List, MD, on Rigosertib in Relapsed/Refractory Higher-Risk Myelodysplastic Syndrome Julie M. Vose, MD, MBA, FASCO, on the AETHERA trial Hagop Kantarjian, MD, on Treating Philadelphia Chromosome–Positive ALL Keith McCrae, MD, on Managing Heparin-Induced Thrombocytopenia Sagar Lonial, MD, on Monoclonal Antibodies in Multiple Myeloma Matthew Lunning, DO, on Ublituximab Plus TGR-1202 in Lymphoma Laurie Sehn, MD, on Lenalidomide Plus Rituximab in Previously Untreated Mantle Cell Lymphoma Ayalew Tefferi, MD, on Imetelstat as Therapy for Myelofibrosis

From SABCS Lisa A. Carey, MD, on Pembrolizumab in Advanced Triple-Negative Breast Cancer William M. Sikov, MD, on the CALGB 40603 Trial Jack Cuzick, PhD, on the IBIS-I Trial Gunter von Minckwitz, MD, on the Phase III ICE Trial Matthew J. Ellis, MD, on Endocrine Therapy–Resistant Breast Cancer Jame Abraham, MD, FACP, on Immunotherapy in Triple-Negative Breast Cancer Prudence Francis, MD, and Hope Rugo, MD, on the Phase III SOFT Trial Clifford A. Hudis, MD, FACP, on Enzalutamide in Androgen Receptor–Positive, Triple-Negative Breast Cancer Edith A. Perez, MD, on Stromal Tumor-Infiltrating Lymphocytes in Early-Stage HER2Positive Breast Cancer Lisa A. Carey, MD, on the CALGB/Alliance 40603 Trial Charles E. Geyer, Jr, MD, FACP, on the NSABP B-36 Trial

APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown. RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.” mCRC = metastatic colorectal cancer; OS = overall survival. WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Important Safety Information • In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. • A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory. • Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving

FOLFOX alone (HR = 1.16, 95% CI: 0.94–1.41). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for treatment with Vectibix®. • Progressively decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. • In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. • Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. • Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. • In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4 • The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone • Prespecified major efficacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02) • Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC • Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm (n = 331) (HR = 0.83; 95% CI: 0.70, 0.98) • There were no OS or PFS benefits in Vectibix®-treated patients with mutant KRAS/RAS mCRC • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. • Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis. • In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/ acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). • NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. • As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. • Advise patients of the need for adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal

harm when administered to pregnant women. • Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®. • Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. • In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. • In Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inﬂammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-aﬂibercept) prescribing information, sanoﬁ-aventis. Avastin® is a registered trademark of Genentech, Inc. Erbitux® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap® is a registered trademark of Regeneron Pharmaceuticals, Inc. Please see Brief Summary of full Prescribing Information on adjacent page. ©2014 Amgen Inc. All rights reserved. 10/14 61007-R7-V1

Visit www.vectibix.com

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Vectibix (panitumumab) ®

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Growth of eyelashes GASTROINTESTINAL DISORDERS Nausea Diarrhea Vomiting Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Mucosal inﬂammation INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea Cough SKIN AND SUBCUTANEOUS TISSUE DISORDERS Erythema Pruritus Acneiform dermatitis Rash Skin ﬁssures Exfoliative rash Acne Dry skin Nail disorder Skin exfoliation Skin ulcer

Study 1 Vectibix® Plus Best Supportive Care Best Supportive Care (N = 234) (N = 229) Any Grade Grade 3-4 Any Grade Grade 3-4 n (%) n (%) n (%) n (%) 13 (6) 52 (23) 49 (21) 43 (19) 15 (7)

2 (< 1) 4 (2) 6 (3)

37 (16) 26 (11) 28 (12) 2 (< 1)

1 (< 1)

60 (26) 15 (7)

10 (4) 1 (< 1)

34 (15) 2 (< 1)

7 (3)

57 (25)

4 (2)

41 (18) 34 (15)

12 (5) 1 (< 1)

30 (13) 17 (7)

8 (3)

150 (66) 132 (58) 131 (57) 51 (22) 45 (20) 41 (18) 31 (14) 23 (10) 22 (10) 21 (9) 13 (6)

13 (6) 6 (3) 17 (7) 3 (1) 3 (1) 4 (2) 3 (1)

2 (< 1) 4 (2) 2 (< 1) 2 (< 1) 1 (< 1)

2 (< 1)

2 (< 1) 1 (< 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%). In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix ®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)]. In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix ®-treated patients [see Dosage and Administration (2.3)]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported. Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®. Table 2: Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type (WT) KRAS Tumors Treated with Vectibix® and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 3)

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS Diarrhea Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inﬂammation Asthenia INFECTIONS AND INFESTATIONS Paronychia INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Anorexia Hypomagnesemia Hypokalemia Dehydration RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

FOLFOX Alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

58 (18)

5 (2)

10 (3)

201 (62) 87 (27)

59 (18) 15 (5)

169 (52) 42 (13)

29 (9) 1 (< 1)

82 (25) 79 (25)

14 (4) 16 (5)

53 (16) 62 (19)

1 (< 1) 11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

116 (36) 96 (30) 68 (21) 26 (8)

14 (4) 21 (7) 32 (10) 8 (2)

85 (26) 26 (8) 42 (13) 10 (3)

46 (14)

30 (9)

6 (2) 1 (< 1) 15 (5) 5 (2)

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

FOLFOX Alone (n = 327) SYSTEM ORGAN CLASS Any Grade Grade 3-4 Preferred Term n (%) n (%) SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash 179 (56) 55 (17) 24 (7) 1 (< 1) Acneiform dermatitis 104 (32) 33 (10) Pruritus 75 (23) 3 (< 1) 14 (4) Dry skin 68 (21) 5 (2) 13 (4) Erythema 50 (16) 7 (2) 14 (4) Skin fissures 50 (16) 1 (< 1) 1 (< 1) Alopecia 47 (15) 30 (9) Acne 44 (14) 10 (3) 1 (< 1) Nail disorder 32 (10) 4 (1) 4 (1) Palmar-plantar erythrodysesthesia 30 (9) 4 (1) 9 (3) 2 (< 1) syndrome Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix ®. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vectibix®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-7726436) to enroll. Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix ® monotherapy. Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix ® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

This brief summary is based on the Vectibix® Prescribing Information v22, 10/14. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2014 Amgen Inc. All rights reserved. 80748-R2-V1 – v22 10/14

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INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)]. Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)]. RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.” DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix ®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix ®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS- and KRAS-Mutant mCRC A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory [see Indications and Usage (1.2)]. Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving FOLFOX alone (HR = 1.16, 95% CI: 0.94-1.41). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®. Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix ® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix ®. Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)]

• Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)] • Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an openlabel, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

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2015

2015 Oncology Meetings January 2015 The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

15th Annual Targeted Therapies of the Treatment of Lung Cancer February 18-21 • Santa Monica, California For more information: www.iaslc.org/events/15th-annualtargeted-therapies-treatment-lungcancer The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 19-21 • San Diego, California For more information: www.imedex.com/anti-angiogenesisand-immune-therapies/

7th Annual T-Cell Lymphoma Forum January 29-31 • San Francisco, California For more information: www.tcellforum.com

February 26th International Congress on Anti-Cancer Treatment February 3-5 • Paris, France For more information: http://www.icact.fr Translation of the Cancer Genome February 7-9 • San Francisco, California For more information: www.aacr.org AACR-SNMMI Joint Conference: State-of-the-Art Molecular Imaging in Cancer Biology and Therapy February 11-14 • San Diego, California For more information: www.aacr.org 2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11-15 • San Diego, California For more information: www.asbmt.org 5th International Conference on Innovative Approaches in Head & Neck Oncology February 12-14 • Nice, France For more information: www.estro.org/congressesmeetings/items/5th-ichno

Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org 6th Current Concepts in the Management of Thyroid and Parathyroid Neoplasms February 26-28 • Houston, Texas For more information: www.mdanderson.org 32nd Annual Miami Breast Cancer Conference® February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/32nd-Annual-MiamiBreast-Cancer-Conference Society of Interventional Radiology February 28-March 5 • Atlanta, Georgia For more information: www.sirmeeting.org

March

13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org

Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers March 5-8 • Orlando, Florida For more information: www.aacr.org

American Society of Preventive Oncology (ASPO) Annual Meeting March 15-17 • Birmingham, Alabama For more information: http://aspo.org/annual-meeting

16th European Congress: Perspectives in Lung Cancer March 6-7 • Torino, Italy For more information: www.imedex.com

ACCC 41st Annual National Meeting March 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ calendar.asp

Advances in the Management of Multiple Myeloma March 6-7 • Saint Petersburg, Florida For more information: http://moffitt .org/for-physicians-healthcareprofessionals/conferences/conferences Hematology and Medical Oncology Board Review: Contemporary Practice From Memorial SloanKettering Cancer Center March 6-9 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse Advanced Prostate Cancer Consensus Conference March 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

14th St. Gallen International Breast Cancer Conference March 18-21 • Vienna, Austria For more information: www.oncoconferences.ch State-of-the-Art Neuro-Oncology Conference: 3rd Annual Meeting March 19-20 • Clearwater Beach, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences 21st Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 19-21 • Stevenson, Washington For more information: www.ohsu.edu/bbb Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/

NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp 8th Annual Interdisciplinary Prostate Cancer Congress™ March 14 • New York, New York For more information: http://www.gotoper.com/conferences/ ipcc/meetings/8th-AnnualInterdisciplinary-Prostate-CancerCongress 25th Annual Interdisciplinary Breast Center Conference March 14-18 • Las Vegas, Nevada For more information: www2.breastcare.org

EORTC-EANO-ESMO 2015 March 27-28 • Istanbul, Turkey For more information: www.ecco-org.eu/Events/EORTC_ EANO_ESMO-2015 46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

April American Brachytherapy Society Annual Meeting April 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index.cfm continued on page 138

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2015

2015 Oncology Meetings continued from page 137

Hematologic Malignancies: New Therapies and the Evolving Role of Transplant April 10-11 • Chicago, Illinois For more information: www.mayo.edu/cme/hematologyand-oncology-2015r919 International Society of Geriatric Oncology (SIOG) USA Forum April 11 • Tampa, Florida For more information: www.siog.org HPV-Induced Head and Neck Cancer: Screening, Detection and Less Invasive Therapies April 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx ASCO/C-KIN Joint Session at Cancer & the Kidney International Network’s First Annual Conference (C-KIN 2015) April 14-15 • Brussels, Belgium For more information: www.c-kin.org/conference2015/ ASCO Multidisciplinary Cancer Management Course (MCMC) April 15 • Vina Del Mar, Chile

Save the Date

For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ELCC2015-Lung-Cancer Multidisciplinary Spine Oncology Symposium April 17-18 • New York, New York For more information: www.mskcc.org/events/cme/ multidisciplinary-spine-oncologysymposium/form American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org ONS 40th Annual Congress April 23-26 • Orlando, Florida For more information: www.ons.org/conferences/ congress-2015 3rd ESTRO Forum April 23-28 • Barcelona, Spain For more information: http://www.estro.org/congressesmeetings/items/3rd-estro-forum

May

13th International Conference on Malignant Lymphoma (ICML) June 17–20, 2015 Lugano, Switzerland The 13th ICML will bring 3,000 physicians to Lugano from all over the world: hematologists, clinical oncologists, radiation oncologists, pediatricians, pathologists, and leading researchers involved in the study and treatment of lymphoid neoplasms. For more information, visit www.lymphcon.ch/imcl/index.php

American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org

The 28th Annual Meeting of the American Society of Pediatric Hematology/Oncology May 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/content/ annualmeeting.html IMPAKT 2015 Breast Cancer Conference May 7-9 • Brussels, Belgium For more information: www.esmo.org/Conferences/ IMPAKT-2015-Breast-Cancer 13th Annual Meeting of the Association for Cancer Immunotherapy (CIMT) May 11-13 • Mainz, Germany For more information: www.meeting.cimt.eu

CAP-ACP 2015 Annual Meeting June 20-23 • Montreal, Canada For more information: www.cap-acp.org/annual_meeting .php International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/

ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

June

July

International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/

7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp

2015 Clinical Update: 21st Century Prevention of HPV-Associated Cancer June 5-7 • Baltimore, Maryland For more information: www.asccp .org/Education/2015-21st-CenturyPrevention-of-HPV-Associated-Cancer

NRG Oncology Meeting July 10-13 • Chicago, Illinois For more information: www.gog.org/meetinginformation .html

Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org

13th International Conference on Malignant Lymphoma (ICML) June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2 Anticancer Drug Action and Resistance: From Cancer Biology to the Clinic June 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015

14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com/conferences/ibc/ meetings/14th-Annual-InternationalCongress-on-the-Future-of-BreastCancer The 13th Annual Scientific Meeting of JSMO July 16-18 • Sapporo, Japan For more information: www.congre.co.jp/jsmo2015/en/ index.html APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28-August 1 • Washington, DC For more information: http://www.apos-society.org/ professionals/meetings-ed/ annualconference.aspx

THE 1 ST FDA-APPROVED ANTI–PD-1 THERAPY

In appropriate patients with advanced melanoma

KEYTRUDA:

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

24% overall response rate in the 2 mg/kg arm (95% confidence interval [CI], 15–34; n=89); 1 complete response (1%) and 20 partial responses (23%). 86% of patients with an objective response (n=18/21) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 patients with ongoing responses of 6 months or longer. Releases programmed death receptor-1 (PD-1) pathway–mediated inhibition of the immune response. KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or diseaserelated symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

SELECTED SAFETY INFORMATION • Immune-mediated adverse reactions occurred with KEYTRUDA, including pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered. For more information regarding immune-mediated adverse reactions, please read the additional Selected Safety Information on the next page. Please see additional Selected Safety Information on the next page and the Brief Summary of Prescribing Information on the adjacent pages.

11%% 23 23%%

• •There Therewere wereobjective objectiveresponses responsesininpatients patientswith withand and without withoutBRAF BRAFV600 V600mutation–positive mutation–positivemelanoma. melanoma.

Complete CompleteResponse Response(CR) (CR)(n=1) (n=1)

Partial PartialResponse Response(PR) (PR)(n=20) (n=20) (%(% ofof patients) patients)

KEYTRUDA responded KEYTRUDA provided provided ongoing responses in patients who responded

86%

(n=18/21) (n=18/21)

Of responses were ongoing in patients patients who who responded responded to KEYTRUDA

Questions Questions about about access for KEYTRUDA? Call Call The The Merck Merck Access Access Program at 855-257-3932.

Scan Scan here here or visit keytruda.com keytruda.com to to learn learn more.

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use (continued)

DRUG INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

THE 1 ST FDA-APPROVED ANTI–PD-1 THERAPY USE IN SPECIFIC POPULATIONS Table 1: Adverse Reactions in ≥10% of Patients with Unresectable or Metastatic Melanoma

Pregnancy: Pregnancy Category D.

Adverse Reaction

KEYTRUDA: All Grades (%)

Grade 3* (%)

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

All Grades (%)

Grades 3–4 (%)

SELECTED SAFETY INFORMATION

on the adjacent pages.

The Merck Access Program for KEYTRUDA for Injection Visit

merckaccessprogram-keytruda.com OR

Call

855-257-3932 • Speak with a dedicated representative Monday to Friday between 8 AM and 8 PM ET.

• Ask to be contacted by a field reimbursement associate.

ASCOPost.com | JANUARY 25, 2015

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2015

2015 Oncology Meetings 16th Annual International Lung Cancer Congress® July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/ meetings/16th-International-LungCancer-Congress

September International Palliative Care Workshop September 3-5 • Fez, Morocco For more information: www.asco.org/ international-programs/internationalpalliative-care-workshops 9th Annual Conference of the International Liver Cancer Association September 4-6 • Paris, France For more information: www.ilca2015.org

Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

August Best of ASCO - San Francisco August 7-8 • San Francisco, California For more information: http://boa.asco.org/ World Congress on Cancer and Prevention Methods August 27-29 • Dubai, United Arab Emirates For more information: http://scientificfuture.com/ oncology-2015/ ASCO Multidisciplinary Cancer Management Course (MCMC) August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/international-programs/ multidisciplinary-cancer-managementcourses Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/ European Society for Medical Oncology Academy 2015 August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

AMOS-TMOS Joint Session on Multidisciplinary Management of Gastrointestinal Cancers September 5-6 • Konya, Turkey For more information: http://kanser.org/en/ 16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org 25th World Congress of Lymphology September 7-11 • San Francisco, California For more information: www.lymphology2015.com/ American Society of Head & Neck Radiology Annual Meeting September 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ashnrannual-meeting/ ASCO Multidisciplinary Cancer Management Course (MCMC) September 10-11 • Candos Quatre Bornes, Mauritius For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses ISEH 44th Annual Scientific Meeting September 17-19 • Kyoto, Japan For more information: www.iseh.org/?page=Meeting International Conference on Immunotherapy in Pediatric Oncology (CIPO2015) September 25-26 • Seattle, Washington For more information: www.seattlechildrens.org/cipo2015

ASCO Breast Cancer Symposium September 25-27 • San Francisco, California For more information: breastcasym.org The European Cancer Congress September 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/ European-Cancer-Congress-2015

October American College of Surgeons Clinical Congress October 4-8 • Chicago, Illinois For more information: www.facs.org/education/clinicalcongress/future-clinical-congresses 6th InterAmerican Oncology Conference: Current Status and Future of Anti-Cancer Targeted Therapies October 8-9 • Buenos Aires, Argentina For more information: www.oncologyconferences.com.ar Palliative Care in Oncology Symposium October 9-10 • Boston, Massachusetts For more information: www.pallonc.org

Advanced Breast Cancer Third International Consensus Conference November 5-7 • Lisbon, Portugal For more information: www.abc-lisbon.org International Society of Geriatric Oncology (SIOG) 15th Annual Conference November 12-14 • Prague, Czech Republic For more information: www.siog.org 12th International Conference of the Society for Integrative Oncology November 15-16 • Boston For more information: www.integrativeonc.org/index.php/ events Workshop in Palliative and End of Life Care for Health Care Providers—Advanced Cancer Course November 17-18 • Kathmandu, Nepal For more information: www.asco.org/internationalprograms/international-palliativecare-workshops

ASTRO’s 57th Annual Meeting October 18-21 • San Antonio, Texas For more information: www.astro.org ACCC 32nd National Oncology Conference October 21-24 • Portland, Oregon For more information: www.accc-cancer.org/meetings/ calendar.asp The 53rd Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www.jsco.or.jp/english/index/page/ id/73

November Chemotherapy Foundation Symposium November 3-7 • New York, New York For more information: www. chemotherapyfoundationsymposium .org

December American Society of Hematology December 5-8, 2015 Orlando, Florida For more information: www. hematology.org 38th Annual San Antonio Breast Cancer Symposium  December 8-12 • San Antonio, Texas For more information: www.sabcs.org ESMO Asia 2015 Congress December 18-21 • Singapore For more information: www.esmo.org/Conferences/ ESMO-Asia-2015-Congress

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In the Clinic

Gardasil 9 Adds Protection Against Cancer Caused by Additional Human Papillomavirus Types By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n December 10, 2014, Gardasil 9 (human papillomavirus 9-valent vaccine, recombinant) was approved for the prevention of cervical, vulvar, vaginal, and anal cancers caused by human papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58 and for the prevention of genital warts caused by HPV types 6 or 11.1,2 Compared with the previously approved quadrivalent Gardasil vaccine, the vaccine adds protection against HPV types 31, 33, 45, 52, and 58, which are estimated to cause 20% of cervical cancers. Gardasil 9 is approved for use in females aged 9 to 26 years and males aged 9 to 15 years. It is dosed at a schedule of 0, 2, and 6 months.

vaccination. The primary endpoint was the composite of cervical, vulvar, and vaginal cancers, high-grade cervical/ vulvar/vaginal disease (cervical intraepithelial neoplasia 2/3) or adenocarcinoma in situ, vulvar intraepithelial neoplasia 2/3, and vaginal intraepithelial neoplasia 2/3 due to HPV types 31, 33, 45, 52, or 58 in the per-protocol population. The efficacy rate for the primary endpoint for Gardasil 9 was 96.7% (1 case in the Gardasil 9 group vs 30 cases in the Gardasil group). Efficacy rates for secondary endpoints were 98.6% against cervical intraepithelial neoplasia 1 (1 vs 69 cases), 96.3% against cervical intraepithelial neoplasia 2/3 or

ity studies. Efficacy of Gardasil 9 in girls and boys aged 9 to 15 years against all nine HPV types is inferred from immunogenicity studies showing noninferior geometric mean titers compared with those in the 16- to 26-year-old women after Gardasil 9. In a study of immunogenicity in 921 girls and women aged 12 to 26 years who had previously been vaccinated with Gardasil, administration of Gardasil 9 starting at 12 to 36 months after the last injection of Gardasil resulted in antibody seropositivity to all HPV types ranging from 98.3% to 100% by month 7. Anti-HPV 31, 33, 45, 52, and 58 geometric mean titers were 25% to 63% of those compared with vaccinees who

Gardasil 9 for Prevention of Cancers Caused by Human Papillomavirus ■■ Gardasil 9 was approved for the prevention of cervical, vulvar, vaginal, and anal cancers caused by human papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58 and for the prevention of genital warts caused by HPV types 6 or 11. ■■ Gardasil 9 is approved for use in females aged 9 to 26 years and males aged 9 to 15 years and is dosed at a schedule of 0, 2, and 6 months.

Vaccine Efficacy Approval of Gardasil 9 was based in part on a double-blind trial in which 14,204 women aged 16 to 26 years with no screening for the presence of HPV infection were randomized to receive vaccination with Gardasil 9 (n = 7,099)

OF NOTE Gardasil 9 carries warnings/precautions for syncope and allergic reactions. It is contraindicated in patients with hypersensitivity, including severe allergic reactions, to yeast, which is a component of the vaccine.

or Gardasil (n = 7,105). The median follow-up was 40 months after the last

adenocarcinoma in situ (1 vs 27 cases), 93.8% against vulvar or vaginal disease (1 vs 16 cases), 96.2% against persistent HPV infection of at least 6 months (26 vs 642 cases), 96.1% against persistent HPV infection of at least 12 months (15 vs 375 cases), 92.6% against abnormal Pap tests (35 vs 462 cases), 96.9% against biopsy (7 vs 222 cases), and 87.5% against definitive therapy (4 vs 32 cases). Efficacy of Gardasil 9 against the previously covered HPV types 6, 11, 16, and 18 in women aged 16 to 26 and in girls aged 9 to 15 years is inferred by the finding of noninferior anti-HPV antibody geometric mean titers compared with those found after Gardasil quadrivalent vaccine in immunogenic-

had not previously received Gardasil; the clinical relevance of these differences is unknown. The efficacy of Gardasil 9 in preventing infection and disease related to HPV types 31, 33, 45, 52, and 58 in this setting has not been assessed.

Safety Profile In all studies, the most common (≥ 10%) local and systemic adverse events were injection-site pain (89.9%), injection-site swelling (40.0%), injectionsite erythema (34.0%), and headache (14.6%) in females aged 16 to 26 years; injection-site pain (89.3%), injectionsite swelling (47.8%), injection-site erythema (34.1%), and headache (11.4%) in girls aged 9 to 15 years; and injectionsite pain (71.5%), injection-site swelling

(26.9%), and injection-site erythema (24.9%) in boys aged 9 to 15 years. Conditions potentially indicative of a systemic autoimmune disorder were observed in 2.4% of 13,234 Gardasil 9 and 3.3% of 7,378 Gardasil recipients. These rates are similar to those reported with Gardasil, amorphous aluminum hydroxyphosphate sulfate control, or saline placebo in historic clinical trials. Gardasil 9 carries warnings/precautions for syncope and allergic reactions. Syncope, sometimes resulting in falling with injury, has occurred in vaccine recipients. Thus, observation of patients for 15 minutes after administration is recommended. Syncope associated with tonic-clonic movements and other seizure-like activity has been observed. Tonic-clonic activity usually is transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position. Appropriate medical treatment and supervision must be readily available in case of anaphylactic reactions following vaccine administration. Gardasil 9 is contraindicated in patients with hypersensitivity, including severe allergic reactions, to yeast, which is a component of the vaccine, and in patients with hypersensitivity reaction after a previous dose of Gardasil 9 or Gardasil. n References 1. FDA News Release: FDA approves Gardasil 9 for prevention of certain cancers caused by five additional types of HPV. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm426485.htm. Accessed January 7, 2015. 2. Gardasil 9 (human papillomavirus 9-valent vaccine, recombinant) prescribing information, Merck & Co, Inc, 2014. Available at http://www.merck.com/product/ usa/pi_circulars/g/gardasil_9/gardasil_9_pi.pdf. Accessed January 7, 2015.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | JANUARY 25, 2015

PAGE 141

Expert’s Corner Clinical Trials

Smarter Trial Design Saves Money and Produces Better Drugs By Ronald Piana testing and then adapt the clinical trial methodology (design) to appropriately identify early markers of clinical benefit, which may correlate with survival and allow for patient selection.

Drugs With Proven Benefit

William Douglas Figg, Sr, PharmD

he process of identifying a promising molecule and moving it from the laboratory through the highly complex series of clinical trials necessary to garner U.S. Food and Drug Administration (FDA) approval is a costly scientific gauntlet during which many new agents fail. New trial design, pharmacology principles, and emerging biomarkers will play a large role in ensuring the future of a robust pipeline of antineoplastic agents. The ASCO Post recently spoke with William Douglas Figg, Sr, PharmD, Deputy Chief, Genitourinary Malignancies Branch, National Cancer Institute (NCI). Dr. Figg elucidated the role of clinical trial design, addressed the need for clinically meaningful endpoints, and offered his expertise on other important issues in oncology.

Clinically Meaningful Endpoints Some experts contend that too many cancer clinical trials are underpowered, and their endpoints, such as progressionfree-survival and objective response, leave too much room for interpreting responses that do not necessarily benefit patients. What are your thoughts on this issue? The approval of regular new drug applications is based on a demonstration of clinical benefit or an effect on an established surrogate marker. We definitely need to revisit the statistical design of trials and ask the question of whether the size and scope of the study allow us to further assess endpoints in specific patient subsets. One of the most important aspects in designing a late-phase trial is to choose a clinically meaningful endpoint for the target population in the study. Demonstrable clinical benefits vary with cancer type and status of disease. We need to understand the target agent being investigated and how it works for that particular patient population in

There is a move in the community to raise the bar for a drug’s approval, in an effort to limit the amount of drugs being brought to market that offer minimal survival advantage. However, some experts contend that we need to lower the bar, which would allow more drugs on the market, thus giving researchers the ability to test more indications and drug combinations. What are your thoughts? I would argue against lowering the approval bar. We have to have drugs that have proven benefit for patients, especially given their huge costs to our health-care system. Moreover, the more drugs that get to market simply because they show some activity, the more difficult it becomes to get meaningful endpoints, especially overall survival. One of my main concerns is the crossover trial design, in which the investigators allow those patients who fail

whom the drug is appropriate. Plus, the adaptive design both lowers costs and saves time by eliminating the number of study failures; however, the adaptive design works best in exploratory phases through phase II. It’s been shown that the adaptive trial design saves sponsors hundreds of millions of dollars. Amending protocols and more quickly shutting down one arm of the study and adjusting statistics on the fly as you see activity not only save time and money but help us better inform which agents are destined for early failure.

Improving the Preclinical Environment Pharmacology, pharmacokinetics, and biomarkers have shown merits in oncology research, especially in preclinical drug development. Where are we in this area, and what do you see on the horizon? With the number of late-stage clinical trial failures and the cost of drug development increasing, there is a strong need to continue to improve the preclinical environment, such as through incorporating predictive biomarkers

We have to have drugs that have proven benefit for patients, especially given their huge costs to our system. The more drugs that get to market simply because they show some activity, the more difficult it becomes to get meaningful endpoints, especially overall survival. —William Douglas Figg, Sr, PharmD

to respond to the control arm, ultimately receive the investigational drug. The trial then gauges its success on patients who have received standard of care plus the investigational agent. Therefore, if that investigational drug is truly active, are you ever going to get a meaningful endpoint on the trial, such as overall survival?

Adaptive Trial Design In recent years, the use of adaptive trial design methods in clinical research and development based on accrued data has become very popular due to its flexibility and efficiency. What are your thoughts on this direction? I was slow to embrace the adaptive trial design methods. But I now see that this method more quickly identifies drugs that have a therapeutic effect, and it zeros in on patient populations for

into preclinical models. We also need to enhance rigorous methodology with improved validation strategies and proper controls and adopt more robust preclinical cancer models (eg, translation and pharmacodynamic indicators and murine models that are appropriately designed to mimic specific disease subtypes). The idea is to prioritize and move drugs with optimal preclinical validation, so the preclinical data can be translated to success at the bedside. Simply put, the goal is to improve the trial success rate and limit the testing of what would ultimately prove to be ineffective targeted therapy. In addition, another limitation of preclinical evaluation is the inability to accurately predict the toxicity of a particular agent, especially in combination with other chemotherapeutic agents.

Another area on the horizon that should be addressed is understanding how to apply preclinical pharmacokinetic and pharmacodynamic data and evaluation to guide the phase I trial setting in areas such as dose selection and minimize toxicity. The overall objective is to make drug development an iterative process to continue to improve the accuracy of preclinical models in predicting clinical benefit.

Biomarker Signature The screening debate in cancer is ceaseless, but detection is also part of clinical trial design. As a prostate cancer expert, do you foresee a prostate cancer–specific biomarker down the pike? Because cancer is heterogeneous and multiple tumor pathways are altered, identifying and validating a “biomarker signature” (gene or serum proteins) would be a more appropriate global platform for detection or even prognosis. For prostate cancer, a combination of markers will improve the predictive accuracy and decrease the number of unnecessary biopsies. In fact, we are currently seeing this explosion in genomic data and can use this information to identify disease subtypes; differentiate indolent vs aggressive prostate cancer; and, further down the line, distinguish between responders and nonresponders to treatment.

Antiangiogenic Therapy In early work, the promise of antiangiogenic therapies was the buzz of the oncology community. Are we stalled or rebooting this intriguing way to kill tumors? The field has clearly taken a hit, but antiangiogenic therapy still has a role in the cancer treatment paradigm for specific tumor types. A lot of these drugs work very well in showing progression-free-survival, but when it comes to overall survival, they seem to fail. I’ve said for years that it’s not rational to think that an antiangiogenic agent is going to control a tumor without help from combinations of drugs. In fact, we may need two or more antiangiogenic agents that have different mechanisms plus chemotherapy and molecular targeted therapies to have the most activity. As with any cancer targeting strategy, we need to fine-tune the antiangiogenic process by understanding the mechanisms of evasive resistance— continued on page 145

NEW INDICATION

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

sion s e r g o r p e diseas your patients t a I D N A Start XT static CRPC fo1 r to meta therapy* on GnRH

*Or af

1 omy. chiect r o l a r e r bilat

Important Safety Information Contraindications XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In Study 1, conducted in patients

with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Adverse Reactions The most common adverse reactions (≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Other Adverse Reactions include: • Laboratory Abnormalities: In the two studies, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). • Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Significantly extended radiographic progression-free survival†1

Significantly improved overall survival†1 • 29% reduction in risk of death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.71 [95% CI, 0.60-0.84]; P < 0.0001)

• 83% reduction in risk of radiographic disease progression or death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.17 [95% CI, 0.14-0.21]; P < 0.0001)

• Estimated median overall survival was 32.4 months (95% CI, 30.1-not reached) for XTANDI + GnRH therapy* and 30.2 months (95% CI, 28.0-not reached) for placebo + GnRH therapy*1

• Estimated median radiographic progression-free survival was not reached (95% CI, 13.8-not reached) for XTANDI + GnRH therapy* and was 3.7 months (95% CI, 3.6-4.6) for placebo + GnRH therapy*1

Oral, once-daily dosing with no required steroid coadministration1

Significantly delayed time to chemotherapy initiation†1 • Delayed time to chemotherapy initiation by a median of 28.0 months with XTANDI + GnRH therapy* vs 10.8 months with placebo + GnRH therapy* (HR = 0.35 [95% CI, 0.30-0.40]; P < 0.0001)

• Dosage: XTANDI 160 mg (four 40 mg capsules) is administered orally, once daily • Steroids were allowed but not required‡

Visit XtandiHCP.com or snap the QR code for more information

• Falls: In the two studies, falls including fall-related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas. • Hypertension: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients.

Drug Interactions • Effect of Other Drugs on XTANDI - Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible.

• Effect of XTANDI on Other Drugs - XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information. †As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC that progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,2 ‡In the PREVAIL trial, 27% of patients in the XTANDI arm and 30% of patients in the placebo arm received glucocorticoids for varying reasons. In the AFFIRM trial (Study 1), 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids. AFFIRM was a phase 3, multicenter, placebocontrolled, randomized trial that enrolled 1199 patients with metastatic CRPC who had previously received docetaxel.1 References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433.

Table 2. Adverse Reactions in Study 2

Table 1. Adverse Reactions in Study 1 XTANDI N = 800 XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information. INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)]. WARNINGS AND PRECAUTIONS Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure. Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDItreated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

XTANDI N = 871

Placebo N = 399

Grade Grade Grade Grade 3-4 1-4 3-4 1-4a (%) (%) (%) (%) General Disorders Asthenic 50.6 9.0 44.4 Conditionsb Peripheral 15.4 1.0 13.3 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 5.3 24.3 Arthralgia 20.5 Musculoskeletal 15.0 Pain Muscular 9.8 Weakness Musculoskeletal 2.6 Stiffness Gastrointestinal Disorders Diarrhea

21.8

9.3 0.8

4.0

2.5

17.3

1.8

1.3

11.5

0.3

1.5

6.8

1.8

0.3

0.0

Grade 1-4a (%)

Grade Grade Grade 3-4 1-4 3-4 (%) (%) (%)

General Disorders Asthenic 46.9 3.4 33.0 Conditionsb Peripheral 11.5 0.2 8.2 Edema Musculoskeletal And Connective Tissue Disorders

2.8 0.4

Back Pain

28.6

2.5

22.4

3.0

Arthralgia

21.4

1.6

16.1

1.1

Gastrointestinal Disorders Constipation

23.2

0.7

17.3

0.4

Diarrhea

16.8

0.3

14.3

0.4

Vascular Disorders 1.1

17.5

0.3

Vascular Disorders Hot Flush

20.3

0.0

10.3

0.0

Hypertension

6.4

2.1

2.8

1.3

Hot Flush

18.0

0.1

7.8

0.0

Hypertension

14.2

7.2

4.1

2.3

Nervous System Disorders

Dizzinessc

11.3

0.3

7.1

0.0

Headache

11.0

0.2

7.0

0.4

7.6

0.1

3.7

0.0

5.7

0.0

1.3

0.1

2.1

0.1

0.4

0.0

0.6

8.5

0.6

10.5

0.0

4.7

1.1

0.1

5.7

0.0

1.3

5.8

1.3

Headache

12.1

0.9

5.5

0.0

Dysgeusia

Dizzinessc Spinal Cord Compression and Cauda Equina Syndrome Paresthesia Mental Impairment Disordersd Hypoesthesia

9.5

0.5

7.5

0.5

7.4

6.6

4.5

3.8

Mental Impairment Disordersd Restless Legs Syndrome

6.6

0.0

4.5

0.0

Respiratory Disorders

4.3

0.3

1.8

0.0

4.0

0.3

1.8

0.0

6.5

0.3

2.4

4.8

1.3

Infections And Infestations Upper Respiratory 10.9 Tract Infectione Lower Respiratory 8.5 Tract And Lung f Infection Psychiatric Disorders 8.8

0.0

6.0

0.5

Anxiety

6.5

0.3

4.0

0.0

11.0

Infections And Infestations Upper Respiratory 16.4 0.0 Tract Infectionf Lower Respiratory Tract And 7.9 1.5 Lung Infectiong Psychiatric Disorders 8.2

Renal And Urinary Disorders Hematuria

8.8

Injury, Poisoning And Procedural Complications

Renal And Urinary Disorders Hematuria

6.9

1.8

4.5

1.0

Pollakiuria

4.8

0.0

2.5

0.0

Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 Non-pathologic 4.0 1.4 0.8 Fractures Skin And Subcutaneous Tissue Disorders

0.0 0.3

Pruritus

3.8

0.0

1.3

0.0

Dry Skin

3.5

0.0

1.3

0.0

0.1

1.3

0.3

Respiratory Disorders 3.3

Dyspneae

Insomnia

Epistaxis

Placebo N = 844

a CTCAE v4 b Includes asthenia and fatigue. c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebotreated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Fall

12.7

1.6

5.3

NonPathological 8.8 2.1 3.0 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 16.4 Appetite

0.7 1.1

0.7

Investigations Weight Decreased

12.4

0.8

8.5

0.2

Reproductive System and Breast Disorders Gynecomastia

3.4

0.0

1.4

0.0

a b c d

CTCAE v4 Includes asthenia and fatigue. Includes dizziness and vertigo. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections In Study 1, 1% of patients treated with

XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included nonpathologic fractures, joint injuries, and hematomas. Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)]. Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)]. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)]. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category X [see Contraindications (4)]. Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during

ASCOPost.com | JANUARY 25, 2015

MEDXT14535_PREVAIL Brief Summary PI-TAB Colors: Black Trim/live: DO NOT PRINT Bleed: None Trim: 10.5"w × 13.5"h Live: 9.5"w × 12.5"h Output @ 100% Giant Creative Strategy

treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day,and cleft palate and absent palatine bone at 30 mg/kg/ day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)]. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)]. OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day

(0.3 times the human exposure based on AUC). Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: September 2014 14B006-XTA-BRFS Rx Only © 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

076-0516-PM

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Expert’s Corner William D. Figg, Sr, PharmD continued from page 141

for example, ongoing effects to target known resistance mechanisms—identify predictive markers of response and resistance, and develop combination therapies that can synergize with angiogenesis inhibitors. To that end, ongoing studies are looking at combining angiogenic inhibitors with immunotherapies. So, antiangiogenic therapy holds promise, we just need to keep studying this type of therapy until we hone into more specific ways to use it.

Challenges Ahead As a last thought, although our research efforts have delivered drugs that have greatly improved survival, are NCI’s research capabilities ready for the challenges ahead? The researchers are ready, but unfortunately without proper funding,

our efforts will be stalled. Over the past few years, when you factor inflation into the equation, the NCI’s research funding has flatlined. It’s important to note that every single cancer drug on the market has had some help getting there from the NCI. Although we (the NCI) may not have discovered the molecule, the target that the drug hits was most likely discovered by an NCI basic science grant, or the trials were most likely conducted in cancer centers that were funded by the NCI, or the investigators conducting the trials were most likely funded by the NCI. Each year, the top two cancer drugs drive more income for their respective companies than the entire NCI budget. The NCI needs more funding. What we do is valuable, because it directly improves the lives of cancer patients. It’s that simple. n Disclosure: Dr. Figg reported no potential conflicts of interest.

City of Hope Celebrates Hope in the 2015 Tournament of Roses Parade

n January 1, 2015 for the 43rd year, cancer research and treatment center City of Hope participated in the 126th Tournament of Roses Parade. In the photo below, the Wolfrank family, including former stem cell recipient Gavin, 9, stands atop City of Hope’s float during its preparation for the parade in Pasadena, California. Gavin was one of six cancer survivors offered the chance to ride the float on New Year’s Day with their loved ones. The float’s theme, “Made Possible by HOPE,” illustrated the connection between City of Hope’s research and the futures it makes possible. Also on the float during the parade and representing the institution’s people and care teams, were:

Robert W. Stone, President and Chief Executive Officer; Steven T. Rosen,

Steven T. Rosen, MD

MD, Provost and Chief Scientific Officer; and Anne Bourque, RN, Clinical Nursing Director of Hematology and Hematopoietic Cell Transplantation. n

The Wolfrank family, including former stem cell recipient Gavin, 9, stands atop City of Hope’s float during its preparation for the parade in Pasadena, California. Photo courtesy of City of Hope.

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Expert’s Corner

What It Means to Be Mortal

A Conversation With Atul Gawande, MD, MPH By Jo Cavallo Complications: A Surgeon’s Notes on an Imperfect Science (Metropolitan Books, 2002), Better: A Surgeon’s Notes on Performance (Picador, 2007), and The Checklist Manifesto: How to Get Things Right (Metropolitan Books, 2009). In a wide-ranging interview with The ASCO Post, Dr. Gawande talked about how his research for Being Mortal led to changes in his medical practice, the controversy of physician-assisted suicide, and the definition of a good death. Atul Gawande, MD, MPH

“I

learned a lot of things in medical school, but mortality wasn’t one of them,” writes Atul Gawande, MD, MPH, in his new book on the medicalization of aging and dying, Being Mortal: Medicine and What Matters in the End (Metropolitan Books, 2014). In the book, Dr. Gawande critiques the American medical system and shows how it is so focused on battling death, that when a patient dies, it is viewed as a failure rather than a normal occurrence of life. In addition, he describes his own inadequacy in confronting the subject of death with his patients. “Our reluctance to honestly examine the experience of aging and dying has increased the harm we inflict on people and denied them the basic comforts they most need. Lacking a coherent view of how people might live successfully all the way to their very end, we have allowed our fates to be controlled by the imperatives of medicine, technology, and strangers,” writes Dr. Gawande. Being Mortal includes detailed accounts of the experiences of the ill and dying, including the story of Dr. Gawande’s father, Atmaram Gawande, MD, who had an inoperable cervical spinal cord tumor but remained determined to live life as fully as possible all the way to the end. (A review of Being Mortal was published in the December 1, 2014, issue of The ASCO Post [volume 5, issue 19] and is available online at www.ascopost.com.) Dr. Gawande is a surgeon at Brigham and Women’s Hospital, Professor in the Department of Health Policy and Management at the Harvard School of Public Health, and Professor in the Department of Surgery at Harvard Medical School. He is also a staff writer for The New Yorker magazine and the author of three other best-selling books:

We Often Miss the Big Picture You have said that you weren’t always effective in situations in which you had no more reasonable treatments to offer your terminally ill cancer patients and that you didn’t know how to break bad news to patients. What have you learned since researching Being Mortal? I realized that we in medicine haven’t fully recognized that people have priorities besides just living longer. Their priorities might be to remain cognitively intact or to spend more time at home vs in the hospital or even just to be able to take care of their dog. We are so used to focusing on what we consider our tech-

I think the evidence is accumulating that although we are extremely good at making sure that we’re technically well prepared—in my case, as a surgeon— we are not nearly as effective at recognizing that developing effective communication skills for patients can take just as much training and practice.

Matching Priorities to Medical Options How has the information you discovered changed the way you practice medicine and interact with dying patients? I think the biggest lessons I learned are how to communicate better and that it is okay to have these difficult conversations with patients, even though they can be very emotional. I learned that the aims and goals of those conversations are very different from the way I understood them. I thought that I needed to bring across as much information as I could for patients about the facts of their disease and the risks and benefits of the various pathways available. But in fact, what people are looking for is an understanding of how to match their

The goal is not to have a good death. The goal is to have as good a life as possible all the way to the very end. —Atul Gawande, MD, MPH

nical successes—do we extend life and survival, do we reduce complications— that we often miss the big picture. Another thing I learned is that the most effective way to find out what people’s priorities and goals are for the end of their lives is simply to ask them. And, according to data from studies of patients with advanced cancer, we have those discussions less than one-third of the time. There are a lot of different reasons why we aren’t having those discussions—anxiety, lack of training, financial incentives—but patients who have those conversations with their physicians and have them earlier in their illness do better. They do better in making decisions about when to shift from simply trying to extend time to trying to preserve quality of life. Ironically, by forgoing aggressive treatment at a certain stage, these patients are also more likely to live longer.

priorities and concerns to the medical options that we have available. And those priorities change as circumstances change. So it is not sufficient just to be informative. We have to learn what matters most to patients in their lives— what they wouldn’t want to sacrifice— and be willing to offer and recommend choices that give them their best chances of preserving what matters to them as they approach the end of their lives.

Listening More, Talking Less Now the critical part that was the most difficult for me to incorporate into my practice was to be more effective at listening. One palliative care physician told me that a marker of an effective conversation with a patient is that the physician talks less than half the time. Once I started paying attention, I found that I was talking 90% of the time. To talk less and come to better decisions with patients, I needed to

ask questions more effectively. I’ve picked up some basic questions that have been very useful in my clinic. For example, what is your understanding of where you are with your health or condition; what are your fears and worries for the future; what are your goals if your time is short; and what are the outcomes that are unacceptable to you? And then I’m using the answers to guide us toward a decision. I found out how important asking these types of questions were with my father, who had an astrocytoma in his brain stem and spinal cord. When his symptoms began worsening, I asked him those exact questions. And it opened a discussion that made clear what level of function and outcome was still worth fighting for to him and what levels were not. That became terribly important as his condition progressed, and we had to make a series of choices about surgery, radiation, chemotherapy, and hospice.

Priorities Change as Conditions Change One thing we learned was that we had to have the conversation repeatedly. As conditions change, priorities change. His top priority at first was to preserve his ability to do surgery. Later, as he developed signs of quadriplegia and pain that ended his practice, his priorities changed again, and the goals of his therapies changed. It wasn’t just an end-oflife conversation we were having. It was a conversation about what his evolving goals and priorities were for his care. Those conversations are something that all patients need to have with their physicians and family—well before the end is upon them.

Missing Parts of Medical Training In Being Mortal, you show how the medical system is so focused on preventing death, when a patient dies, it is viewed as a failure instead of a normal occurrence of life. How can this perception be changed? Should there be a greater emphasis in medical training on preserving the highest quality of life a patient can have rather than prolonging life at all costs? There are a variety of things about quality-of-life care and aging we don’t learn during training, and some of that needs to be taught in medical school and some of it needs to be taught in res-

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Expert’s Corner

idency and fellowship and some even afterward. One of the gaps is in understanding the science of aging and frailty and what actually happens to people as we grow old. That includes some basic issues like falls—when do people develop risk for serious falls; what are the risk factors and signs; what are the known ways to reduce those risks? This knowledge is well established and very important but barely taught. Geriatric and palliative knowledge and skill are not well incorporated into our residency, fellowship, or specialty training. The other missing part is teaching how to put a plan in place to deal with the evolving trajectory of a patient with a serious illness. We seem to know that crisis will some day come and are never prepared for it. Patients arrive at the end stage of what I’ve come to call the ODTAA syndrome—when One Damn Thing After Another starts to go wrong. When we do our first round of chemotherapy, radiation, or surgery, and things go well, it’s natural to hope that this is the way it will continue to go, but that’s not the same as having a plan for what happens if the situation takes a turn for the worse. When we are onto second- or thirdline therapy, we need to make it normal and routine to discuss patients’ goals and priorities for the possibility that their health worsens. And we need to bring the family into the conversation, because two-thirds of patients at the end stage of illness have to rely on somebody else to make decisions for them.

Simply making conversations about a patient’s goals and priorities a normal part of medical care takes the terror out of asking these questions. They become a normal part of the visit.

Sign of Health System Failure On November 1, Brittany Maynard, 29, diagnosed with stage IV glioblastoma multiforme, underwent physician-assisted suicide to avoid the pain and loss of control she feared would happen if the disease took its natural course. Do you support physician-assisted suicide? I have complex views on this subject. On the most basic level, I think if people have unbearable suffering, I would be in favor of their having the option of assisted death. In the approach that has been taken in states like Washington and Oregon, where physician-assisted death is legal and carefully vetted to ensure that treatable conditions like depression aren’t being missed, less than 1% of the population chooses this option, and half of the people who get the prescription filled don’t end up using it, because often they are just relieved to know that they have an option if the suffering becomes so terrible. That said, I feel like Brittany Maynard’s death was a sign of the health system’s failure. We should be deploying our capabilities, our knowledge, and our discovery to assure a Brittany Maynard that she can count on her caregivers to ensure care that would prevent her from having to face unbearable pain and suffering.

The fact that she could not count on this is a sign of our system’s failure. The goal is not to have a good death. The goal is to have as good a life as possible all the way to the very end. And I think there are many instances when the reason people are experiencing unbearable suffering is because we have not adequately treated their pain or misery. Or it may be because we have failed to present them with the kinds of priorities and options that might be available to them to make the best of the limited time they have. Many people who enter hospice care experience great relief from the realization that there is some chance for making positive use of the time they have left. And we often send them to hospice care way too late for the approach to reap such benefits for patients.

As Good a Life as Possible What is your definition of a good death? I’m skeptical about the idea of a good death. I describe several deaths in Being Mortal, and it’s not always dignified and it’s not always pretty. What I’m interested in is that even in a very narrow space, where a patient isn’t getting better and his/her life is very constricted, there is still the possibility of having as good a life as possible all the way to the end. My father eventually became quadriparetic from his astrocytoma. He was in pain and suffering difficult consequences from radiation therapy

that had not been successful, and yet we were able to identify priorities to sustain his quality of life. He eventually decided to forgo chemotherapy, because the cost to his life was greater than the intended benefit. He and his caregivers focused on reducing his falls, which rebuilt his strength. They tuned his medications to more effectively relieve his pain and anxieties. We worked to assure he still had the capacity, as long as possible, to connect and communicate with the people he loved. He had dinner parties, and he e-mailed. Skype was a lifeline, and tuning his medication so he could be coherent enough to talk every day with family back in India was important to him. In the end, he lived for 4 months without chemotherapy and many of the side effects he had been experiencing. I don’t know if he had a good death, but he had a life he felt worth living during the remaining time he had. And I knew that because we asked him about what mattered to him most. The main thing, it seemed to me, is that we ask about peoples’ priorities not just as they come to the end of their life, but as they face difficult choices earlier in the course of their disease to determine what sacrifices they are willing to make in their care and what sacrifices they are not willing to make. n Disclosure: Dr. Gawande has received royalties from numerous publishers for his writing, including from Being Mortal.

Don’t Miss These Important Reports in This Issue of The ASCO Post Prudence Francis, MD, on Ovarian Suppression Plus Hormonal Therapy in Breast Cancer see page 1

Keith Stewart, MB, ChB, on Carfilzomib and Relapsed Myeloma Remission see page 1

Marina Konopleva, MD, PhD, on Venetoclax and AML and CLL Treatment see page 116

Oliver G. Ottmann, MD, on Nilotinib and Philadelphia Chromosome–Positive ALL see page 11

Visit The ASCO Post online at ASCOPost.com

Joseph M. Connors, MD, and Frederick Hagemeister, MD, on Brentuximab Vedotin and Hodgkin Lymphoma see page 3

The ASCO Post | JANUARY 25, 2015

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In Memoriam

‘Mother of Bone Marrow Transplantation’ Dorothy ‘Dottie’ Thomas Dies at 92

orothy “Dottie” Thomas, wife and research partner to 1990 Nobel laureate E. Donnall Thomas, MD, died Friday, January 9, at her home near Seattle. She was 92. Dr. Donnall Thomas, Pioneer of the Bone Marrow Transplant and former Director of the Clinical Research Division at Fred Hutchinson Cancer Research Center,

Dottie Thomas, known as “the mother of bone marrow transplantation,” may have gotten the name from the late George Santos, MD, a bone marrow transplantation expert at Johns Hopkins University School of Medicine in Baltimore and a professional colleague. “If Dr. Thomas is the father of bone marrow transplantation, then Dottie Thomas is the mother,” he once said.

Partnership in Love and Work

E. Donnall Thomas, MD and Dorothy “Dottie” Thomas

preceded Mrs. Thomas in death on October 20, 2012, also at age 92. Dr. and Mrs. Thomas formed the core of a team that proved bone marrow transplantation could cure leukemias and other blood cancers, work that spanned several decades. “Dottie’s life had a profound impact, not just on those who knew her personally, but also countless patients,” said Fred Hutchinson President and Director Gary Gilliland, MD, PhD.1 “She and Don were amazing together in both what they accomplished and the way they cared for each other. Now their legacy continues through the many whose lives have been saved by bone marrow transplant and those who will be saved in the future. Dottie truly helped change the future of medicine. All of us at Fred Hutchinson are part of her legacy.”

A snowball to the face during a rare Texas snowfall in 1940 precipitated a partnership in love and work between Dr. Thomas and the former Dorothy Martin that spanned 70 years. In an interview with The ASCO Post in 2012, Dr. Thomas said, “A young student named Dorothy Martin appealed to me greatly and we hit it off, literally.

was admitted to Harvard University Medical School under a U.S. Army program. Mrs. Thomas got a job as a secretary with the Navy while Dr. Thomas attended medical school. “Dottie and I talked it over, and we decided that if we were going to spend time together, which it turned out we liked to do, that she probably ought to change her profession,” Don told The Seattle Times in a 1999 interview. “She’d taken a lot of science in her time in school, much more than most journalists. She liked science.” Mrs. Thomas left her Navy job and enrolled in the medical technology training program at New England Deaconess Hospital. “Because Dottie was a hematology technician, we used to look at smears and bone marrow together when we were students,” Dr. Thomas said.

Besides raising three children together, Dottie was Don’s partner in every aspect of his professional life, from working in the laboratory to editing manuscripts and administering his research program. —Fred Appelbaum, MD

During a freak snowstorm in Austin, I was leaving my shift at the dorm dining room and pow! a snowball smacked me in the head. I turned and there was Dottie, smiling. We married 2 years later [December 1942],” Dr. Thomas said, adding that Dottie would work with him in the lab throughout his career. Mrs. Thomas was a journalism major in college when, in March 1943, Don

She worked as a medical technician for some doctors in Boston until eventually Dr. Thomas had his own laboratory, and then she began to work with him. She worked part-time when their children were small, but otherwise was in the lab full time with her husband. “Dottie was there at Don’s side through every part of developing marrow transplantation as a science,” said

Fred Appelbaum, MD, Executive Vice President and Deputy Director of Fred Hutchinson Cancer Research Center. “Besides raising three children together, Dottie was Don’s partner in every aspect of his professional life, from working in the laboratory to editing manuscripts and administering his research program.” Mrs. Thomas’ journalism training was a big asset to the team, her husband recalled. “In the laboratory days, my friends pointed out that Dottie, who had the library experience, would go to the library and look up all the background information for a study that we were going to do, and then she would go into the laboratory and do the work and get the data, and then with her writing skills, she’d write the paper and complete the bibliography,” Dr. Thomas had recalled. “All I would do is sign the letter to the editor.” The couple moved to Seattle in 1963. Dr. Thomas joined Fred Hutchinson in 1975, the year its doors opened in Seattle’s First Hill neighborhood. For the next 15 years, Mrs. Thomas served as the Chief Administrator for the Hutchinson Clinical Research Division. Dr. Thomas stepped down from the clinical leadership position in 1990 and retired from Fred Hutchinson in 2002. Dr. and Mrs. Thomas are survived by two sons and a daughter, eight grandchildren, and two great-grandchildren. The family requests that people who wish to honor her do so by contributing to Dottie’s Bridge (www.fredhutch.org/ en/news/center-news/2014/03/ dottie-s-bridge.html). n

 In Memoriam

Dorothy “Dottie” Thomas 1924 – 2015 

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Palliative Care in Oncology Incorporating Physical Medicine and Rehabilitation Into Palliative Care A Conversation With Sean Smith, MD By Jo Cavallo

Cancer Rehabilitation Gains Support

Sean Smith, MD

lthough cancer rehabilitation has been a part of oncology clinical practice for several decades, it has largely gone unrecognized as an integral part of palliative medicine and survivorship care. Now, the role of physical medicine and rehabilitation in oncology care may increase as patients with cancer are living longer and need relief from residual physical, emotional, and cognitive impairments resulting from their disease or its treatment. A review of data by the American Cancer Society (ACS) on the complex set of issues cancer survivors often face has found that poor physical health is reported by 1 in 4 survivors, compared to about 1 in 10 of those without a history of cancer.1 In addition, poor mental health is reported by 10% of cancer survivors compared with 6% of adults without a cancer diagnosis. According to the review, the numbers suggest that as many as 3.3 million cancer survivors in the United States may have poor physical health and that 1.4 million may have poor mental health as a result of their disease. According to the ACS report, studies show that multidisciplinary cancer rehabilitation— which often involves a team of rehabilitation professionals that includes physiatrists, physical therapists, occupational therapists, speechlanguage pathologists, and rehabilitation nurses—improves pain control, physical and cognitive function, and overall quality of life in cancer survivors. It is for these reasons, said Sean Smith, MD, Director of the Cancer Rehabilitation Program at the University of Michigan Department of Physical Medicine and Rehabilitation in Ann Arbor, that survivors should be screened and treated for impairments all along the care continuum to minimize their disability and maximize their quality of life.

Interest in the field of cancer rehabilitation is gaining momentum as hospitals and cancer centers work toward implementing new standards of patientcentered care established by the American College of Surgeons’ Commission on Cancer (CoC), which go into effect in 2015. Three of the new standards— psychosocial distress screening, patient navigation process, and survivorship care plans—significantly impact cancer rehabilitation, which is an eligibility requirement for CoC accreditation. Physical medicine and rehabilitation is also becoming integrated into palliative care services, although limited availability in cancer centers to phys-

lems resulting from graft-vs-host disease or a cognitive impairment caused by chemotherapy or frontal lobe disinhibition from brain surgery for tumors. From there, I create a targeted treatment program to address specific impairments. This is distinct from prescribing general exercise or generic forms of physical therapy. Because it is far more effective than more broad approaches to treatment management, impairment-driven cancer rehabilitation is specifically cited by the ACS as a valuable patient-care service. Exercise and physical activity are well and good, but oftentimes patients are functionally limited or unsure of what they can do physically, or it may take more than this type of broad ap-

The entire field of physical medicine and rehabilitation is underresearched, and data speak louder than my talking about its merit. —Sean Smith, MD

iatrists and a lack of understanding on the difference between general exercise or wellness programs and impairmentdriven cancer rehabilitation are preventing the gap between the need for rehabilitative care in the palliative care setting and the delivery of services from closing. The ASCO Post talked with Dr. Smith about the use of physical medicine and rehabilitation in the palliative care setting; how cancer rehabilitation can ameliorate the effects of graft-vs-host disease in transplant patients; and how the field of physical medicine and rehabilitation can become an integral part of oncology care.

Impairment-Driven Rehabilitation Please talk about how you are using physical medicine and rehabilitation for patients with cancer in the palliative care setting. Many of the patients I see are survivors of breast, brain, and head and neck cancers or sarcomas or recipients of bone marrow transplantation. I determine what their impairment is, which could include a physical impairment, such as painful joints; spasticity preventing their ability to walk; back pain; neuropathy; radiation fibrosis syndrome; lymphedema; fatigue; or prob-

proach to improve patient outcomes. This is where a physiatrist can be helpful.

Potential Problems for Transplant Recipients What are some of the issues patients experience following a bone marrow transplant? Nearly all of the functional problems after a transplant stem from graft-vshost disease or its treatment. The latter includes steroids, which may cause myopathy and muscle atrophy. Avascular necrosis of the bone, another potential complication of steroids, is treated as a form of progressive arthritis by physiatrists. If a joint replacement is not a viable option due to a patient’s age or medical condition, or if the degree of joint destruction is not yet advanced enough to warrant arthroplasty, avascular necrosis is treated with a combination of interventions, including medications, physical and/or occupational therapies, and splinting/ bracing of the joint. Other potential problems for transplant recipients are contractures of the hands and skin, which can benefit from targeted treatment approaches. I have a patient who had two fingers on each hand amputated because they were so contracted, the function of her hands

GUEST EDITOR

Jamie H. Von Roenn, MD

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department.

was badly impaired. The amputations took place before she became my patient, and I wonder if earlier intervention would have been able to prevent them. All of these symptoms can lessen patients’ independence, decrease their quality of life, and put them at risk for adverse events, such as falls, which can be particularly devastating in this oftenthrombocytopenic population.

Role of the Physiatrist How does physical medicine and rehabilitation differ from physical therapy in the treatment of these conditions? Physical medicine and rehabilitation physicians have extensive medical training. To become a rehabilitation physician, individuals must graduate from medical school followed by 4 additional years of postdoctoral training in a physical medicine and rehabilitation residency. Physical therapists are trained in the clinical features of common musculoskeletal pathology, but they do not have medical degrees. This is not meant to imply that physical therapists are not skilled at what they do; they are, but the scope of physical therapy is limited in the context of cancer rehabilitation. The role of the physiatrist is to manage the medical issues of patients as they go through the rehabilitation process. A physiatrist will assess patients and diagnose conditions using imaging studies, continued on page 153

SECOND FDA APPROVAL Now for use both as monotherapy and in combination with paclitaxel

CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal (GE) junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinumcontaining chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, which evaluated CYRAMZA plus paclitaxel, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients who received CYRAMZA plus paclitaxel (1.2%) as compared to patients who received placebo plus paclitaxel (0.3%). Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

CYRAMZA® (ramucirumab) PLUS PACLITAXEL SIGNIFICANTLY EXTENDED OVERALL SURVIVAL (OS)1 RAINBOW OS: MEDIAN - MONTHS (95% CI)*1 1.0

CYRAMZA + paclitaxel (8.5, 10.8)

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

9.6

MONTHS

30% INCREASE IN MEDIAN OS

0.6

Hazard Ratio=0.81 (0.68, 0.96); P=0.017

0.4

7.4

0.2

MONTHS

CYRAMZA + paclitaxel Placebo + paclitaxel (6.3, 8.4)

Placebo + paclitaxel

0.0 0

TIME FROM RANDOMIZATION (MONTHS) Number at Risk

CYRAMZA 330 + paclitaxel Placebo 335 + paclitaxel

308

267

228

185

148

116

294

241

180

143

109

• The percentage of deaths at the time of analysis was 78% (256 patients) and 78% (260 patients) in the CYRAMZA plus paclitaxel and placebo plus paclitaxel treatment arms, respectively1 The phase III RAINBOW trial evaluated the efficacy and safety of CYRAMZA plus paclitaxel vs placebo plus paclitaxel in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma who had progressed on or after prior fluoropyrimidine- and platinum-containing chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were progression-free survival (PFS) and objective response rate (ORR). All patients were Eastern Cooperative Oncology Group performance status 0 or 1. Prior to enrollment, 97% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease. Twenty-five percent of patients had received anthracycline in combination with platinum/fluoropyrimidine therapy, while 75% did not. Patients were randomized 1:1 to CYRAMZA 8 mg/kg (n=330) or placebo (n=335) every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle.1,3 CI=confidence interval. *Intent-to-treat [ITT] population.

CYRAMZA PLUS PACLITAXEL ALSO SIGNIFICANTLY DELAYED DISEASE PROGRESSION AND PROVIDED SIGNIFICANTLY GREATER ORR VS PLACEBO PLUS PACLITAXEL (SUPPORTIVE EFFICACY OUTCOME MEASURES)*1 • Median PFS with CYRAMZA plus paclitaxel was 4.4 months (95% CI: 4.2, 5.3) vs 2.9 months (95% CI: 2.8, 3.0) with placebo plus paclitaxel (hazard ratio 0.64 [95% CI: 0.54, 0.75]; P<0.001)1 - The percentage of events at the time of analysis was 85% (279 patients) and 88% (296 patients), respectively • Significantly more patients responded to CYRAMZA combined with paclitaxel (28%; 95% CI: 23, 33) than to placebo plus paclitaxel (16%; 95% CI: 13, 20) (P<0.001)†1,2 ITT population. ORR was defined as complete plus partial response. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.2

†

VISIT WWW.CYRAMZAHCP.COM FOR MORE INFORMATION, INCLUDING CYRAMZA MONOTHERAPY TRIAL DATA Most Common Adverse Reactions—Single Agent • The most commonly reported adverse reactions (all grades; grade 3-4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%). • The most common serious adverse events with CYRAMZA in Study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo. • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%). • Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZAtreated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Most Common Adverse Reactions—Combination with Paclitaxel • The most commonly reported adverse reactions (all grades; grade 3-4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel and ≥2% higher than placebo plus paclitaxel in Study 2 were fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%; 41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%; 0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema (25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%), proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2% vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal hemorrhage events (10% vs 6%; 4% vs 2%). • The most common serious adverse events with CYRAMZA plus paclitaxel in Study 2 were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. • Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%). • Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel-treated patients in Study 2 were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo plus paclitaxel) and gastrointestinal perforations (1.2% for CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).

Drug Interactions • No pharmacokinetic (PK) interactions were observed between ramucirumab (CYRAMZA) and paclitaxel.

Use in Specific Populations • Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. • Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant. • Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility. Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on next page. RB HCP ISI 05NOV2014 References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014. 2. Wilke H, Muro K, Van Cutsem E, et al; for the RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. 3. Data on file, Eli Lilly and Company. ONC09302014b.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information. WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. INDICATIONS AND USAGE Gastric Cancer CYRAMZA as a single agent, or in combination with paclitaxel, is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety data are presented from two randomized, placebo controlled clinical trials in which patients received CYRAMZA: Study 1, a randomized (2:1), double-blind, clinical trial in which 351 patients received either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks and Study 2, a double-blind, randomized (1:1) clinical trial in which 656 patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either CYRAMZA 8 mg/kg intravenously every two weeks or placebo every two weeks. Both trials excluded patients with ECOG performance status of 2 or greater, uncontrolled hypertension, major surgery within 28 days, or patients receiving chronic anti-platelet therapy other than once daily aspirin. Study 1 excluded patients with bilirubin ≥1.5 mg/dL and Study 2 excluded patients with bilirubin >1.5 times the upper limit of normal. CYRAMZA Administered as a Single Agent Among 236 patients who received CYRAMZA (safety population) in Study 1, median age was 60 years, 28% were women, 76% were White, and 16% were Asian. Patients in Study 1 received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months. In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo. Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 Adverse Reactions (MedDRA)a System Organ Class

CYRAMZA (8 mg/kg) N=236 All Grades Grade 3-4 (Frequency %) (Frequency %)

Gastrointestinal Disorders Diarrhea Metabolism and Nutrition Disorders Hyponatremia Nervous System Disorders Headache Vascular Disorders Hypertension

Placebo N=115 All Grades (Frequency %)

Grade 3-4 (Frequency %)

MedDRA Version 15.0.

CYRAMZA® (ramucirumab) injection

RB HCP BS 05NOV2014

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo). Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. CYRAMZA Administered in Combination with Paclitaxel Among 327 patients who received CYRAMZA (safety population) in Study 2, median age was 60 years, 31% were women, 63% were White, and 33% were Asian. Patients in Study 2 received a median of 9 doses of CYRAMZA; the median duration of exposure was 18 weeks, and 93 (28% of 327) patients received CYRAMZA for at least six months. In Study 2, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus paclitaxel at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with CYRAMZA plus paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%); 19% of patients treated with CYRAMZA plus paclitaxel received granulocyte colony-stimulating factors. Adverse reactions resulting in discontinuation of any component of the CYRAMZA plus paclitaxel combination in 2% or more patients in Study 2 were neutropenia (4%) and thrombocytopenia (3%). Table 2: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA plus Paclitaxel in Study 2 CYRAMZA plus Paclitaxel (N=327) All Grades Grade ≥3 (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Neutropenia 54 41 Thrombocytopenia 13 2 Gastrointestinal Disorders Diarrhea 32 4 Gastrointestinal 10 4 hemorrhage events Stomatitis 20 1 General Disorders and Administration Site Disorders Fatigue/Asthenia 57 12 Peripheral edema 25 2 Metabolism and Nutrition Disorders Hypoalbuminemia 11 1 Renal and Urinary Disorders Proteinuria 17 1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 31 0 Vascular Disorder Hypertension 25 15 Adverse Reactions (MedDRA) System Organ Class

Placebo plus Paclitaxel (N=329) All Grades Grade ≥3 (Frequency %) (Frequency %) 31 6

19 2

23 6

2 2

44 14

6 1

Clinically relevant adverse reactions reported in ≥1% and <5% of the CYRAMZA plus paclitaxel treated patients in Study 2 were sepsis (3.1% CYRAMZA plus paclitaxel versus 1.8% placebo plus paclitaxel) and gastrointestinal perforations (1.2% CYRAMZA plus paclitaxel versus 0.3% for placebo plus paclitaxel). Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 53/884 (6%) of CYRAMZAtreated patients with post baseline serum samples tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 9 of the 53 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and paclitaxel. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and fetoplacental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population PK analysis. Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin >1.0-1.5 times upper limit of normal [ULN] and any AST) based on population PK analysis. Clinical deterioration was reported in patients with ChildPugh B or C cirrhosis who received single-agent CYRAMZA. CYRAMZA® (ramucirumab) injection

RB HCP BS 05NOV2014

Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility. Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. Recommended Dose and Schedule The recommended dose of CYRAMZA either as a single agent or in combination with weekly paclitaxel is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. When given in combination, administer CYRAMZA prior to administration of paclitaxel. Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to paclitaxel, refer to the current respective prescribing information. PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Of increased risk of an arterial thromboembolic event. • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment. Additional information can be found at www.CYRAMZAhcp.com.

ASCOPost.com | JANUARY 25, 2015

Palliative Care in Oncology Sean Smith, MD continued from page 149

electromyography (physiatrists are often also Board-certified in electrodiagnostic medicine), and laboratory tests. In some cases, specific targeted physical therapy prescribed by a physiatrist is warranted; in other cases, interventions including medications, nerve and neuromuscular blocks for pain management, a home exercise program designed by a physiatrist, occupational therapy, rehabilitation psychology, or speech-language therapy may be prescribed. One example I can give that reflects the difference between the role of physical therapy and physical medicine and rehabilitation in impairment-driven cancer rehabilitation is a patient of mine with breast cancer who was suffering from radiation fibrosis, which pulled her pectoralis and posterior shoulder muscles tightly, causing headaches. Prescribing exercise or generic physical therapy would not have fixed this problem; it takes specialized treatment. For a patient like this, I would start her on a nerve-stabilizing medication to stop the muscle contractions and cramping and perhaps do a nerve block for the headaches. And if those interventions didn’t work, I would add a different medication or inject botulinum toxin (Botox) into the muscles to alleviate the tightness and prevent the headaches. In addition, I would prescribe condition-specific exercises to do at home. Determining treatment is a big process, and it all depends on the cause of the impairment.

Cognitive Dysfunction

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Please talk about how you treat patients with cognitive impairments. Cognitive dysfunction can include changes in short-term memory or concentration and may cause fatigue. Usually, prescribing a gentle central nervous system stimulant such as methylphenidate or amantadine, along with working with a speech-language pathologist, can help to restore memory and concentration. Methylphenidate can also help with fatigue, which is one of the most common symptoms cancer survivors’ have. I’ve had multiple patients tell me how life-changing getting over their fatigue was for them. To determine the exact problem, we have patients assessed by a rehabilitation psychologist, who offers a more sophisticated and in-depth way of evaluating cognition. This approach is helpful for patients who wish to return to work or other high-level activities.

Evaluation for symptoms of depression and anxiety is an essential component of the workup of patients with cognitive impairment. These symptoms may be addressed pharmacologically or through work with the psychology members of the team. Our main concern is to identify the issues patients are having, determine their goals for treatment, and then prescribe the most effective therapy.

Referral Process Are physiatrists becoming part of the palliative care team in cancer centers? And how are patients referred to cancer rehabilitation specialists? Here at the University of Michigan, patients are referred to me when a provider identifies a need. I have support from the clinical director at our cancer center, and that helps get the word out. At other centers, there are referral algorithms that are followed if a patient has a certain function score on an intake questionnaire, but that process is not well defined, and it is something that we in this field need to address to improve patient care. For example, I would like to see any physical or emotional symptom flagged on a survivorship care plan and then have patients referred to cancer rehabilitation if appropriate. I think that would be an easy way to get patients the services they need to improve their quality of life. One of the challenges we face is that palliative care teams have been around in an institution longer than have physiatrists specializing in cancer, so it is difficult to become incorporated into the palliative care team.

Underappreciated Service Are more cancer institutions starting to recognize the importance of cancer rehabilitation for survivors and implementing similar programs? I can’t say whether that is true, but I think that more physical medicine and rehabilitation physicians are realizing that we should be engaging more with oncology providers, and so from our end, the interest is growing. A survey of 15 prominent cancer centers has found that only 28% of cancer centers even mention cancer rehabilitation on their websites, and most of the time, it is in reference to physical therapy.2 I think many cancer centers still believe that recommending exercise to address physical impairments or a therapist for problems like lymphedema, for example, is adequate to resolve continued on page 154

The ASCO Post | JANUARY 25, 2015

PAGE 154

News

MD Anderson, UnitedHealthcare Launch New Cancer Care Payment Model

he University of Texas MD Anderson Cancer Center and UnitedHealthcare have launched a pilot to explore a new cancer care payment model for head and neck cancers that focuses on quality patient care and outcomes. The collaboration is among the first using bundled payments in a large, comprehensive cancer center. The bundled payment method reimburses a care provider or hospital for

launched a similar pilot in 2010 involving 810 breast, colon and lung cancer patients who were treated at five medical oncology groups around the United States. A recent issue of Journal of Oncology Practice1 featured the results of that study, which showed cancer costs were cut by a third and quality was improved. Those results prompted UnitedHealthcare to expand the bundled payment model and explore more complete models like the one

Bundled pricing is something that patients and care providers want, and this is our first opportunity to better understand how we can manage costs without sacrificing quality care and patient outcomes. —Thomas W. Feeley, MD

a defined episode of care under a single fee or payment. This is a shift away from the common fee-for-service structure in which a care provider is paid for each treatment, drug, appointment, or test.

Pre-Priced Payment The program is based on MD Anderson’s extensive mapping of the complex tests, treatments, follow-up care, and supportive services required for the most common head and neck cancer diagnoses. The pre-priced payment provides an incentive to focus on the essential elements of care and to avoid unnecessary steps. This careful mapping is expected to produce improved patient outcomes, lower costs, and a better quality of life for patients. Similar payment models have shown to help reduce overall costs while providing for continuity of care and improving outcomes for patients. UnitedHealthcare

Sean Smith, MD continued from page 153

these issues, when in fact cancer rehabilitation is much more involved. Kevin C. Oeffinger, MD, Chair of ASCO’s Cancer Survivorship Committee and Director of the Adult LongTerm Follow-Up Program at Memorial Sloan-Kettering Cancer Center, told The Washington Post in an interview,3 “Rehabilitation services are probably the single most underappreciated service among cancer survivors right now.” And I’m glad that experts outside of the physical medicine and rehabilitation

at MD Anderson. The report, “Changing Physician Incentives for Affordable, Quality Cancer Care: Results of an Episode Payment Model,” demonstrates the potential effectiveness of new approaches to the current “fee-for-service” payment model for cancer therapy.

Pilot Study The new 3-year pilot will be conducted in MD Anderson’s Head and Neck Center for up to 150 patients newly diagnosed with cancers of the salivary glands, oral cavity (including the mouth, lips, tongue, soft palate), throat, and larynx, and who are enrolled in certain employer-sponsored benefit plans insured or administered by UnitedHealthcare. Eight bundled payment models have been developed by MD Anderson and UnitedHealthcare for the program. Each bundled payment model was developed for the research-based clinical practices field are recognizing this deficiency in patient care.

Need for Collaboration What can the field do to make more oncologists aware of the need and benefits of cancer rehabilitation for palliative care patients? One thing we can do is to reach out to societies like ASCO to see how we can collaborate to integrate cancer rehabilitation into palliative care services. Another way we can improve utilization is to do more research to show the effectiveness of cancer rehabilitation on

and protocols that have been created and refined over decades at the cancer center. “For the last 5 years, MD Anderson and its Institute for Cancer Care Innovation have been looking at how to best approach a single price for treating cancers. It is a complex question because cancer is a complex disease and each patient unique,” said Thomas W. Feeley, MD, Head of Anesthesiology and Critical Care, and Head of the institute. “Bundled pricing is something that patients and care providers want, and this is our first opportunity to better understand how we can manage costs without sacrificing quality care and patient outcomes.”

About the Partnership “Our partnership with MD Anderson Cancer Center marks an important step toward expanded bundled care payment models and away from the traditional fee-for-service payments for oncology care,” said Lee N. Newcomer, MD, United Healthcare’s Vice President, Oncology. “Our recently completed pilot shows that these

working with care providers to transition to value-based reimbursement methods, which emphasize quality and patient outcomes over the volume of procedures performed. Care providers are showing strong interest, as UnitedHealthcare’s total care provider reimbursements that are tied to a variety of value-based arrangements have nearly tripled since 2011 to $36 billion, and are expected to reach $65 billion by the end of 2018. Randal S. Weber, MD, Professor and Chair of the Department of Head and Neck Surgery said patients will receive the same care, approach, treatment, and diagnostics for their disease as those who are not part of the program. The new payment model is designed to bill patients just once for their cancer treatment at MD Anderson, and because the cost of the tests, treatment and other services are priced upfront, they will know the cost of care early in their treatment program. “Innovative health-care payment reform among patients, employers, care providers, and payers continues to be

Our recently completed pilot shows that these creative new cancer care payment models can reduce healthcare costs while improving patient outcomes. —Lee N. Newcomer, MD

creative new cancer care payment models can reduce health-care costs while improving patient outcomes. MD Anderson’s work with value-based workflows makes them a natural partner for bundled payments.” Bundled payments are one of the many different ways UnitedHealthcare is survivors’ well-being and quality of life. The entire field of physical medicine and rehabilitation is underresearched, and data speak louder than my talking about its merits. Our field’s national organizations also need to work with the Commission on Cancer and the National Cancer Institute to improve patient-centered care. Until, we show that we as physiatrists are interested in collaborating with oncologists, we won’t be seen as legitimate contributors in the continuum of cancer care to organizations like ASCO or oncology providers in general. n

a topic that calls for careful study,” said Brad Gibson, Associate Vice President and Treasurer of MD Anderson. n Reference 1. Trent L: Potential approaches to sustainable, long-lasting payment reform in oncology. J Oncol Pract 10:254-258, 2014.

Disclosure: Dr. Smith reported no potential conflicts of interest.

References 1. Silver JK, Baima J, Mayer RS: Impairment-driven cancer rehabilitation: An essential component of quality care and survivorship. CA Cancer J Clin 63:295-317, 2013. 2. Smith SR, Reish AG, Andrews C: Cancer survivorship: A growing role for physiatric care. PM R. December 18, 2014 (early release online). 3. Aschwanden C: How to get healthy after the cancer treatments are done. The Washington Post. July 29, 2013.

ASCOPost.com | JANUARY 25, 2015

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In the Clinic Gynecologic Oncology

Olaparib for BRCA-Mutated Previously Treated Advanced Ovarian Cancer By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n December 19, 2014, olaparib (Lynparza) was granted accelerated approval as monotherapy for treatment of patients with deleterious or suspected deleterious germline BRCAmutated advanced ovarian cancer who have received at least three prior lines of chemotherapy; mutations must be detected by a U.S. Food and Drug Administration (FDA)-approved test.1,2 The FDA concurrently approved the BRACAnalysis CDx test for the qualitative detection and classification of variants in the BRCA1 and BRCA2 genes.

Supporting Study Approval is based on objective response rate observed in an international single-arm trial including 137 patients with measureable deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who had received at least three prior lines of chemotherapy. Patients had a median age of 58 years, 94% were white, and 93% had an Eastern Cooperative Oncology Group performance status of 0 or 1. Deleterious or suspected deleterious germline BRCA mutation status was verified retrospectively in 97% (59/61) of the patients with available blood

OF NOTE Olaparib is a PARP inhibitor that impedes growth of select tumor cell lines in vitro and decreases tumor growth in mouse xenograft models.

samples by the companion diagnostic BRACAnalysis CDx. Patients received 400 mg twice daily until disease progression or intolerable toxicity. The objective response rate was 34% (95% confidence interval [CI] = 26%–42%), with complete response in 2%, and the median response duration

was 7.9 months (95% CI = 5.6–9.6 months).

How It Works Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. The roles of PARP enzymes in normal cellular homeostasis include DNA transcription, cell-cycle regulation, and DNA repair. The drug inhibits growth of select tumor cell lines in vitro and decreases tumor growth in mouse xenograft models as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and antitumor activity of olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies

comitant use of strong CYP3A inducers (eg, rifampin, carbamazepine, St. John’s wort), which may reduce olaparib efficacy, should be avoided. No adjustment to the starting dose is required in patients with mild renal impairment, although patients should be

OF NOTE Olaparib carries warnings/precautions for MDS/AML, pneumonitis, and embryo-fetal toxicity.

monitored closely for toxicity. Patients with bilirubin greater than 1.5 times upper limit of normal and AST/ALT at least 2.5 times the upper limit of normal (≥ 5 times upper limit of normal in the

Olaparib for Treating Ovarian Cancer ■■ Olaparib (Lynparza) was granted accelerated approval as monotherapy for deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer after at least three prior lines of chemotherapy; the BRACAnalysis CDx test for detecting requisite mutations was concurrently approved. ■■ The recommended olaparib dosage is 400 mg twice daily, with treatment continued until disease progression or unacceptable toxicity.

showed that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.

How It Is Given The recommended dosage of olaparib is 400 mg twice daily, with treatment continued until disease progression or unacceptable toxicity. For management of adverse events, recommended dose reductions are to 200 mg twice daily and subsequently to 100 mg twice daily. Concomitant use of strong (eg, clarithromycin, indinavir, ketoconazole) or moderate (eg, aprepitant, ciprofloxacin, imatinib) CYP3A inhibitors should be avoided; if use of such an agent cannot be avoided, the olaparib dose should be reduced to 150 mg twice daily for concurrent use of a strong CYP3A inhibitor and 200 mg twice daily for use of a moderate CYP3A inhibitor. Con-

presence of liver metastases) were excluded from olaparib clinical trials. No data are available on olaparib use in patients with hepatic impairment or moderate or severe renal impairment.

Safety Profile The most common adverse events of any grade among 223 patients with germline BRCA-mutated ovarian cancer who received at least three prior lines of chemotherapy in olaparib clinical trials (median exposure, 158 days) were fatigue/asthenia (66%), nausea (64%), abdominal pain/discomfort (43%), vomiting (43%), anemia (34%), and diarrhea (31%). The most common grade 3 or 4 adverse events were anemia (18%), abdominal pain/discomfort (8%), and fatigue/asthenia (8%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (17%), anemia (15%), and neutropenia (7%). Adverse reactions led to dose interruption in 40% of patients, dose reduction in

4%, and discontinuation in 7%. Adverse events led to death in eight patients (4%), with two deaths attributed to acute leukemia and one each to chronic obstructive pulmonary disease, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was observed in 2% of patients in a singlearm trial of olaparib monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated advanced cancers and 2% of patients in a randomized comparison with placebo in advanced ovarian cancer. Olaparib carries warnings/precautions for MDS/AML, including fatal cases, pneumonitis, including fatal cases, and embryo-fetal toxicity. Patients should be monitored for hematologic toxicity at baseline and monthly thereafter, and olaparib should be interrupted for prolonged hematologic toxicity and discontinued for MDS/AML. Treatment should be interrupted for suspected pneumonitis and discontinued in confirmed cases. n References 1. U.S. Food and Drug Administration: Olaparib. Available at www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm427598.htm. Accessed January 14, 2015. 2. LynparzaTM (olaparib) capsules prescribing information, AstraZeneca, December 2014. Available at www.accessdata.fda.gov/dr ugsatfda_docs/ label/2014/206162lbl.pdf. Accessed January 14, 2015.

The ASCO Post | JANUARY 25, 2015

PAGE 156

International Conference of the Society for Integrative Oncology Personalized Integrative Cancer Care: Focus of the 11th International Conference of the Society for Integrative Oncology By Jo Cavallo

here were several aspects of the 11th International Conference of the Society for Integrative Oncology (SIO), held October 26-28, 2014, in Houston, that distinguished it from past years. One major change was that this year’s conference was held in collaboration with The University of Texas MD Anderson Cancer Center, bridging conventional oncology and the use of evidence-based integrative oncology modalities. “We are making great inroads in establishing evidence-based information

to guide the use of integrative medicine in oncology care,” said Heather Greenlee, ND, PhD, MPH, Immedi-

Heather Greenlee, ND, PhD, MPH

ate Past President of SIO and Assistant Professor in the Department of Epidemiology at the Mailman School of Public Health at Columbia University in New York. “It was very exciting that the conference was cohosted by the MD Anderson Cancer Center. Several basic and clinical scientists from the institution presented their research on where integrative medicine can intersect with state-of-the-art oncology care.” The theme of the 2014 conference, Personalized Integrative Oncology:

Targeted Approaches for Optimal Outcomes, also marked a first. The keynote address, “The Contribution of Genomics to Integrative Oncology,” presented by John Mendelsohn, MD, Director of the Institute for Personalized Cancer Therapy at MD Anderson and past President of MD Anderson, built on that concept of personalized integrative oncology and explored how integrative modalities can support patients both during and after conventional treatment. continued on page 164

The Best of SIO By Jo Cavallo

he following five abstracts, which include four clinical studies and one basic research study, were named the top abstracts at the 2014 International Conference of the Society for Integrative Oncology.

Therapeutic Effects of Lyophilized Leech Saliva Extract Hassona MDH, Ammar AE, Gao TY, et al: In vivo assessment of the therapeutic effects of lyophilized leech saliva extract from (Huridinaria manillensis) on different tumor xenograft models in nude mice. 11th International Conference of the SIO. Abstract 12. Presented October 28, 2014. This study investigated the in vivo toxicity and efficacy of leech saliva extract from Huridinaria manillensis. The researchers concluded that leech saliva extract is safe when it is administered in doses up to 20 mg/kg, with no toxicity. They also found a significant decrease in tumor growth of PC3 prostate cancer xenograph models treated with either docetaxel or leech saliva extract compared with the vehicle-cont arolled mice.

Personalized Acupuncture Therapy Bauml J, Xie SX, Farrar JT, et al: Baseline response expectancy: A potential tool for personalized acupuncture therapy. 11th International Conference of the SIO. Abstract 23. Presented October 28, 2014. The researchers analyzed data from

a randomized control trial using electroacupuncture and sham electroacupuncture. The study was conducted among 67 women with stage I to III breast cancer who experienced joint pain attributable to aromatase inhibitors. The researchers found that the relationship between expectancy and treatment response is distinct between real and sham acupuncture. They concluded that although patients receiving electroacupuncture had a clinically significant improvement in pain regardless of expectancy, patients receiving sham acupuncture gained a benefit only if they expected one. “Patients with baseline expectancy may gain equivalent benefit from a less aggressive form of acupuncture, such as superficial needling with minimal manipulation,” wrote the study authors.

Effect of Chinese Medicine on Colorectal Cancer Recurrence Yang Y, Yun XU, Wang J, et al: Effect of traditional Chinese medicine on the recurrence and metastasis of stage II and III colorectal cancer after radical operation: A prospective, multicenter cohort study (the 5-year follow-up results). 11th International Conference of the SIO. Abstract 87. Presented October 28, 2014. This study included 312 Chinese patients: 167 patients had colon cancer, and 145 had rectal cancer. All the patients had received conventional Western treatment, and follow-up visits were conducted according to the National Comprehensive Cancer

Network guidelines. The exposure factor was defined as whether a patient used traditional Chinese medicine. The researchers concluded that long-course, high-exposure traditional Chinese medicine treatment might improve the prognosis of stage II and III colorectal cancer patients. “The rate of recurrence and metastasis of stage II and III post radical operation in colorectal cancer patients can be reduced by 1 year of consistent treatment with syndrome differentiation traditional Chinese medicine– based therapy together with routine Western medicine treatment,” wrote the study authors.

Acupuncture in Children and Adolescents McDaniel D, Chokshi S, Jin Z, et al: Demographic predictors of use and safety of acupuncture in children and adolescents undergoing treatment for cancer. 11th International Conference of the SIO. Abstract 116. Presented October 28, 2014. This prospective study evaluated predictors of use and safety of acupuncture in 90 children and adolescents undergoing cancer treatment. Acupuncture was more often delivered to patients diagnosed with leukemia or lymphoma. The researchers concluded that acupuncture is widely accepted and safe among children undergoing treatment for cancer. “Sociodemographic variables and persistent symptom burden predict the use of acupuncture, suggesting

target populations for the delivery and scientific evaluation of acupuncture in pediatric oncology,” wrote the study authors.

Eradicating Human Papillomavirus in Women Smith JA, Faro J, Bai Y, et al: Evaluation of active hexose correlated compound (AHCC) for the eradication of human papillomavirus infections in women. 11th International Conference of the SIO. Abstract 138. Presented October 28, 2014. The objective of this pilot study was to determine the effectiveness of active hexose correlated compound (AHCC), a fermented mushroom extract that is commercially available and promoted for immune support, in eradicating cervical high-risk human papillomavirus infections. Ten women were enrolled in the study and prescribed 3 g of oral AHCC once daily. The researchers concluded that preliminary results from the study are consistent with their preclinical findings that AHCC appears effective for eradication of human papillomavirus infections. “Further investigation in a formal phase II randomized placebo controlled study is planned,” according to the study abstract. n To read the full description of the five Best of SIO abstracts, visit http:// www.integrativeonc.org/index.php/ public-documents/149-best-of-sio2014abstracts-1/file

indications

ignited we stand with

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

Important Safety Information CONTRAINDICATIONS WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a doselimiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non– small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

Important Safety Information (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis • Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with singleagent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/ asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported • Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229) • In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%) • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Non–Small Cell Lung Cancer (NSCLC) Study • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin– treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group • Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively • Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively • Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

Pancreatic Adenocarcinoma Study • See next page for most common adverse reactions • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%) Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN • For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely

For more information, please visit www.abraxane.com.

ABRAXANE® is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

in first-line MPAC

ignite survival ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone 1.0

Median OS

0.9

ABRAXANE + gemcitabine (n=431)

Proportion of survival

0.8 0.7

Gemcitabine (n=430)

0.6 0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months (95% CI: 6.0-7.2)

0.4 0.3

HR: 0.72 (95% CI: 0.62-0.83)a

0.2

P<0.0001b

0.1 0.0 Patients at risk A+G: G:

431 430

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

0 0

Time (months)

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. Stratified Cox proportional hazard model. b Stratified log-rank test stratified by geographic region (North America vs Others), KPS (70-80 vs 90-100), and presence of liver metastasis (yes vs no). a

STUDY DESIGN The multinational, randomized, phase 3 MPACT trial compared ABRAXANE (125 mg/m2) + gemcitabine (1000 mg/m2) on Days 1, 8, and 15 of each 28-day cycle vs gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks, followed by a 1-week rest period in Cycle 1, then on Days 1, 8, and 15 of each subsequent 28-day cycle) in 861 patients with MPAC. The primary end point was OS.

Most common adverse reactions in the pancreatic adenocarcinoma study • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

ABRAXANE is also indicated in MBC and NSCLC ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. • The primary end point in the metastatic breast cancer (MBC) phase 3 trial was reconciled target lesion response rate (recTLRR) vs paclitaxel injection ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. • The primary end point in the NSCLC phase 3 trial was overall response rate (ORR) vs paclitaxel injection + carboplatin

Overall survival (secondary end point) was not statistically significant in the MBC and NSCLC trials vs comparator arms.

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary; refer to full Prescribing Information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies (14.2)]. 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)]. 2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc MBC NSCLCc Adenocarcinoma Mild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2 ≤ 1.25 x ULN Moderate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not 2 x ULN recommended 50 mg/m2 not Severe < 10 x ULN AND 2.01 to 130 mg/m2 b 5 x ULN recommended > 10 x ULN OR > 5 x ULN not not not recommended recommended recommended MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer. 2.5 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. • In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2. • Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL) Neutropenic Fever (ANC less than First 75 4.5 500/mm3 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm3 OR ANC less than 500/mm3 for more than 7 days Platelet count less than 50,000/mm3 Severe sensory Neuropathy – Grade 3 or 4

Second

Third First Second First Second Third

Discontinue Treatment 75 4.5 Discontinue Treatment 75 4.5 50 3 Discontinue Treatment

Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3. Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2) Full dose 125 1000 1st dose reduction 100 800 2nd dose reduction 75 600 If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine Day 1 < 1500 OR < 100,000 Delay doses until recovery Day 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count. Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5. Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at Febrile Neutropenia: Grade 3 or 4 next lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at next No dose reduction lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at Grade 3 mucositis or diarrhea next lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)]. 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)]. 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine. 5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%). In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%). 6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 175 mg/m2 over 3 hb 260 mg/m2 over 30 min (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of doseand schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (200 mg/m2 every 3 weeks) (100 mg/m2 weekly) plus carboplatin plus carboplatin Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 MedDRA v 12.1 Toxicity Toxicity Toxicity Toxicity System Organ Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General disorders Edema peripheral 10 0 4 <1 and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0 and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective Myalgia 10 <1 19 2 tissue disorders a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%. Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/ Gemcitabine Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group. Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE Gemcitabine (N=402) (125 mg/m2) and gemcitabine (N=421) Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%) General disorders and administration site Peripheral conditions edema 194 (46%) 13 (3%) 122 (30%) 12 (3%) Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%) Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%) Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%) 228 (54%) 27 (6%) 192 (48%) 14 (3%) Gastrointestinal disorders Nausea Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%) Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%) Alopecia 212 (50%) 6 (1%) 21 (5%) 0 Skin and subcutaneous tissue disorders Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%) Nervous system disorders Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%) Dysgeusia 68 (16%) 0 33 (8%) 0 Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%) Metabolism and nutrition Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%) disorders Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%) Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%) Respiratory, thoracic and Cough 72 (17%) 0 30 (7%) 0 mediastinal disorders Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%) Infections and infestations Urinary tract infectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%) Musculoskeletal and Pain in connective tissue extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%) disorders Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%) Myalgia 44 (10%) 4 (1%) 15 (4%) 0 Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0 a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died. 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history. Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)]. • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)]. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)]. • Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)]. Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: See www.celgene.com. ABR_ALL_HCP_BSv007 10_2013

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International Conference of the Society for Integrative Oncology Personalized Integrative Cancer Care continued from page 156

“Dr. Mendelsohn’s address sparked a dynamic discussion in which the audience members asked questions about how to apply genomics to determine

Cancer Symptom Control; Energy Balance; and The Impact of Sleep, Fatigue, and Circadian Rhythms on Patients With Cancer. “We have been hearing for a long time that some clinicians, while interested in the research presented, also wanted to have relevant take-home information they can apply in their practices the next day,” said Dr. Greenlee. “So, we listened and created a clinical track, which was very popular.”

receiving breast cancer treatment. The recommendations presented in the clinical practice guidelines are organized by patient outcome and graded

Worldwide Attraction

John Mendelsohn, MD

Suzanna Zick, ND, MPH

which patients would benefit most from the use of various integrative therapies to ameliorate side effects from their cancer and its treatment,” said Suzanna Zick, ND, MPH, President of SIO and Associate Research Professor in the Department of Family Medicine at the University of Michigan in Ann Arbor. “I think that conversation was novel for some people, and for others, it was one they had been waiting to have for a long time.” Also new in 2014 was the incorporation of a clinical track into the program geared toward providing physicians with information they can use in their clinical practice, including sessions on

The 2014 conference attracted over 300 oncologists, internal medicine physicians, researchers, nurses, integrative medicine practitioners, cancer survivors, and patient advocates from 17 countries and presented 151 scientific abstracts, setting a new record. For a second year in a row, SIO received a National Cancer Institute conference grant to fund travel expenses for patient advocates, which also provided a specific training track for the advocates. In addition, travel scholarships were awarded to five junior investigators.

Clinical Practice Guidelines for Breast Cancer Survivors One of the conference highlights was the presentation of new clinical practice guidelines on the use of integrative therapies as supportive care during breast cancer treatment, which were developed by SIO members and published in the Journal of the National Cancer Institute Monographs.1 The guidelines’ authors followed the Institute of Medicine’s guideline development process, which included a systematic review of randomized controlled clinical trials testing the use of integrative therapies for supportive care in patients

Debu Tripathy, MD

based on a modified version of the U.S. Preventive Services Task Force grading system.2 The new guidelines are meant to provide both clinicians and breast cancer survivors with evidence-based information on specific integrative therapies that are effective in the supportive care setting. “We wanted to create a tool for both providers and patients, so they can have an informed discussion about which integrative therapies work and which ones don’t, depending on their specific goals. We are now in the process of taking the information in these guidelines and creating patient-friendly educational materials,” said Dr. Greenlee. Dr. Greenlee co-chaired the guideline development process with Debu Tripathy, MD, Professor and Chair of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center and Vice Chair of the Southwest Oncology Group Breast Committee.

Looking Ahead The goal of SIO is to ensure even greater participation by integrative practitioners, researchers, cancer survivors, and patient advocates in the 2015 con-

ference and to continue building support for the incorporation of evidence-based integrative medicine into oncology care by educating medical professionals about the state of the science. “In addition to attracting more people to our conference with the best science in integrative medicine and producing more clinical practice guidelines, we want to tackle developing educational guidelines in integrative medicine for oncologists and oncology nurses,” said Dr. Zick. “We want integrative practitioners to have the latest knowledge about integrative therapies, and we are looking into developing a benchmark for training. We want to ensure that as more cancer centers develop integrative programs, they have guidance on what constitutes a qualified practitioner.”

Save the Date The 12th International Conference of the SIO will be held November 14-16, 2015, in Boston. The first day will include a joint program of the Society for Acupuncture Research, the Fascia Research Society, and SIO. For more information on SIO, visit www.integrativeonc.org. n

Disclosure: Drs. Greenlee, Mendelsohn, and Zick reported no potential conflicts of interest.

References 1. Greenlee H, Balneaves LG, Carlson LE, et al: Clinical practice guidelines on the use of integrative therapies as supportive care in patients treated for breast cancer. J Natl Cancer Monogr 50:346-358, 2014. 2. U.S. Preventive Services Task Force: Grade definitions. Available at http://www. uspreventiveservicestaskforce.org/Page/ Name/grade-definitions. Accessed December 22, 2014.

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ASCOPost.com | JANUARY 25, 2015

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Journal Spotlight Integrative Oncology

SIO Clinical Practice Guidelines on the Use of Integrative Therapies as Supportive Care in Patients Treated for Breast Cancer By Matthew Stenger

he Society for Integrative Oncology (SIO) Guidelines Working Group has recently released clinical practice guidelines on the use of integrative therapies as supportive care in patients receiving treatment for breast cancer. The guidelines, reported by Heather Greenlee, ND, PhD, MPH, of Mailman School of Public Health, Columbia University, and colleagues in the Journal of the National Cancer Institute Monographs,1 were developed by a multidisciplinary panel with ex-

ed, with high certainty of substantial net benefit. B = Recommended, with high certainty of moderate benefit or moderate certainty of moderate to substantial benefit. C = Selectively recommended based on professional judgment or patient preference, with at least moderate certainty that net benefit is small. D = Recommendation against, with moderate to high certainty of no net benefit. H = Recommendation against, with moderate or high certainty that harm outweighs benefit.

Specific integrative therapies can be recommended as evidence-based supportive care options during breast cancer treatment. Most integrative therapies require further investigation via well-designed controlled trials with meaningful outcomes. —Heather Greenlee, ND, PhD, MPH, and colleagues

pertise in medical oncology, radiation oncology, nursing, psychology, naturopathic medicine, traditional Chinese medicine, acupuncture, epidemiology, biostatistics, and patient advocacy. The guidelines are based on evidence from 203 articles, of 4,900 considered, in the literature published between January 1990 and December 2013. The guidelines answer an unmet need. As stated by the authors: “The majority of breast cancer patients use complementary and/or integrative therapies during and beyond cancer treatment to manage symptoms, prevent toxicities, and improve quality of life. Practice guidelines are needed to inform clinicians and patients about safe and effective therapies.” In brief, meditation, yoga, and relaxation with imagery are recommended for routine use for common conditions in breast cancer patients, including anxiety and mood disorders (evidence grade A). Stress management, yoga, massage, music therapy, energy conservation, and meditation are recommended for stress reduction, anxiety, depression, fatigue, and quality of life (grade B). The guidelines are summarized below, with evidence grade indicated by letters in parentheses. A = Recommend-

Anxiety/Stress Reduction • Music therapy is recommended for reducing anxiety during radiation therapy and chemotherapy sessions (B). • Meditation is recommended for reducing anxiety in all patients and in those undergoing radiation therapy (B). • Stress management is recommended for reducing anxiety during treatment; longer group programs are likely better than self-administered home programs or shorter programs (B). • Yoga is recommended for reducing anxiety in patients undergoing radiation therapy or chemotherapy and is suggested for fatigued patients (B). • Acupuncture can be considered for reducing anxiety in fatigued patients (C). • Massage can be considered for

short-term reduction of anxiety (C). • Relaxation can be considered for treating anxiety during treatment (C).

Depression/Mood • Meditation, particularly mindfulness-based stress reduction, is recommended for treating mood disturbance and depressive symptoms in patients undergoing radiation therapy (A). • Relaxation is recommended for improving mood and depressive symptoms when added to standard care (A). • Yoga is recommended for improving mood in patients undergoing radiation therapy or chemotherapy and in fatigued patients in addition to standard care (A). • Massage is recommended for improving mood disturbance in posttreatment patients (B). • Music therapy is recommended for improving mood in newly diagnosed patients (B). • Acupuncture can be considered for improving mood in postmenopausal women with hot flashes or fatigue (C). • Healing touch can be considered for improving mood in patients undergoing chemotherapy (C). • Stress management interventions with or without exercise can be considered for improving mood (C).

Fatigue • Energy-conservation counseling is recommended for the treatment of fatigue (B). • American ginseng can be considered as an herbal approach for treatment of fatigue (C). • Acupuncture can be considered for treatment of fatigue after completion of cancer treatments (C). • Modified qigong can be considered for treatment of fatigue (C). • Acetyl-l-carnitine is not recom-

Integrative Therapies in Breast Cancer ■■ Meditation, yoga, and relaxation with imagery are recommended for routine use for common conditions in breast cancer patients, including anxiety and mood disorders. ■■ Stress management, yoga, massage, music therapy, energy conservation, and meditation are recommended for stress reduction, anxiety, depression, fatigue, and quality of life.

mended for treatment of fatigue, due to lack of effect (D). • Guarana is not recommended as herbal treatment of fatigue, due to lack of effect (D).

Sleep • Stress management techniques (C) and gentle yoga (C) can be considered for treatment of sleep disruption.

Quality of Life and Physical Functioning • Meditation is recommended for improving quality of life (A). • Acupuncture (C), guided imagery (C), mistletoe (C), qigong (C), reflexology (C), stress management (C), and yoga (C) can be considered for improving quality of life. • Exercise/awareness can be considered for improving functioning (C). • Energy conservation is not recommended for improving functioning, due to lack of effect (D).

Chemotherapy-Induced Nausea/Vomiting • Acupressure can be considered as an addition to antiemetics to help control nausea and vomiting during chemotherapy (B). • Electroacupuncture can be considered as an addition to antiemetics to control vomiting during chemotherapy (B). • Ginger can be considered in patients receiving chemotherapy without concurrent radiation therapy as an addition to antiemetics for the control of acute nausea (C). • Progressive muscle relaxation can be considered as an addition to antiemetics to help control nausea and vomiting during chemotherapy (C). • Glutamine is not recommended for treatment of chemotherapy-induced nausea/vomiting, due to lack of effect (D).

Pain • Energy and sleep enhancement can be considered for pain associated with chemotherapy among unemployed individuals (C). • Massage and healing touch can be considered for pain associated with chemotherapy (C). • Music therapy can be considered to relieve pain associated with surgery (C). continued on page 166

The ASCO Post | JANUARY 25, 2015

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Journal Spotlight SIO Guidelines continued from page 165

• A physical training program that includes a mind-body modality can be considered for relieving pain associated with surgery (C). • Hypnosis can be considered for relief of pain associated with surgery (C). • Acupuncture (C) and electroacupuncture (C) can be considered as approaches to short-term treatment of aromatase inhibitor–associated musculoskeletal symptoms.

treatment of hot flashes, due to lack of effect (D).

Acute Radiation Skin Reaction • Aloe vera (D) and hyaluronic acid cream (D) are not recommended as a standard therapy to prevent or treat acute radiation skin reaction, due to lack of effect.

The authors concluded: “Specific integrative therapies can be recommended as evidence-based supportive care options during breast cancer treatment. Most integrative therapies require further investigation via well-designed controlled trials with meaningful outcomes.” n Disclosure: The work was funded by the Society for Integrative Oncology.

Reference 1. Greenlee H, Balneaves LG, Carlson LE, et al, for the Society for Integrative Oncology Guidelines Working Group: Clinical practice guidelines on the use of integrative therapies as supportive care in patients treated for breast cancer. J Natl Cancer Inst Monogr 2014 50:346-358, 2014.

Neuropathy • Acetyl-l-carnitine is not recommended for prevention of neuropathy, due to harm (H).

Lymphedema • Laser therapy can be considered as a treatment for lymphedema (C). • Manual lymphatic drainage and compression bandaging have been shown to be equivalent. Manual lymphatic drainage can be considered for treatment of lymphedema in patients who have sensitivity to bandaging (C).

Hot Flashes • Acupuncture (C) and electroacupuncture (C) can be considered for decreasing the number of hot flashes. • Soy is not recommended for the See commentary by Barrie R. Cassileth, MS, PhD, on page 167.

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com © 2014 Genentech USA, Inc. All rights reserved. COB/092414/0002 Printed in USA.

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Perspective

The Long and Winding Road to Modern Integrative Oncology By Barrie R. Cassileth, MS, PhD

t has been a long road from the blind acceptance of unproven “alternative” remedies for the treatment

of cancer to the development of rigorous guidelines for integrative care, which address symptom control. The

recently released Society for Integrative Oncology (SIO) guidelines applicable to breast cancer patients—

reviewed in this issue of The ASCO Post—are a vivid example of that progress.1

Historic Context

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

“Alternative therapies,” including many that are clearly bogus, have been around for centuries. But, they found new life in 1992, when the Office of Alternative Medicine was created at the National Institutes of Health (NIH). The motivation for this was not scientific; it was political. The new office was initiated by members of Congress who strongly believed in actual alternatives to mainstream cancer care. One of these congressmen claimed that, although he had been successfully treated with mainstream cancer care, it was the bogus “alternative therapy” he received thereafter that cured him— although the U.S. Food and Drug Administration found that it was simply a solution of 5% nitrate, 1.4% ammonium, and traces of 22 additional chemicals. But politics trumps science, and “alternative medicine” was planted at the highest levels, an action that, tragically, legitimized unproven methods of care, including bogus therapies for cancer such as laetrile, krebiozen, and numerous others. Having studied the use of unproven cancer treatments for more than a decade, I was invited to join the board of the then-new NIH Office of Alternative Medicine. At the first meeting, each participant sat down to find a large newsletter headed “Which side is she on?” I turned out to be the token scientist. Most in the room felt that science was neither necessary nor applicable to “alternative” cancer therapies. Belief in scientific research was the “other side.” Their side was a multibillion-dollar industry that was beyond scientific inquiry. The SIO guidelines are a potent answer. continued on page 168

Dr. Cassileth is Founding Chief, Integrative Medicine Service, Laurance S. Rockefeller Chair in Integrative Medicine, Memorial Sloan Kettering Cancer Center, New York.

The ASCO Post | JANUARY 25, 2015

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Perspective

Barrie R. Cassileth, MS, PhD continued from page 167

‘Alternative’ vs ‘Complementary’ Therapies It turned out that not all interventions in the catch-all “alternative therapies” category were bogus. Although none was curative, many nonpharmacologic approaches were potentially helpful for symptom control. In 1995, I attempted to sort through these interventions in what became the Alternative Medicine Handbook, a taxonomy that distinguished between useless “alternative cancer treatments,” many of which were downright quackery, and useful adjunctive or complementary therapies. These were not primary treatment options, but rather valuable nonpharmacologic adjuncts aimed to reduce symptoms associated with cancer and with legitimate cancer treatment. The “About Herbs” website that my colleagues and I developed shortly after I joined Memorial Sloan Kettering Cancer Center in 1999 supplemented this with data on hundreds of natural substances— some useful, many not.

To reduce the physical and emotional sequelae associated with cancer and cancer treatment, safe and useful adjunctive complementary therapies were identified. They would be safely integrated with conventional treatments for a better overall

be evaluated and applied? Within 3 years, the first set of SIO Clinical Practice Guidelines were published. Updates followed, including “Complementary Therapies and Integrative Oncology in Lung Cancer,” developed with the American College

Surely more progress will occur in the future, but thanks to those who developed this new set of SIO Clinical Practice Guidelines, the well-being of breast cancer patients will be improved. —Barrie R. Cassileth, MS, PhD

patient experience. They were “integrative therapies,” and the field that studied and applied them became known as “Integrative Medicine.”

Society for Integrative Oncology Is Born In 2002, a small group of us gathered to form the SIO. We were confronted with the fact that many approaches outside of mainstream care were useful—but how should they

of Chest Physicians in 2007 and updated in 2013. SIO’s latest achievement is a new set of guidelines addressing the use of integrative/complementary therapies in breast cancer. As described in the accompanying article in The ASCO Post, these guidelines set forth the appropriate use of a broad range of nonpharmacologic treatments, including meditation, yoga, music therapy, acupuncture, relaxation

therapy, and more. They outline their use to control symptoms such as stress, sleep disorders, pain, neuropathy, chemotherapy-induced side effects, and others that plague cancer patients. But just as with mainstream treatments, each has its place, its potentials and limitations, and guidelines are just as necessary. From the “alternatives” dangerously touted as viable cancer treatments, a compendium of useful, symptom-control adjuncts has been documented in the field of integrative oncology. Surely more progress will occur in the future, but thanks to those who developed this new set of SIO Clinical Practice Guidelines, the well-being of breast cancer patients will be improved. n

Disclosure: Dr. Cassileth reported no potential conflicts of interest.

Announcements

CDC Awards Grant to Program for Young Women With Breast Cancer at Dana-Farber Cancer Institute

he Centers for Disease Control and Prevention’s (CDC’s) Division of Cancer Prevention and Control has awarded a $1.75 million, 5-year grant to the Program for Young Women with Breast Cancer at Dana-Farber Cancer Institute to increase the awareness of breast cancer among women and enhance the support services for those diagnosed and treated. The Program for Young Women with Breast Cancer at Dana-Farber was one of seven organizations to be awarded this competitive grant.

Funding Goals The funding will help women who are at elevated risk of breast cancer learn about the importance of knowing their personal risk factors, screening options, genetic testing and counseling, as

well as encouraging beneficial lifestyle changes. The second goal is to strengthen existing programs that help women who have been diagnosed with breast cancer, or those who are being treated or who have been treated. “This funding helps expand our support services to help more young women with breast cancer and develop a national network for providers and patients,” said Ann H. Partridge, MD, MPH, Founder and Director, Program for Young Women with Breast Cancer and director, Adult Survivorship Program at Dana-Farber. Young and Strong: A Program for Young Women with Breast Cancer was established at Dana-Farber in 2005 and helps patients and providers address concerns about fertility and reproduc-

tive options, genetics, psychosocial matters, and other treatment and survivorship issues facing young women. This grant will expand the program to include women in satellite and community network locations around Massachusetts and in New Hampshire and Connecticut. The Program for Young Women with Breast Cancer at DanaFarber is a program of the Susan F. Smith Center for Women’s Cancers at Dana-Farber.

Common Challenges Acting Director of CDC’s Division of Cancer Prevention and Control, Pamela Protzel Berman, PhD, MPH, said of the new effort, “We are excited about partnering with Dana-Farber Cancer Institute and this new group

of grantees to provide much needed support to young women living with breast cancer. Their efforts will address a broad range of education, resources, and communication needs which have been identified as common challenges for young breast cancer survivors and their families. We look forward to working with our new grantees to serve these women.” About 11% of all new cases of breast cancer in the United States are found in women younger than 45 years of age. CDC’s Division of Cancer Prevention and Control is working to increase awareness of breast cancer and improve the health and quality of life of young breast cancer survivors and young women who are at higher risk of getting breast cancer. n

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Reflections

Life Is Like Riding a Bicycle By Bruce D. Cheson, MD

The following essay by Bruce D. Cheson, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon. com and thebigcasino.org.

he ride epitomizes the role that a doctor can play that extends far beyond making a diagnosis and prescribing a treatment. Albert Einstein famously compared life to a bicycle ride: “To keep your balance, you must keep moving,” he said. In 2006, my wife, Christine, and I decided to explore ways to give back to our community. I am a lymphoma doctor, so a focus on that disease seemed appropriate. I was impressed at how many of my patients were avid bicyclists; my wife and I enjoyed riding as well. Thus, here was the perfect pairing: we’d organize a charity bicycle ride. Given my long-term involvement with the Lymphoma Research Foundation (LRF), I approached the organization hoping to interest it in being the sponsor—and the recipient of the money we’d raise. The LRF readily agreed. We organized an exploratory committee consisting of a few cycling patients and their spouses, a couple of dedicated pharmaceutical representatives (also cyclists), my nurse practitioner, and a representative of the LRF. We needed someone who actually knew what he or she was doing, and, at a knitting convention

Dr. Cheson is Professor of Medicine, Deputy Chief of Hematology-Oncology, and Head of Hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington, DC.

(go figure), my wife spoke to a woman who knew someone who planned outdoor activities like hiking, climbing, and cycling events. We invited Robin aboard, and she enthusiastically agreed.

Planning the Ride We held monthly dinner meetings at our house. The patients were at various stages of their clinical course: Alex, several years out from a stem cell transplant for rapidly relapsing Hodgkin lymphoma; Lisa, whose follicular lymphoma was progressing and would soon require treatment; and David, who had recently completed treatment for follicular lymphoma on a clinical trial. David had delayed initiation of his therapy for several months so that he could participate in a century (100-mile) charity ride in Lake Tahoe. He returned to be treated and recovered in enough time to participate in the same ride the following year. We named our project the Lymphoma Research Ride (LRR) and commissioned a marketing student to produce a logo for posters, brochures, bicycle jerseys, and caps. A route was created, permits secured, jerseys designed, supplies purchased, breakfast and lunch planned, a DJ hired, and a photographer identified.

lymphoma survivor, to a 76-year-old rider who completed all 50 miles.

Providing Hope We are now at 7 years and counting. Each year, I make some introductory remarks, quite different from giving a “rubber chicken” dinner talk to my peers on new lymphoma drugs or the appropriate use of PET scans. This audience hangs on to my every word. They are patients, survivors, and family members waiting for encouragement and hope—optimistic that all our efforts will lead to a cure. I name those whom we lost during the past year, young and old, some of whom had been active in the ride. Their families are here, raising money, cheering, and deriving solace from the fact that their loved ones are not forgotten. I name our new patients who are embraced as family members.

Too many doctors have no idea of their impact on the patient’s world beyond the clinic room. The ride gives me greater insight into this world, and it is a humbling feeling. —Bruce D. Cheson, MD

Celebrating the Day Our first ride took place on a beautiful Sunday. More than 100 riders donned their LRR jerseys, checked tire pressures, and posed for pictures. We had tents for registration, breakfast, and lunch. The first-aid tent was manned by Georgetown University Hospital nurses and my fellows. Several bike stores volunteered support staff to perform last-minute repairs, including fixing two flat tires on a patient’s borrowed bike. Other volunteers were out on the roads holding signs to guide the way and shouting encouragement; others camped out at rest stops and distributed water and other supplies. To ensure safety, there were police officers at busy intersections and volunteers at every turn. Many were patients and family members directing riders and cheering them on. As I peddled out, I thought that there was something wrong with my bike. I was literally shimmying down the road. It took a while for me to realize that it wasn’t the bike, but my nervousness after 11 months of nonstop planning and worrying. It was a great day. About a quarter of the riders were lymphoma patients, ranging in age from a 12-yearold boy riding with his dad, himself a

ride with her daughter yelling, “It’s all downhill from here!” It wasn’t, but the patient was deliriously happy: she’d survived to attend that daughter’s wedding. Another patient just out of chemotherapy managed to finish the 25-mile ride. The next year, he and his wife passed me pedaling along the 50-mile route. She was pregnant with their first child. Another man with a history of highly aggressive lymphoma missed the race the year after his diagnosis (he was just completing chemotherapy). Cured, he rode the next 2 years, but missed the next race, which fell on his wedding day. Last year, his wife was pregnant. This year, he rode again, now the proud father of a 9-month-old girl. What more could any doctor hope for? A woman currently on a clinical trial had to rent a bike and needed instructions on how to shift gears. She finished 25 miles with pride, a group of her co-

The ride epitomizes the role a doctor can play that extends far beyond making a diagnosis and prescribing a treatment. It also gives a doctor a unique perspective on the world of the patient—its sorrows, hopes, and joys. It is also a step away from being a patient and a big step toward normalcy. Patients ride their hearts out. One year, bandanas cover heads rendered bald by chemotherapy; the next, they show up with full heads of hair. I challenged one inactive, overweight patient to drop some pounds. He took up cycling and lost 40 pounds in preparation for the ride, making him feel healthier than he had in years. He is now a competitive cyclist. Another lymphoma patient had presented with palpable skull involvement. She wore a hat to each clinic visit. I always asked her to remove it, so I could examine her scalp. Post chemo, she had a negative scan, and I didn’t feel the need to have her remove her hat. This time she was insistent, and when I did, I saw a smiley face painted on her scalp to honor her remission! Five years later, this same woman was at the 43-mile point of the

workers encouraging her up the steepest hill of the route. Another year, 18 family members and friends surprised a young patient by showing up en masse from as far away as Chicago with rented bikes and jerseys they’d designed that bore the logo: “Kick Cancer’s Butt!” Children ride for their parents and parents for their children. This year, an Orthodox Jewish woman rode with a long dress and a head covering. She’d seen our ride poster hanging on a bulletin board and joined us because her sister had died of lymphoma. She has promised to ride again next year.

Turning Tragedy Into Triumph Survivors say they see the ride as an opportunity to turn something awful into something positive and how much they appreciate doctors and nurses taking time out of their lives to support them. One woman said it was a way of regaining some control over an awful situation that had taken control of her life, an opportunity to turn this disease around and fight back. Over the years, the number of riders continued on page 172

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION:

SHAPING THE WAY FORWARD

Indication KyprolisÂŽ (carfilzomib) for Injection is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma. Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis, and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. ÂŠ2014 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-KYPR-100826J November 2014 Printed in USA

for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications. Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment. Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline. Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur. Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be

Kyprolis® (carfilzomib) for Injection: 003-A1 Phase 2 Study Results* n

22.9% OVERALL RESPONSE RATE (ORR) (95% CI: 18.0, 28.5)1

7.8-MONTH MEDIAN DURATION OF RESPONSE (95% CI: 5.6, 9.2)1

Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event1,2 - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each)1

*Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and whose disease had a ≤25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved. Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated. Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently. Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of full Prescribing Information on adjacent pages. References: 1. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012. 2. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98(11):1753-1761.

The ASCO Post | JANUARY 25, 2015

PAGE 172

Reflections Bruce D. Cheson, MD continued from page 169

and volunteers has grown enormously; we have raised millions of dollars for lymphoma research. Nonetheless, every year just before ride day, my wife and I decide we have done enough; it’s time to turn it over to someone else. But with ride day comes another realization: how

much the event means to all involved; the hope, the ever-growing family, the love, and enthusiasm. And so we start the wheels turning for the next year.

Gaining Insight Into the Patient’s World In 2013, I accepted a Congressional Commendation for the work we and

the LRF have done to combat lymphoma. My wife and I received the LRF’s Distinguished Achievement Award this year as well. We accept these awards on behalf of those who really deserve them: our ride committee, the riders, and the volunteers, many of whom are patients. They inspire us with their courage and remind us why we do what we do.

Too many doctors have no idea of their impact on the patient’s world beyond the clinic room. The ride gives me greater insight into this world, and it is a humbling feeling. So as I struggle to pedal up a steep hill or through the rough terrain of life, I think about the patients and how much harder it is for them to live every day with lymphoma. And off I go! n

B:16.75” T:16.25” S:14.625”

a Table 2: Dose Table Modifications 2: Dose Modifications for Toxicityafor during Toxicity KYPROLIS duringTreatment KYPROLIS(continued) Treatment (continued) Renal Toxicity Renal Toxicity • Withhold until renal function has • Withhold until renal function has recovered to recovered Grade 1 to Grade 1 to baseline and monitor monitor renal function.renal function. • Serum creatinine • Serum creatinine equal to or equal toororto baselineorand • Iftoattributable KYPROLIS, at the next scheduled • If attributable KYPROLIS,to restart at the restart next scheduled than 2 × baseline greater than 2greater × baseline 2 at a reduced (from treatment at atreatment reduced dose (from 27dose mg/m to 27 mg/m2 to Adverse Reactions] [see Adverse [see Reactions] 2 202,mg/m OR from to 15 20 mg/m mg/m22).to 15 mg/m2). 20 mg/m2, OR20from mg/m KYPROLIS™KYPROLIS™ (carfilzomib) (carfilzomib) for Injectionfor Injection Brief Summary BriefofSummary Prescribing of Prescribing Information.Information. Please see Please the KYPROLIS see the package KYPROLISinsert package insert • If not attributable • If nottoattributable KYPROLIS,torestart KYPROLIS, at the restart dose used at the dose used for full prescribing for full prescribing information.information. prior to the event. prior to the event. INDICATIONS INDICATIONS AND USAGE: AND KYPROLIS USAGE:is KYPROLIS indicated for is indicated the treatment for theof treatment patients with of patients multiplewith multiple • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the myeloma who myeloma have received who haveat received least twoat prior least therapies two prior including therapiesbortezomib including and bortezomib an and an previous doseprevious at the discretion dose at the of the discretion physician. of the physician. immunomodulatory immunomodulatory agent and have agentdemonstrated and have demonstrated disease progression disease on progression or within on 60 ordays within of 60 Peripheral days of Neuropathy Peripheral Neuropathy • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. completion ofcompletion the last therapy. of the Approval last therapy. is based Approval on response is based rate on response [see Clinical rate Studies [see Clinical section Studies of fullsection of full • Restart at •theRestart dose used at the prior dose to used the event priororto reduced the event or reduced • Grade 3 or• 4 Grade 3 or 4 PI]. Clinical benefit, PI]. Clinical such benefit, as improvement such as improvement in survival or in symptoms, survival orhas symptoms, not beenhas verified. not been verified. 2 2 dose (from 27dose mg/m (from to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from 20 mg/m2 [see Adverse [see Reactions] Adverse Reactions] DOSAGE AND DOSAGE ADMINISTRATION: AND ADMINISTRATION: Dosing Guidelines. Dosing Guidelines. KYPROLIS is KYPROLIS administered is administered intravenously intravenously 2 2 to 15 mg/m ),toat15themg/m discretion ), at the of the discretion physician. of the physician. over 2 to 10 over minutes, 2 to on 10two minutes, consecutive on twodays, consecutive each week days,foreach threeweek weeks for (Days three weeks 1, 2, 8,(Days 9, 15,1,and 2, 8, 9, 15, and • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the 16), followed 16), by a followed 12‑day rest by aperiod 12‑day (Days rest 17 period to 28). (Days Each 1728‑day to 28). Each period28‑day is considered period isone considered treatmentone treatment previous doseprevious at the discretion dose at the of the discretion physician. of the physician. 2 cycle (Table 1). cycle In Cycle (Table1,1). KYPROLIS In Cycle is 1, administered KYPROLIS is administered at a dose of 20 at mg/m a dose2.ofIf tolerated 20 mg/min . IfCycle tolerated 1, thein Cycle 1, the Other Other • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. dose should be dose escalated should to be27 escalated mg/m2 beginning to 27 mg/m in2 Cycle beginning 2 andincontinued Cycle 2 and at 27 continued mg/m2 in at subsequent 27 mg/m2 in subsequent • Consider restarting • Consider at the restarting next scheduled at the next treatment scheduled treatment • Grade non‑hematological 3 or 4 non‑hematological cycles. Treatment cycles. may Treatment be continued may be untilcontinued disease progression until diseaseorprogression until unacceptable or until unacceptable toxicity occurstoxicity [see occurs [see 3 or• 4 Grade 2 with one dosewith levelone reduction dose level (from reduction 27 mg/m (from to 27 mg/m2 to toxicities toxicities Dosage and Administration]. Dosage and Administration]. The dose is calculated The dose isusing calculated the patient’s using the actual patient’s body surface actual body area surface at area at 2 2 2 2 20 ,mg/m OR from to 20 15 mg/m ).to 15 mg/m2). 20 mg/m , OR20from mg/m baseline. Patients baseline. with Patients a body surface with a body area surface greater than area 2.2 greater m2 should than 2.2 m2 should receive a dosereceive basedaupon doseabased upon a 2 • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the body surface body area of surface 2.2 marea of 2.2 m2. Dosedo . Dose adjustments adjustments not need todobenot made needfortoweight be made changes for weight of less changes than of less than previous doseprevious at the discretion dose at the of the discretion physician. of the physician. or equal to 20%. or equal to 20%. a Table 1: KYPROLIS Table 1:Dosage KYPROLIS Regimen Dosage forRegimen Patients for with Patients Multiple with Myeloma Multiple Myeloma National CanceraNational InstituteCancer Common Institute Terminology Common Criteria Terminology for Adverse Criteria Events for Adverse (NCI CTCAE) Events Version (NCI CTCAE) 3.0. Version 3.0. Administration Administration Precautions.Precautions. The quantity The of KYPROLIS quantity ofcontained KYPROLIS in contained one single‑use in onevial single‑use (60 mg vial (60 mg Cycle 1 Cycle 1 carfilzomib) may carfilzomib) exceed may the required exceed the dose. required Cautiondose. should Caution be used should in calculating be used inthe calculating quantity the quantity Week 1 Week 1 Week 2 Week 2 Week 3 Week Week 3 4 Week 4 delivered to prevent delivered overdosing. to prevent Do overdosing. not mix KYPROLIS Do not mix with KYPROLIS or administer with or as administer an infusion as with an infusion other with other DaysDayDayDays Day Day DaysDayDayDays Day Day DaysDayDays Days Days Day Day Day medicinal Theproducts. intravenous Theadministration intravenous administration line should beline flushed shouldwith be normal flushed saline with normal or 5% saline or 5% 2 1 3–7 2 8 3–79 10–14 8 9 1510–14 16 15 17–2116 22–28 17–21 medicinal 22–28 products. 1 Dextrose Injection, Dextrose USPInjection, immediately USP before immediately and after before KYPROLIS and after administration. KYPROLIS administration. KYPROLIS should KYPROLIS not should not KYPROLIS KYPROLIS 20 20 No 20 20 No20 20No 20 20 No 20 20 No 20 No No No 20 administered be administered as a bolus. KYPROLIS as a bolus. should KYPROLIS be administered should be administered over 2 to 10 minutes. over 2 toReconstitution 10 minutes. Reconstitution (20 mg/m2):(20 mg/m2): Dosing Dosing Dosing Dosing Dosing Dosing Dosing be Dosing and Preparation and Preparation for Intravenous for Intravenous Administration. Administration. KYPROLIS vials KYPROLIS containvials no antimicrobial contain no antimicrobial a Cycles 2 andCycles Beyond 2 and Beyonda preservativespreservatives and are intended and are onlyintended for singleonly use.forUnopened single use. vials Unopened of KYPROLIS vials of areKYPROLIS stable until arethe stable until the Week 1 Week 1 Week 2 Week 2 Week 3 Week Week 3 4 Week 4 date indicated date on the indicated package on when the package stored in when the original stored inpackage the original at 2°C package to 8°Cat(36°F 2°C to to 8°C 46°F). (36°F Theto 46°F). The DaysDayDayDays Day Day DaysDayDayDays Day Day DaysDayDays Days reconstituted Days Day Day Day reconstituted solution contains solution carfilzomib contains atcarfilzomib a concentration at a concentration of 2 mg/mL.ofRead 2 mg/mL. the complete Read the complete 2 1 3–7 2 8 3–79 10–14 8 9 1510–14 16 15 17–2116 22–28 17–21 preparation 22–28 1 instructions preparationprior instructions to reconstitution. prior to reconstitution. Reconstitution/Preparation Reconstitution/Preparation Steps: 1. Remove Steps:vial 1. Remove vial KYPROLIS KYPROLIS 27 27 No 27 27 No27 27No 27 27 No 27 27 No 27 No No No refrigerator 27 from fromjust refrigerator prior to use. just prior 2. Aseptically to use. 2.reconstitute Aseptically each reconstitute vial by each slowlyvial injecting by slowly 29 injecting mL 29 mL Dosing Dosing Dosing Dosing Dosing Dosing Sterile DosingWater Sterile (27 mg/m2):(27 mg/m2): Dosing Water USP, for Injection, the solution ontoWALL the INSIDE OFminimize THE VIAL to minimize for Injection, directingUSP, the directing solution onto the INSIDE OF THEWALL VIAL to a If previous cycle a If dosage foaming. Gently invert swirl and/or slowly for about 1 minute, or until complete dissolution foaming. 3. Gently swirl3.and/or the vialinvert slowlythe forvial about 1 minute, or until complete dissolution previousiscycle tolerated. dosage is tolerated. of powder any cakeoccurs. or powder occurs. DO to NOT SHAKE avoid foamIfgeneration. If foaming cake or DO NOT SHAKE avoid foamtogeneration. foaming occurs, allowoccurs, allow Hydration and Hydration Fluid Monitoring. and Fluid Monitoring. Hydrate patients Hydrate to reduce patients thetorisk reduce of renal the toxicity risk of renal and oftoxicity tumor andofofany tumor solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, lysis syndrome lysis (TLS) syndrome with KYPROLIS (TLS) withtreatment KYPROLIS [see treatment Warnings[see andWarnings Precautions]. and Precautions]. Maintain adequate Maintain adequate KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, fluid volume status fluid volume throughout statustreatment throughout andtreatment monitor blood and monitor chemistries bloodclosely. chemistries Prior closely. to each Prior dose to in each dose in colorless If any discoloration particulate matter do is observed, not use the reconstituted colorless If anysolution. discoloration or particulateormatter is observed, not use thedoreconstituted Cycle 1, give Cycle 250 mL 1, give to 500 250mLmLoftointravenous 500 mL ofnormal intravenous salinenormal or othersaline appropriate or otherintravenous appropriatefluid. intravenous fluid.solution. product. 5. When administering in anbag, intravenous calculated dose and [see Dosage and product. 5. When administering in an intravenous withdrawbag, the withdraw calculatedthe dose [see Dosage Give an additional Give an250 additional mL to 250 500 mL mL to of 500 intravenous mL of fluids intravenous as needed fluids following as neededKYPROLIS following KYPROLIS and50dilute into Dextrose 50 mL 5% Dextrose USP bag. intravenous bag. from the vialfrom and the dilutevialinto mL 5% Injection, USPInjection, intravenous administration. administration. Continue intravenous Continue hydration, intravenousashydration, needed, in as subsequent needed, in cycles. subsequent Also cycles. monitorAlsoAdministration] monitor Administration] 6. Immediately the vialthe containing unused of reconstituted 6. Immediately discard the discard vial containing unused the portion. The portion. stabilitiesTheof stabilities reconstituted patients during patients this period during for thisfluid period overload for fluid [seeoverload Warnings [see andWarnings Precautions]. and Precautions]. Dexamethasone Dexamethasone KYPROLIS various and temperature container shown variousunder temperature containerand conditions areconditions shown in are Table 3. in Table 3. Premedication. Premedication. Pre‑medicatePre‑medicate with dexamethasone with dexamethasone 4 mg orally or4intravenously mg orally or intravenously prior to all doses priorofto allKYPROLIS doses of under Table of 3: Reconstituted Stability of Reconstituted Table 3:toStability KYPROLIS KYPROLIS KYPROLIS during KYPROLIS Cycle during 1 and prior Cycleto1alland KYPROLIS prior to all doses KYPROLIS during doses the first during cyclethe of dose first cycle escalation of dose to escalation 2 27 mg/m2 to 27 mg/m reduce the toincidence reduce the andincidence severity ofand infusion severity reactions of infusion [seereactions Warnings[see andWarnings Precautions]. and Precautions]. a Stabilitya perStability Container per Container Reinstate dexamethasone Reinstate dexamethasone premedicationpremedication (4 mg orally or(4intravenously) mg orally or intravenously) if these symptoms if these develop symptoms or develop or Storage of Conditions of Reconstituted Storage Conditions Reconstituted reappear during reappear subsequent during cycles. subsequent Dosecycles. Modifications Dose Modifications based on Toxicities. based on Recommended Toxicities. Recommended IV Bag IV Bag KYPROLIS KYPROLIS actions and dose actions modifications and dose modifications are presentedare in Table presented 2. in Table 2. Vial Vial Syringe Syringe (D5Wb) (D5Wb) a Table 2: Dose Table Modifications 2: Dose Modifications for Toxicityafor Toxicity during KYPROLIS duringTreatment KYPROLIS Treatment RefrigeratedRefrigerated (2°C to 8°C;(2°C 36°Ftoto8°C; 46°F) 36°F to 46°F) 24 hours 2424 hours hours 2424hours hours 24 hours HematologicHematologic Toxicity Recommended Action Toxicity Recommended Action

• Withhold dose. • Withhold dose. • Grade 3a or Neutropenia • 4Grade 3a or 4 Neutropenia Room Temperature Room Temperature (15°C to 30°C; (15°C 59°F to to 30°C; 86°F) 59°F to 86°F) 4 hours 4 hours 4 hours 4 4hours hours 4 hours • If fully recovered • If fully before recovered next scheduled before next dose, scheduled continue dose, continue • Grade 4 Thrombocytopenia • Grade 4 Thrombocytopenia a b b Total time fromaTotal reconstitution time fromtoreconstitution administration to should administration not exceed should 24 hours. not exceed 5% 24 Dextrose hours.Injection, 5% Dextrose USP. Injection, USP. at same doseatlevel. same dose level. [see Warnings[see andWarnings Precautions] and Precautions] AND PRECAUTIONS: AND PRECAUTIONS: Cardiac Arrest, Cardiac Congestive Arrest, Congestive Heart Failure, Heart Myocardial Failure, Myocardial • If recovered • toIf recovered Grade 2 neutropenia to Grade 2 or neutropenia Grade 3 or Grade 3 WARNINGS WARNINGS Ischemia. Death Ischemia. due toDeath cardiacdue arrest to cardiac has occurred arrest has within occurred a day of within KYPROLIS a day of administration. KYPROLIS administration. New New thrombocytopenia, thrombocytopenia, reduce dose by reduce one dose level by one dose level onset onset or of worsening pre‑existingofcongestive pre‑existingheart congestive failure with heartdecreased failure withleftdecreased ventricularleftfunction ventricular or function or 2 2 2 (from 27 mg/m (from to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from to 20 mg/m to or worsening myocardial ischemia myocardial have ischemia occurred have following occurred administration following administration of KYPROLIS. of Cardiac KYPROLIS. failure Cardiac events failure events 15 mg/m2). 15 mg/m2). (e.g., cardiac (e.g., failurecardiac congestive, failurepulmonary congestive,edema, pulmonary ejection edema, fraction ejection decreased) fractionwere decreased) reportedwere in 7% reported in 7% • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalated to the of patients. Monitor of patients. for cardiac Monitorcomplications for cardiac complications and manage and promptly. manage Withhold promptly. KYPROLIS Withhold forKYPROLIS Grade 3 for Grade 3 previous doseprevious at the discretion dose at the of the discretion physician. of the physician. or 4 cardiac events or 4 cardiac until recovery events until and recovery consider and whether consider to restart whether KYPROLIS to restart based KYPROLIS on a benefit/risk based on a benefit/risk Non-Hematologic Non-Hematologic Toxicity Toxicity Recommended Recommended Action Action assessment [see assessment Dosage [see and Administration]. Dosage and Administration]. Patients with Patients New Yorkwith Heart New Association York HeartClass Association III and Class III and IV heart myocardial failure,infarction myocardial in infarction the preceding in the6 preceding months, and 6 months, conduction and abnormalities conduction abnormalities Cardiac Toxicity Cardiac Toxicity • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. IV heart failure, by uncontrolled medications by were medications not eligible werefornottheeligible clinicalfortrials. the clinical These patients trials. These may patients be at greater may be at greater • After of: resolution, • Afterconsider resolution, if restarting considerKYPROLIS if restarting at KYPROLISuncontrolled at Grade 3 or 4, new Grade onset 3 oror4,worsening new onsetof: or worsening 2 risk for cardiac riskcomplications. for cardiac complications. Pulmonary Pulmonary Hypertension. Hypertension. Pulmonary arterial Pulmonary hypertension arterial hypertension (PAH) (PAH) a reduced is appropriate dose is(from appropriate 27 mg/m (from to 27 mg/m2 to • congestive•heart congestive failure; heart failure; a reduced dose 2 2 2 2 2 was reported was in 2% reported of patients in 2% treated of patients with KYPROLIS treated with and KYPROLIS was Grade and 3 was or greater Grade in 3 less or greater than 1% in less of than 1% of 20 ,mg/m OR from to 20 15 mg/m ).to 15 mg/m ). mg/m • decreased•leftdecreased ventricularleft ventricular 20 mg/m , OR20from patients. withEvaluate cardiac with imaging cardiac and/or imaging other and/or tests as other indicated. tests asWithhold indicated. KYPROLIS WithholdforKYPROLIS for • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedpatients. to the Evaluate function; function; pulmonary hypertension until resolveduntil or returned resolved to or baseline returned and to baseline considerand whether consider to restart whether to restart at the discretion dose at the of the discretion physician. of the physician.pulmonary hypertension • or myocardial • orischemia myocardial ischemia previous doseprevious KYPROLIS based KYPROLIS on a based benefit/risk on a assessment benefit/risk assessment [see Dosage[see and Dosage Administration]. and Administration]. Pulmonary Pulmonary [see Warnings[see andWarnings Precautions] and Precautions] Complications. Complications. Dyspnea wasDyspnea reported was in 35% reported of patients in 35% enrolled of patients in clinical enrolled trials. in clinical Grade 3trials. dyspnea Grade 3 dyspnea occurred no Grade in 5%; 4 events, no Grade and4 1events, death and (Grade 1 death 5) was (Grade reported. 5) was Monitor reported. and Monitor manage and manage Pulmonary Hypertension Pulmonary Hypertension • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. occurred in 5%; dyspnea immediately; dyspnea immediately; interrupt KYPROLIS interrupt until KYPROLIS symptoms until have symptoms resolved have or returned resolved to or baseline returned [see to baseline [see • Restart at •theRestart dose used at the prior dose to used the event priororto reduced the event or reduced [see Warnings[see andWarnings Precautions] and Precautions] 2 2 Administration and Administration and Adverse and Reactions]. AdverseInfusion Reactions]. Reactions. Infusion Infusion Reactions. reactions Infusion were reactions were to 27 20 mg/m mg/m22,toOR20from mg/m 202,mg/m OR from 20Dosage mg/m2 and Dosage dose (from 27dose mg/m (from 2 by a spectrum by ofa systemic spectrum symptoms of systemicincluding symptoms fever, including chills, arthralgia, fever, chills, myalgia, arthralgia, facialmyalgia, facial to 15 mg/m2),toat15themg/m discretion ), at the of the discretion physician. of the physician.characterizedcharacterized edema,facial vomiting, edema, weakness, vomiting, shortness weakness, of breath, shortness hypotension, of breath, syncope, hypotension, chest syncope, tightness, chest tightness, • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedflushing, to the facialflushing, or angina. reactions These canreactions occur immediately can occur following immediately or up following to 24 hours or up after to 24administration hours after administration of of previous doseprevious at the discretion dose at the of the discretion physician. of the physician.or angina. These KYPROLIS.dexamethasone Administer dexamethasone prior to KYPROLIS prior toto KYPROLIS reduce theto incidence reduce the andincidence severity and of severity of Pulmonary Complications Pulmonary Complications • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. KYPROLIS. Administer reactions [seereactions Dosage [see and Administration]. Dosage and Administration]. Inform patients Inform of thepatients risk and of symptoms the risk andand symptoms to contactand to contact • Consider restarting • Consider at the restarting next scheduled at the next treatment scheduled treatment • Grade 3 or• 4 Grade 3 or 4 physician if symptoms physicianofif symptoms an infusionofreaction an infusion occurreaction [see Patient occurCounseling [see PatientInformation]. Counseling Tumor Information]. LysisTumor Lysis 2 with one dosewith levelone reduction dose level (from reduction 27 mg/m (from to 27 mg/m2 to [see Warnings[see andWarnings Precautions] and Precautions] Syndrome. Tumor Syndrome. lysis syndrome Tumor lysis (TLS) syndrome occurred (TLS) following occurred KYPROLIS following administration KYPROLIS administration in < 1% of in < 1% of 2 202,mg/m OR from to 20 15 mg/m mg/m22).to 15 mg/m2). 20 mg/m2, OR20from mg/m patients. Patients patients. withPatients multiple with myeloma multiple andmyeloma a high tumor and aburden high tumor should burden be considered should betoconsidered be at to be at • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedgreater to the risk for greater TLS. Prior risk for to receiving TLS. PriorKYPROLIS, to receivingensure KYPROLIS, that patients ensure that are well patients hydrated are well [seehydrated Dosage [see Dosage previous doseprevious at the discretion dose at the of the discretion physician. of the physician.and Administration]. and Administration]. Monitor for evidence Monitor for of TLS evidence duringoftreatment, TLS duringand treatment, manage and promptly. manage Interrupt promptly. Interrupt Hepatic Toxicity Hepatic Toxicity • Withhold until • Withhold resolveduntil or returned resolvedtoorbaseline. returned to baseline. KYPROLIS until KYPROLIS TLS is resolved until TLS[see is resolved Dosage [see and Dosage Administration].Thrombocytopenia. and Administration].Thrombocytopenia. KYPROLIS KYPROLIS • After consider resolution, if restarting considerKYPROLIS if restarting is KYPROLIS iscauses thrombocytopenia • Grade 3 or• 4 Grade elevation 3 orof4 elevation•of After resolution, causes thrombocytopenia with platelet with nadirsplatelet occurring nadirs around occurring Day 8around of each Day28‑day 8 of each cycle28‑day and cycle and may appropriate; be reinitiated may at beareinitiated reduced dose at a reduced (from doserecovery (from to baseline transaminases, transaminases, bilirubin or other bilirubin orappropriate; other recoverybytothe baseline start ofbythe thenext start28‑day of the cycle. next 28‑day In patients cycle. with In patients multiple with myeloma, multiple 36% myeloma, of 36% of 2 27 mg/m2 to 20 27 mg/m22, to OR20from mg/m 202mg/m , OR from to 15 20 mg/m mg/m22) to 15patients mg/m2) experienced liver abnormalities liver abnormalities patients experienced thrombocytopenia, thrombocytopenia, including Grade including 4 in 10%. Grade Thrombocytopenia 4 in 10%. Thrombocytopenia following following with frequentwith monitoring frequentofmonitoring liver function. of liver function. KYPROLIS administration KYPROLIS administration resulted in aresulted dose reduction in a dose in reduction 1% of patients in 1% and of patients discontinuation and discontinuation of of [see Warnings[see andWarnings Precautions] and Precautions] • If tolerated, • the If tolerated, reduced dose the reduced may be dose escalated may be to the escalatedtreatment to the with treatment KYPROLIS within KYPROLIS < 1% of patients. in < 1%Monitor of patients. platelet Monitor counts platelet frequently countsduring frequently treatment during treatment previous doseprevious at the discretion dose at the of the discretion physician. of the physician.with KYPROLIS. withReduce KYPROLIS. or interrupt Reduce dose or interrupt as clinically dose indicated as clinically [seeindicated Dosage [see and Dosage Administration]. and Administration]. Hepatic Toxicity Hepatic andToxicity Hepaticand Failure. Hepatic Cases Failure. of hepatic Cases failure, of hepatic including failure, fatalincluding cases, have fatalbeen cases, have been (continued) (continued)

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PAGE 173

FDA Update

B:16.75” T:16.25” S:14.625”

FDA Approves Denosumab for the Treatment of Hypercalcemia of Malignancy Refractory to Bisphosphonate Therapy

he U.S. Food and Drug Administration has approved a new indication for denosumab (Xgeva) for the treatment of hypercalcemia of malignancy refractory to bisphosphonate

therapy. Denosumab was approved and granted Orphan Drug designation by the FDA, which is reserved for drugs that are intended for the treatment of rare diseases affecting fewer than

200,000 people in the United States. Hypercalcemia of malignancy is a serious complication in patients with advanced cancer, including those with hematologic malignancies, and indi-

Clinical Study

B:11.25”

T:10.875”

S:10” B:11.25”

The approval is based on positive results from an open-label, single-arm study, which enrolled patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment. The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) < 11.5 mg/dL within 10 days after the first dose of denosumab. Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC < 10.8 mg/dL) by day 10, time to response, and response duration (defined as the number of days from the first occurrence of CSC < 11.5 mg/dL). The study achieved its primary endpoint, with a response rate at day 10 of 63.6% in the 33 patients evaluated. The overall complete response rate was 63.6%. The estimated median time to response (CSC < 11.5 mg/dL) was 9 days, and the median duration of response was 104 days. The most common adverse reactions in patients receiving denosumab for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea. n S:10”

One event wasbOne Grade event 5 severity. was Grade 5 severity.

impairment, coma, and death. In 2012, the estimated prevalence of hypercalcemia in cancer patients in the United States was 2.7%.

T:10.875”

reported (< 1%). reported KYPROLIS (< 1%).can KYPROLIS cause elevations can causeof elevations serum transaminases of serum transaminases and bilirubin.and Withhold bilirubin.Description Withhold Description of SelectedofAdverse Selected Drug Adverse Reactions. Drug Renal Reactions. Events: Renal The Events: most common The most renal common renal KYPROLIS in KYPROLIS patients experiencing in patients experiencing Grade 3 or greater Gradeelevations 3 or greater of elevations transaminases, of transaminases, bilirubin, or other bilirubin,adverse or otherreactions adverse were reactions increasewere in blood increase creatinine in blood (24%) creatinine and renal (24%) failure and (9%), renal which failurewere (9%),mostly which were mostly liver abnormalities liver abnormalities until resolveduntil or returned resolved to or baseline. returned to After baseline. resolution, Afterconsider resolution, if restarting consider if restarting Grade 1 or Grade Grade 21 inorseverity. Grade 2Grade in severity. 3 renalGrade adverse 3 renal reactions adverse occurred reactions in 6% occurred of patients in 6%and of patients and KYPROLIS is KYPROLIS appropriate. is appropriate. Monitor liver Monitor enzymesliver frequently enzymes[see frequently Dosage [see and Dosage Administration and Administration and Gradeand 4 events Grade occurred 4 events in 1%. occurred Discontinuations in 1%. Discontinuations due to increased due to blood increased creatinine blood andcreatinine acute renal and acute renal Adverse Reactions]. AdverseEmbryo-fetal Reactions]. Embryo-fetal Toxicity. KYPROLIS Toxicity. canKYPROLIS cause fetal canharm cause when fetaladministered harm when administered to a failuretowere a 1% failure each. were In 1% one each. patient, In death one patient, occurred death withoccurred concurrent withsepsis concurrent and worsening sepsis andrenal worsening renal pregnant woman pregnant basedwoman on its mechanism based on itsofmechanism action and of findings actioninand animals. findings There in animals. are no adequate There are and no adequate and[see function function Dosage and [seeAdministration]. Dosage and Administration]. Peripheral Neuropathy: Peripheral Neuropathy: Peripheral neuropathy Peripheral(including neuropathy (including well‑controlledwell‑controlled studies in pregnant studieswomen in pregnant usingwomen KYPROLIS. using Carfilzomib KYPROLIS.caused Carfilzomib embryo‑fetal caused toxicity embryo‑fetal in all toxicity in of all events peripheral events ofsensory peripheral neuropathy sensoryand neuropathy peripheral andmotor peripheral neuropathy) motor occurred neuropathy) in 14% occurred of in 14% of pregnant rabbits pregnant at doses rabbits that were at doses lower thatthan were in patients lower than receiving in patients the recommended receiving the recommended dose. Femalesdose. of Females patientsofenrolled patients in clinical enrolled trials. in clinical Grade 3trials. peripheral Grade neuropathy 3 peripheraloccurred neuropathy in 1% occurred of patients. in 1%Serious of patients. Serious reproductive potential reproductive should potential be advised should to be avoid advised becoming to avoid pregnant becoming whilepregnant being treated while being with KYPROLIS. treated with KYPROLIS. peripheral neuropathy peripheralevents neuropathy occurred events in <occurred 1% of patients, in < 1%which of patients, resulted which in dose resulted reduction in dose in <reduction 1% in < 1% If this drug isIfused this drug duringis pregnancy, used duringorpregnancy, if the patient or ifbecomes the patient pregnant becomes while pregnant taking this whiledrug, taking thethis and drug,treatment the and discontinuation treatment discontinuation in < 1%. Withhold in < 1%. or discontinue Withhold or treatment discontinue as treatment recommended as recommended [see [see patient shouldpatient be apprised shouldofbethe apprised potential of hazard the potential to the hazard fetus [see to the Usefetus in Specific [see Use Populations]. in Specific Populations]. Dosage and Administration]. Dosage and Administration]. Herpes VirusHerpes Infection: Virus Herpes Infection: zosterHerpes reactivation zosterwas reactivation reportedwas in 2% reported in 2% ADVERSE REACTIONS: ADVERSE REACTIONS: The following adverse The following reactions adverse are discussed reactions are in greater discussed detail in in greater other detail sections in otherofsections patients. Consider of patients. antiviral Consider prophylaxis antiviralfor prophylaxis patients who for patients have a history who have of herpes a history zoster of herpes infection. zoster infection. of the labeling:of the labeling: DRUG INTERACTIONS: DRUG INTERACTIONS: Carfilzomib isCarfilzomib primarily metabolized is primarily via metabolized peptidasevia andpeptidase epoxide and hydrolase epoxide hydrolase • Cardiac Arrest, • Cardiac Congestive Arrest,Heart Congestive Failure,Heart Myocardial Failure,Ischemia Myocardial [seeWarnings Ischemia [see andWarnings Precautions] and Precautions] activities, andactivities, as a result, and the as apharmacokinetic result, the pharmacokinetic profile of carfilzomib profile ofiscarfilzomib unlikely toisbeunlikely affectedto by be affected by • Pulmonary •Hypertension Pulmonary Hypertension [seeWarnings [see andWarnings Precautions] and Precautions] concomitant administration concomitant administration of cytochromeofP450 cytochrome inhibitors P450 andinhibitors inducers.and Carfilzomib inducers.isCarfilzomib not expected is not expected • Pulmonary •Complications Pulmonary Complications [seeWarnings [see andWarnings Precautions] and Precautions] to influence exposure to influence of other exposure drugsof[see otherClinical drugs Pharmacology [see Clinical Pharmacology section of fullsection PI]. of full PI]. • Infusion Reactions • Infusion [see Reactions Warnings [see andWarnings Precautions] and Precautions] USE IN SPECIFIC USE IN POPULATIONS: SPECIFIC POPULATIONS: Pregnancy. Pregnancy. Pregnancy Category PregnancyD Category [see Warnings D [seeand Warnings and • Tumor Lysis•Syndrome Tumor Lysis [see Syndrome Warnings [see andWarnings Precautions] and Precautions] Females of potential reproductive potential shouldtobe advised to avoid becoming pregnant while Precautions].Precautions]. Females of reproductive should be advised avoid becoming pregnant while • Thrombocytopenia • Thrombocytopenia [seeWarnings [see andWarnings Precautions] and Precautions] treated withBased KYPROLIS. on itsofmechanism action and findingsKYPROLIS in animals, KYPROLIS being treatedbeing with KYPROLIS. on its Based mechanism action andoffindings in animals, • Hepatic Toxicity • Hepatic and Hepatic Toxicity Failure and Hepatic [seeWarnings Failure [see andWarnings Precautions] and Precautions] can harm causewhen fetal administered harm when administered a pregnant woman.caused Carfilzomib caused embryo‑fetal can cause fetal to a pregnanttowoman. Carfilzomib embryo‑fetal The most common The most adverse common reactions adverse (incidence reactions of (incidence 30% or greater) of 30%toorKYPROLIS greater) to observed KYPROLIS in clinical observed toxicity in clinical toxicity rabbits in pregnant rabbits doses thatthan wereinlower thanreceiving in patients the recommended in pregnant at doses thatatwere lower patients thereceiving recommended trials of patients trialswith of patients multiple with myeloma multiple were myeloma fatigue,were anemia, fatigue, nausea, anemia, thrombocytopenia, nausea, thrombocytopenia, dyspnea, dose. dyspnea, dose. Ifis KYPROLIS is pregnancy, used duringorpregnancy, or ifbecomes the patient becomes pregnant If KYPROLIS used during if the patient pregnant while taking while this taking this diarrhea, anddiarrhea, pyrexia. and Clinical pyrexia. Trials Clinical SafetyTrials Experience. Safety Experience. Because clinical Because trials clinical are conducted trials are conducted drug,should the patient shouldofbethe apprised of hazard the potential to the fetus.was Carfilzomib was administered drug, the patient be apprised potential to the hazard fetus. Carfilzomib administered under widely under varyingwidely conditions, varyingadverse conditions, reaction adverse ratesreaction observed rates in the observed clinicalintrials the of clinical a drugtrials cannot of a drug cannot intravenously to pregnant ratsduring and rabbits during period of organogenesis at doses intravenously to pregnant rats and rabbits the period of the organogenesis at doses of 0.5, 1, andof 0.5, 1, and be directly compared be directlywith compared rates in with the clinical rates intrials the clinical of another trialsdrug, of another and may drug, not and reflect maythenotrates reflect 2themg/kg/day rates 2inmg/kg/day in rats and 0.8inmg/kg/day in rabbits.was Carfilzomib was notatteratogenic at rats and 0.2, 0.4,and and0.2, 0.8 0.4, mg/kg/day rabbits. Carfilzomib not teratogenic observed in medical observed practice. in medical A total practice. of 526Apatients total of with 526 relapsed patients with and/or relapsed refractory and/or multiple refractory myeloma multiple any myeloma any dose tested.there In rabbits, was in an pre‑implantation increase in pre‑implantation at ≥ 0.4 mg/kg/day dose tested. In rabbits, was anthere increase loss at ≥ 0.4loss mg/kg/day received KYPROLIS received as KYPROLIS monotherapy as monotherapy or with pre‑dose or with dexamethasone. pre‑dose dexamethasone. Patients received Patients a median received of a median and in anearly increase in earlyand resorptions and post‑implantation loss andina fetal decrease in at fetal weight at and an ofincrease resorptions post‑implantation loss and a decrease weight four treatment fourcycles treatment with acycles median withcumulative a medianKYPROLIS cumulativedose KYPROLIS of 993.4 dose mg.ofDeaths 993.4 due mg. to Deaths all due to all thetoxic maternally of 0.8The mg/kg/day. of 0.4 and 0.8inmg/kg/day the maternally dose oftoxic 0.8 dose mg/kg/day. doses ofThe 0.4doses and 0.8 mg/kg/day rabbits arein rabbits are causes withincauses 30 days within of the30last days dose of the of KYPROLIS last dose of occurred KYPROLIS in 37/526 occurred (7%) in 37/526 of patients. (7%)Deaths of patients. not Deaths not approximately 20% and 40%, of respectively, of the recommended doseof in27humans 27 mg/m2 based approximately 20% and 40%, respectively, the recommended dose in humans mg/m2 of based attributed to disease attributed progression to diseasewere progression cardiac were in 5 patients cardiac (acute in 5 patients coronary (acute syndrome, coronary cardiac syndrome, arrest,cardiac on arrest, body surface on body area.surface Nursing area. Mothers. Nursing It isMothers. not known It iswhether not known KYPROLIS whetheris KYPROLIS excreted inishuman excreted in human cardiac disorder), cardiac end‑organ disorder),failure end‑organ in 4 patients failure in(multi‑organ 4 patients (multi‑organ failure, hepatic failure, failure, hepatic renal failure, failure),renalmilk. failure), Since many milk.drugs Since are many excreted drugs are in human excreted milkin and human because milk and of the because potential of for the serious potentialadverse for serious adverse infection in infection 4 patientsin (sepsis, 4 patients pneumonia, (sepsis, pneumonia, respiratory tract respiratory bacterial tract infection), bacterialdyspnea infection), anddyspnea and in nursing reactions reactions infants in nursing from KYPROLIS, infants from a decision KYPROLIS, should a decision be made should whether be made to discontinue whether tonursing discontinue nursing intracranial hemorrhage intracranial in hemorrhage 1 patient each, in 1 patient and 1 each, patientand found 1 patient dead offound unknown dead causes. of unknown Serious causes.orSerious to discontinue or tothe discontinue drug, taking the into drug,account taking into the importance account theofimportance the drug toofthe themother. drug toPediatric the mother. Pediatric adverse reactions adverse were reactions reportedwere in 45% reported patients. in 45% The patients. most common The most serious common adverse serious reactions adverse were reactions Use.were The safety Use.and Theeffectiveness safety and effectiveness of KYPROLISofin KYPROLIS pediatric patients in pediatric havepatients not been have established. not been established. pneumonia (10%), pneumonia acute (10%), renal failure acute (4%), renal pyrexia failure (4%), (3%),pyrexia and congestive (3%), andheart congestive failure (3%). heart Adverse failure (3%).Geriatric Adverse Use. Geriatric In studies Use. of KYPROLIS In studies there of KYPROLIS were nothere clinically weresignificant no clinically differences significantobserved differences in safety observed in safety reactions leading reactions to discontinuation leading to discontinuation of KYPROLIS occurred of KYPROLIS in 15% occurred of patients in 15% and of included patients and congestive included congestive and efficacy between and efficacy patients between less than patients 65 years less than of age 65 and yearspatients of age 65 andyears patients of age 65 and yearsolder. of age Renal and older. Renal heart failure (2%), heart failure cardiac(2%), arrest, cardiac dyspnea, arrest, increased dyspnea, blood increased creatinine, bloodand creatinine, acute renal andfailure acute (1% renal failure (1% Impairment. Impairment. The pharmacokinetics The pharmacokinetics and safety ofand KYPROLIS safety ofwere KYPROLIS evaluated were in evaluated a Phase 2intrial a Phase in 2 trial in each). Adverse each). reactions Adverse occurring reactions at aoccurring rate of 10% at a or rate greater of 10% areorpresented greater are in Table presented 4. in Table 4. patients withpatients normal with renal normal functionrenal and function those with andmild, thosemoderate, with mild,and moderate, severe renal and severe impairment renal impairment on chronic patientsdialysis. on chronic On average, dialysis. patients On average, werepatients treated were for 5.5 treated cyclesforusing 5.5 cycles KYPROLIS using KYPROLIS Table 4: Incidence Table 4:ofIncidence Adverse Reactions of AdverseOccurring ReactionsinOccurring ≥ 10% of in Multiple ≥ 10% Myeloma of Multiple Myelomaand patients and 2 doses of 15 doses mg/m2ofon15Cycle mg/m 1,2 20 on mg/m Cycle 21,on20Cycle mg/m 2,2 and on Cycle 27 mg/m 2, and on27Cycles mg/m32 on andCycles beyond. 3 and beyond. Patients Treated Patients withTreated KYPROLIS with KYPROLIS The pharmacokinetics The pharmacokinetics and safety ofand KYPROLIS safety ofwere KYPROLIS not influenced were notbyinfluenced the degreebyofthe baseline degreerenal of baseline renal Patients Patients (N = 526) (N = 526) impairment, including impairment, the including patients on thedialysis. patientsSince on dialysis. dialysisSince clearance dialysis of clearance KYPROLIS ofconcentrations KYPROLIS concentrations [n (%)] [n (%)] has not beenhas studied, not been the studied, drug should the drug be administered should be administered after the dialysis after procedure the dialysis[see procedure Clinical [see Clinical Grade Grade 3 4 GradePharmacology 4 All Grade 3 All Pharmacology section of fullsection PI]. Hepatic of full Impairment. PI]. Hepatic Impairment. The safety, efficacy The safety, and pharmacokinetics efficacy and pharmacokinetics of of a a EventsEvents Events Event GradesEvents Event Grades KYPROLIS have KYPROLIS not been have evaluated not been in evaluated patients with in patients baselinewith hepatic baseline impairment. hepatic Patients impairment. withPatients the with the following laboratory following values laboratory were excluded values were fromexcluded the KYPROLIS from theclinical KYPROLIS trials:clinical ALT/AST trials: ≥ 3ALT/AST × upper ≥ 3 × upper Fatigue Fatigue 292 (55.5) 292 (55.5) 38 (7.2) 38 (7.2)2 (0.4) 2 (0.4) limit of normallimit (ULN) of normal and bilirubin (ULN) ≥ and 2× bilirubin ULN [see ≥ 2Clinical × ULN Pharmacology [see Clinical Pharmacology section of fullsection PI]. Cardiac of full PI]. Cardiac Anemia Anemia 246 (46.8) 246 (46.8) 111 (21.1) 111 (21.1)7 (1.3) 7 (1.3) Impairment.Impairment. Patients with Patients New Yorkwith Heart New Association York HeartClass Association III and IV Class heartIII failure and IV were heartnot failure eligible were not eligible Nausea Nausea 236 (44.9) 236 (44.9)7 (1.3) 7 (1.3) 0 0 for the clinicalfortrials. the clinical Safety in trials. this Safety population in thishas population not beenhas evaluated. not been evaluated. Thrombocytopenia Thrombocytopenia 191 (36.3) 191 (36.3) 69 (13.1) 69 (13.1) 54 (10.3) 54 (10.3) OVERDOSAGE: OVERDOSAGE: There is no known There isspecific no known antidote specific for KYPROLIS antidote foroverdosage. KYPROLIS In overdosage. the event of In the an event of an b overdosage, monitor overdosage, the patient monitorand theprovide patientappropriate and providesupportive appropriatecare. supportive care. Dyspnea Dyspnea 182 (34.6) 182 (34.6) 25 (4.8) 25 (4.8)1 (0.2)b 1 (0.2) NONCLINICAL NONCLINICAL TOXICOLOGY: TOXICOLOGY: Carcinogenesis, Carcinogenesis, Mutagenesis, Mutagenesis, and Impairment and Impairment of Fertility. of Fertility. Diarrhea Diarrhea 172 (32.7) 172 (32.7)4 (0.8) 4 (0.8)1 (0.2) 1 (0.2) Carcinogenicity Carcinogenicity studies have studies not beenhave conducted not beenwith conducted carfilzomib. withCarfilzomib carfilzomib.was Carfilzomib clastogenic wasinclastogenic the in the Pyrexia Pyrexia 160 (30.4) 160 (30.4)7 (1.3) 7 (1.3)2 (0.4) 2 (0.4) in vitro chromosomal in vitro chromosomal aberration testaberration in peripheral test in blood peripheral lymphocytes. blood lymphocytes. Carfilzomib was Carfilzomib not mutagenic was not mutagenic in the in vitro in bacterial the in vitro reverse bacterial mutation reverse (Ames) mutation test and (Ames) was test not and clastogenic was not in clastogenic the in vivo in the in vivo mouse mouse Upper respiratory Uppertract respiratory infectiontract infection 149 (28.3) 149 (28.3) 17 (3.2) 17 (3.2) 0 0 marrow micronucleus Fertility withhave carfilzomib have not beenNo conducted. No micronucleus assay. Fertilityassay. studies with studies carfilzomib not been conducted. Headache Headache 145 (27.6) 145 (27.6)7 (1.3) 7 (1.3) 0 0 bone marrowbone effects on reproductive were noted during 28‑day repeat‑dose rat and monkey toxicity effects on reproductive tissues weretissues noted during 28‑day repeat‑dose rat and monkey toxicity Cough Cough 137 (26.0) 137 (26.0)1 (0.2) 1 (0.2) 0 0 studies or in studies in and 6‑month rat and 9‑month monkey chronic toxicity studies. Animal and/ Toxicology and/ 6‑monthorrat 9‑month monkey chronic toxicity studies. Animal Toxicology Blood creatinine Blood increased creatinine increased 127 (24.1) 127 (24.1) 13 (2.5) 13 (2.5)1 (0.2) 1 (0.2) or Pharmacology. Monkeys administered single bolusdose intravenous dose ofatcarfilzomib or Pharmacology. Monkeys administered a single bolusa intravenous of carfilzomib 3 mg/kg at 3 mg/kg 2 2 1.3 times recommended doseofin27humans 27 mg/m (approximately(approximately 1.3 times recommended dose in humans mg/m ofbased on body based surface on body area) surface area) LymphopeniaLymphopenia 126 (24.0) 126 (24.0) 84 (16.0) 84 (16.0) 11 (2.1) 11 (2.1) experienced hypotension, experienced increased hypotension, heart increased rate, andheart increased rate, and serum increased levels of serum troponin‑T. levels ofThe troponin‑T. repeated The repeated Edema peripheral Edema peripheral 126 (24.0) 126 (24.0)3 (0.6) 3 (0.6) 0 0 bolus intravenous bolus administration intravenous administration of carfilzomibofatcarfilzomib ≥ 2 mg/kg/dose at ≥ 2 in mg/kg/dose rats and in 2 mg/kg/dose rats and 2 mg/kg/dose in in Vomiting Vomiting 117 (22.2) 117 (22.2)5 (1.0) 5 (1.0) 0 0 monkeys using monkeys dosingusing schedules dosingsimilar schedules to those similar usedto clinically those used resulted clinically in mortalities resulted inthat mortalities were that were due occurring to toxicities in occurring the cardiovascular in the cardiovascular (cardiac failure, (cardiac cardiac failure, fibrosis, cardiac pericardial fibrosis,fluid pericardial fluid Constipation Constipation 110 (20.9) 110 (20.9)1 (0.2) 1 (0.2) 0 0 due to toxicities accumulation,accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal Neutropenia Neutropenia 109 (20.7) 109 (20.7) 50 (9.5) 50 (9.5)4 (0.8) 4 (0.8) (glomerulonephropathy, tubular necrosis, and pulmonary (glomerulonephropathy, tubulardysfunction), necrosis, dysfunction), and(hemorrhage/inflammation) pulmonary (hemorrhage/inflammation) Back pain Back pain 106 (20.2) 106 (20.2) 15 (2.9) 15 (2.9) 0 0 systems. The systems. dose of 2inmg/kg/dose in rats is approximately half the recommended dose in humans dose of 2The mg/kg/dose rats is approximately half the recommended dose in humans 2 Insomnia Insomnia 94 (17.9) 94 (17.9) 0 0 0 0 of 27 mg/m2ofbased 27 mg/m on body based surface on body area.surface The dose area. of 2The mg/kg/dose dose of 2 in mg/kg/dose monkeys isinapproximately monkeys is approximately equivalent to equivalent the recommended to the recommended dose in humans dose based in humans on body based surface on body area. surface area. Chills Chills 84 (16.0) 84 (16.0)1 (0.2) 1 (0.2) 0 0 PATIENT COUNSELING INFORMATION: INFORMATION: Discuss the following Discuss the withfollowing patients with priorpatients to treatment prior with to treatment with Arthralgia Arthralgia 83 (15.8) 83 (15.8)7 (1.3) 7 (1.3) 0 0 PATIENT COUNSELING KYPROLIS: Instruct KYPROLIS: patients Instruct to contact patients their to contact physiciantheir if they physician develop if they any of develop the following any of the symptoms: following symptoms: Muscle spasms Muscle spasms 76 (14.4) 76 (14.4)2 (0.4) 2 (0.4) 0 0 fever, chills, rigors, fever, chills, chest rigors, pain, cough, chest or pain, swelling cough,oforthe swelling feet oroflegs. the Advise feet or patients legs. Advise that patients KYPROLIS that KYPROLIS HypertensionHypertension 75 (14.3) 75 (14.3) 15 (2.9) 15 (2.9)2 (0.4) 2 (0.4) may cause fatigue, may cause dizziness, fatigue, fainting, dizziness, and/or fainting, drop inand/or blooddrop pressure. in blood Advise pressure. patients Advise not topatients drive ornot to drive or operate machinery operate if they machinery experience if theyany experience of these symptoms. any of theseAdvise symptoms. patients Advise that they patients maythat experience they may experience Asthenia Asthenia 73 (13.9) 73 (13.9) 12 (2.3) 12 (2.3)1 (0.2) 1 (0.2) shortness of shortness breath (dyspnea) of breath during (dyspnea) treatment during with treatment KYPROLIS. withThis KYPROLIS. most commonly This mostoccurs commonly withinoccurs within Hypokalemia Hypokalemia 72 (13.7) 72 (13.7) 14 (2.7) 14 (2.7)3 (0.6) 3 (0.6) a day of dosing. a day Advise of dosing. patients Advise to contact patientstheir to contact physicians theirif physicians they experience if theyshortness experience of shortness breath. of breath. Hypomagnesemia Hypomagnesemia 71 (13.5) 71 (13.5)2 (0.4) 2 (0.4) 0 0 Counsel patients Counsel to avoid patients dehydration, to avoid dehydration, since patientssince receiving patients KYPROLIS receivingtherapy KYPROLIS may therapy experience may experience vomiting and/or vomiting diarrhea. and/or Instruct diarrhea. patients Instruct to seek patients medical to seek advice medical if theyadvice experience if theysymptoms experience symptoms Leukopenia Leukopenia 71 (13.5) 71 (13.5) 27 (5.1) 27 (5.1)1 (0.2) 1 (0.2) lightheadedness, dizziness, lightheadedness, or fainting spells. or fainting Counsel spells. females Counsel of reproductive females of reproductive potential to use potential to use Pain in extremity Pain in extremity 70 (13.3) 70 (13.3)7 (1.3) 7 (1.3) 0 0 of dizziness, of effective contraceptive effective contraceptive measures to measures prevent pregnancy to preventduring pregnancy treatment during with treatment KYPROLIS. withAdvise KYPROLIS. the Advise the b Pneumonia Pneumonia 67 (12.7) 67 (12.7) 52 (9.9) 52 (9.9)3 (0.6)b 3 (0.6) patient that ifpatient she becomes that if she pregnant becomes during pregnant treatment, duringto treatment, contact hertophysician contact her immediately. physician immediately. Advise Advise Aspartate aminotransferase Aspartate aminotransferase increased increased 66 (12.5) 66 (12.5) 15 (2.9) 15 (2.9)1 (0.2) 1 (0.2) patients not topatients take KYPROLIS not to take treatment KYPROLIS while treatment pregnant while or breastfeeding. pregnant or breastfeeding. If a patient wishes If a patient to restart wishes to restart breastfeeding breastfeeding after treatment, after advise treatment, her to advise discuss her the to appropriate discuss the timing appropriate with her timing physician. with her Advise physician. Advise Dizziness Dizziness 66 (12.5) 66 (12.5)5 (1.0) 5 (1.0)1 (0.2) 1 (0.2) patientswith to discuss their physician with their anyphysician medication anythey medication are currently they are taking currently prior to taking starting prior to starting HypoesthesiaHypoesthesia 64 (12.2) 64 (12.2)3 (0.6) 3 (0.6) 0 0 patients to discuss treatment withtreatment KYPROLIS, withorKYPROLIS, prior to starting or prior anytonew starting medication(s) any new medication(s) during treatment during withtreatment KYPROLIS. with KYPROLIS. Anorexia Anorexia 63 (12.0) 63 (12.0)1 (0.2) 1 (0.2) 0 0 Pain Pain 63 (12.0) 63 (12.0) 12 (2.3) 12 (2.3) 0 0 Hyperglycemia Hyperglycemia 62 (11.8) 62 (11.8) 16 (3.0) 16 (3.0)3 (0.6) 3 (0.6) Chest wall pain Chest wall pain 60 (11.4) 60 (11.4)3 (0.6) 3 (0.6) 0 0 Hypercalcemia Hypercalcemia 58 (11.0) 58 (11.0) 13 (2.5) 13 (2.5)8 (1.5) 8 (1.5) Manufactured Manufactured for: Onyx Pharmaceuticals, for: Onyx Pharmaceuticals, Inc., 249 EastInc., Grand 249Avenue, East Grand Avenue, Hypophosphatemia Hypophosphatemia 55 (10.5) 55 (10.5) 24 (4.6) 24 (4.6)3 (0.6) 3 (0.6) South San Francisco, South San CAFrancisco, 94080 CA 94080 HyponatremiaHyponatremia 54 (10.3) 54 (10.3) 31 (5.9) 31 (5.9)3 (0.6) 3 (0.6) U.S. Patent Numbers: U.S. Patent7,232,818; Numbers:7,417,042; 7,232,818;7,491,704; 7,417,042;7,737,112 7,491,704; 7,737,112 05‑1088‑00 05‑1088‑00 a National CanceraNational InstituteCancer Common Institute Terminology Common Criteria Terminology for Adverse Criteria Events for Adverse (NCI CTCAE) Events Version (NCI CTCAE) 3.0. Version 3.0. ©2014 Onyx©2014 Pharmaceuticals, Onyx Pharmaceuticals, Inc. TROPIC‑KYPR‑100826J Inc. TROPIC‑KYPR‑100826J November 2014 November 2014

cates a poor prognosis. The condition results from cancer-driven increases in bone resorption and, if untreated, can lead to renal failure, progressive mental

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The ASCO Post | JANUARY 25, 2015

PAGE 174

Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Children and Young Adults With Cancer Compiled by Jo Cavallo

The information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies of children and young adult cancer survivors. The studies include phase I, I/II, III, observational, and interventional trials investigating genomic profiling to personalize treatment; physical therapy interventions to improve care; the long-term effects of cancer and its treatment; genetically modified T cells; vaccine immunotherapy; new chemotherapies and chemotherapy combinations; surgery and proton therapy; and music therapy. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

PILOT Study Type: Observational Study Title: Protocol for the Enrollment on the Official COG Registry, The Childhood Cancer Research Network (CCRN) Children’s Oncology Group Study Sponsor and Collaborators: National Cancer Institute Purpose: The goal of the CCRN is to collect clinical information about every child diagnosed with cancer and similar conditions in the United States and Canada so researchers can study patterns, characteristics, and causes of childhood cancer. Ages Eligible for Study: up to 18 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To collect information on children with cancer (time frame: after initial diagnosis) Principal Investigator: Crystal L. Mackall, MD, National Cancer Institute; 301-402-5940, mackallc@mail. nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01117168 Study Type: Interventional/singlegroup assignment Study Title: A Pilot Trial Testing the Feasibility of Using Molecular Profiling to Guide an Individualized Treatment Plan in Children and Young Adults With Newly Diagnosed DIPG (Diffuse Intrinsic Pontine Glioma)

Study Sponsor and Collaborators: University of California, San Francisco; Translational Genomics Research Institute Purpose: To test a new treatment approach based on each patient’s tumor genomic profiling consisting of whole exome sequencing and RNA sequencing as well as predictive modeling Ages Eligible for Study: up to 25 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Number of patients for whom an individualized treatment plan is provided within 21 business days (time frame: within 21 business days of tumor tissue collection) Principal Investigator: Sabine Mueller, MD, UCSF Helen Diller Family Comprehensive Cancer Center; muellers@neuropeds.ucsf.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02274987 Study Type: Interventional/singlegroup assignment Study Title: A Pilot Study on the Effects of Preoperative Physical Therapy in Adolescents and Young Adults Diagnosed With a Lower Extremity Malignancy Study Sponsor and Collaborators: St. Jude Children’s Research Hospital Purpose: To evaluate the impact of adding a focused physical therapy intervention to the preoperative regimen of individuals diagnosed with a malignancy of the lower extremity Ages Eligible for Study: 6 to 30 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Feasibility of a 10-week physical therapy intervention program (time frame: up to 12 weeks postsurgery) Principal Investigator: Angela M. Corr, PT, DPT, St. Jude Children’s Research Hospital; 866-278-5833, angela. corr@stjude.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01674101 Study Type: Observational/retrospective Study Title: Childhood Cancer Survivor Study Study Sponsor and Collabora-

tors: St. Jude Children’s Research Hospital; National Cancer Institute; Fred Hutchinson Cancer Research Center; Nationwide Children’s Hospital; The University of Texas MD Anderson Cancer Center; University of Southern California; Children’s Hospital Medical Center, Cincinnati Purpose: To investigate the longterm effects of cancer and its associated therapies Ages Eligible for Study: Cancer survivors diagnosed at ages 21 and younger Genders Eligible for Study: Both Accepts Health Volunteers: Yes Primary Outcome Measures: To characterize survivors’ health outcomes with respect to disease-, treatment, and genetic-related factors (time frame: 25 years) Principal Investigator: Gregory T. Armstrong, MD, MSCE, St. Jude Children’s Research Hospital; 866-2785833, inmfo@st.jude.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01120353

PHASE I Study Type: Phase I/interventional/nonrandomized Study Title: A Phase I Trial of Autologous T-Lymphocytes Genetically Targeted to the B-Cell Specific Antigen CD19 in Pediatric and Young Adult Patients With Relapsed B-Cell Acute Lymphoblastic Leukemia Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center; Dana-Farber Cancer Institute; Dana-Farber Children’s Hospital Purpose: To test the safety of giving patients modified T cells after their leukemia has returned to the bone marrow Ages Eligible for Study: up to 26 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Safety of gene-modified autologous T cells targeted to CD19 and infused into patients with relapsed/refractory B-cell ALL. Toxicities that are related to treatment will be graded on a scale of 1 to 5 as described by the NCI Common Terminology Criteria for Adverse Events, version 4.0 (time frame: 1 year). Principal Investigator: Kevin Curren, MD, Memorial Sloan Kettering Cancer Center; 212-639-5836

For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01860937 Study Type: Phase I/interventional/single-group assignment Study Title: Imiquimod/BTIC Lysate-Based Vaccine Immunotherapy for Diffuse Intrinsic Pontine Glioma in Children and Young Adults Study Sponsor and Collaborators: Masonic Cancer Center, University of Minnesota Purpose: To study the modification of current standard of care for diffuse intrinsic pontine glioma (5,580-cGy involved-field radiation), with the final two doses of radiation given at intervals during the vaccination phase of treatment Ages Eligible for Study: 3 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Dose-limiting toxicity (time frame: within 24 hours of vaccination) Principal Investigator: Christopher Moertel, MD, Masonic Cancer Center, University of Minnesota; 612626-2778, moert001@umn.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01400672

PHASE I/II Study Type: Phase I/II/interventional/nonrandomized Study Title: Phase I/II Trial of Mithramycin in Children and Adults With Refractory Extracranial Solid Tumors (Phase I) or Ewing Sarcoma and EWSFLI1 Fusion Transcript (Phase II) Study Sponsor and Collaborators: National Cancer Institute Purpose: To investigate whether mithramycin can be used to treat solid tumors and Ewing sarcoma in children and adults Ages Eligible for Study: 1 year and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Phase I: Determine the tolerability, toxicity, and recommended dose of mithramycin in pediatric patients with extracranial tumors (time frame: 2 years). Phase II: Determine response in children and adults with Ewing sarcoma (time frame: 2 years).

ASCOPost.com | JANUARY 25, 2015

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Clinical Trials Resource Guide

Principal Investigator: Brigitte C. Widemann, MD, National Cancer Institute; 301-496-7387, widemanb@pbmac.nci.nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01610570 Study Type: Phase I/II/interventional/single-group assignment Study Title: A Phase 1/2 Study of AZD1775 (MK-1775) in Combination With Oral Irinotecan in Children, Adolescents, and Young Adults With Relapsed or Refractory Solid Tumors Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the side effects and best dose of WEE1 inhibitor MK1775 and irinotecan hydrochloride in treating younger patients with solid tumors that have recurred or that have not responded to standard therapy Ages Eligible for Study: 1 to 21 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximum tolerated dose defined as the maximum doses of WEE1 inhibitor MK-1775 and irinotecan hyrdochloride at which fewer than one-third of patients experience dose-limiting toxicities when receiving their combination (time frame: 21 days) Principal Investigator: Kristina A. Cole, MD, PhD, COG Phase I Consortium; 267-426-2285, colek@email. chop.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02095132 Study Type: Phase I/II/interventional/single-group assignment Study Title: Treatment of Neuroblastoma and GD2-Positive Tumors With Activated T Cells Armed With OKT3 X Humanized 3F8 Bispecific Antibodies (GD2Bi): A Phase I/II Study Study Sponsor and Collaborators: Barbara Ann Karmanos Cancer Institute; National Cancer Institute Purpose: To study the side effects and best dose of activated T cells armed with GD2 bispecific antibody and how well they work in treating patients with neuroblastoma, osteosarcoma, and other GD1-positive solid tumors Ages Eligible for Study: 13 months to 29 years Genders Eligible for Study: Both

Accepts Health Volunteers: No Primary Outcome Measures: Maximum tolerated dose of GD2BiaATC (time frame: 35 days) Principal Investigator: Maxim Y. Yankelevich, MD, Barbara Ann Karmanos Cancer Institute; 313-745-5516, myankele@med.wayne.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02173093

PHASE II Study Type: Phase II/interventional/randomized Study Title: Pilot Study to Prevent Nephrotoxicity of High-Dose Methotrexate by Prolonging the Infusion Duration and Prevent Nephrotoxicity and Ototoxicity of Cisplatin With Pantoprazole in Children, Adolescents, and Young Adults With Osteosarcoma Study Sponsor and Collaborators: Children’s Hospital of Philadelphia; Gateway for Cancer Research Purpose: To evaluate new approaches to prevent treatment side effects in patients with osteosarcoma without interfering with the beneficial effects of chemotherapy Ages Eligible for Study: 1 to 30 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Change of urinary biomarker concentration from pretreatment and 24 hours after cisplatin or high-dose methotrexate (time frame: pretreatment and 24 hours after cisplatin or high-dose methotrexate) Principal Investigator: Frank M. Balis, MD, Children’s Hospital of Philadelphia; balisf@email.chop.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01848457 Study Type: Phase II/interventional/single-group assignment Study Title: A Phase II Trial of Limited Surgery and Proton Therapy for Craniopharyngioma and Observation for Craniopharyngioma After Radical Resection Study Sponsor and Collaborators: St. Jude Children’s Research Hospital Purpose: To determine the feasibility and safety of treating patients with a brain tumor known as craniopharyngioma with limited surgery and a 5-mm clinical target volume margin in combination with proton therapy

Ages Eligible for Study: up to 21 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Estimate the progression-free and overall survival distributions for children and young adults with craniopharyngioma treated with limited surgery and proton therapy (time frame: 5 years) Principal Investigator: Thomas E. Merchant, DO, PhD, St. Jude Children’s Research Hospital; 866-278-5833, info@stjude.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01419067 Study Type: Phase II/interventional/single-group assignment Study Title: A Reduced-Intensity Conditioning Regimen With CD3Depleted Hematopoietic Stem Cells to Improve Survival for Patients With Hematologic Malignancies Undergoing Haploidentical Stem Cell Transplantation Study Sponsor and Collaborators: St. Jude Children’s Research Hospital Purpose: To help improve overall survival with haploidentical stem cell transplant in patients with high-risk hematologic malignancies by limiting the complication of graft-vs-host disease, enhancing post-transplant immune reconstitution, and reducing nonrelapse mortality Ages Eligible for Study: up to 21 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To determine whether 1-year event-free survival can be improved in pediatric patients undergoing a haploidentical transplant by using a reduced-intensity conditioning regimen and a targeteddose T cell–depleted donor product (time frame: 1 year post-transplant) Principal Investigator: Brandon Triplett, MD, St. Jude Children’s Research Hospital; 866-278-5833, info@ stjude.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00566696 Study Type: Phase II/interventional/randomized Study Title: Music Video for AYAParent Communication and Resilience Study Sponsor and Collaborators: Children’s Oncology Group; National

Cancer Institute Purpose: To evaluate how well music therapy and parents’ education work in improving communication, emotional distress, and recovery in adolescents/young adult patients undergoing treatment for high-risk cancer and their parents Ages Eligible for Study: 11 to 24 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Adolescent and young adult illness-related distress measured by the Mishel Uncertainty in Illness Scale and the McCorkle Symptom Distress scale (time frame: up to 90 days) Principal Investigator: Joan Haase, PhD, RN, Children’s Oncology Group; 317-278-7749, johaase@upui.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01556256

PHASE III Study Type: Phase III/interventional/randomized Study Title: A Phase III Randomized Trial for Newly Diagnosed HighRisk B-Lymphoblastic Leukemia (BALL) Testing Clofarabine in the Very High Risk Stratum Study Sponsor and Collaborators: Children’s Oncology Group; National Cancer Institute Purpose: To investigate how effective combination chemotherapy is in treating young patients with newly diagnosed high-risk acute lymphoblastic leukemia Ages Eligible for Study: 1 to 30 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Comparison of disease-free survival of children with high-risk acute lymphoblastic leukemia receiving postinduction intrathecal triple therapy on a modified Berlin-Frankfurt-Munster interim maintenance high-dose methotrexate backbone compared to age-adjusted intrathecal methotrexate (time frame: at 5 years) Principal Investigator: Michael Burke, MD, Children’s Oncology Group. See clinical trial details for contact information by state. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01406756 n

The ASCO Post | JANUARY 25, 2015

PAGE 176

Patient’s Corner

Ovarian Cancer Has Taught Me to Be Fearless

I’ve learned that what may look like a negative can turn out to be something greater than I ever could have imagined. By Valisia LeKae, as told to Jo Cavallo

n 2013, I was at the top of my professional game. I was a lead performer in the hit Broadway show Motown: The Musical, playing singing legend Diana Ross, which earned me a Tony Award nomination. Performing eight shows a week is exhausting, but I had no problem meeting the physical demands of the show. I was fit and healthy—or so I thought.

cal exams, I was young—just 34—and I didn’t have any symptoms of a serious illness.

Beating the Odds When the pathology report came back 10 days later with a diagnosis of clear cell ovarian carcinoma, I froze. Cancer was the last thing on my radar. There was no history of ovarian cancer

I went public about my cancer soon after my diagnosis, because I wanted women to know that cancer does not discriminate. It does not care if you are in a hit Broadway show or movie. —Valisia LeKae

In the fall of that year, I had my routine annual gynecologic exam and discovered that a small cyst on my right ovary diagnosed several years ago had tripled in size to over 6 cm. My doctor said that the cyst should be removed, because there was a good chance it could rupture, and I agreed. There was no sense of alarm in my doctor’s voice as he gave me the information. I was vigilant about getting my annual physi-

in my family, so the news was totally unexpected and devastating. When I met with a gynecologic oncologist for a consultation, he didn’t mince words. “Until I examine you and explore the situation, I can’t give you an exact prognosis,” he said. “But most people with this cancer have less than a 50% chance of survival.” I know how fortunate I am to have beaten those odds.

I had a unilateral salpingo-oophorectomy to remove my right ovary and right fallopian tube. My cancer was labeled “stage IA–aggressive” on the pathology report, followed by six rounds of a chemotherapy regimen of carboplatin and paclitaxel. Throughout the whole process, my oncologist was my saving grace. He encouraged open dialogue and asked me to tell him about any problems I was having. In April 2014, my oncologist declared me cancer-free.

Being Proactive in Your Health Care Although the cancer caused me to leave the Broadway show, it has not ended my acting career, and my professional goals are the same. However, my life has taken a different turn. Ever since I was a little girl, I wanted to inspire people and give them hope. At first, I accomplished those goals through my singing and acting career. Now, cancer has given me another venue. I went public about my cancer soon after my diagnosis, because I wanted women to know that cancer does not discriminate. It does not care if you are in a hit Broadway show or movie. Cancer can happen to anyone. Since then, I’ve become a spokesper-

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare. • ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship. Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

son for the National Ovarian Cancer Coalition and travel across the country to be a voice for other women struggling with this disease. As a young African American woman, I feel it is important to share my story to educate and encourage others to fight against ovarian cancer. I also want to empower young women to know their bodies and to be proactive in their health care. But most of all, I want women not to be afraid if they suspect something is wrong. I tell women, “To know your body, know your risk.” It’s better to fight than to have fear.

Learning to Surrender Having cancer has taught me important lessons, and I believe it has made me a better actress and person. I’m more grounded and have different experiences I can now bring to my craft. Cancer has also taught me to surrender to the things I cannot control and to accept help from friends and colleagues when I need it. And that has been a blessing. Every day is a new experience now, and I’m more flexible in how I perceive challenges in my life. I’ve learned that what may look like a negative can turn out to be something greater than I ever could have imagined. n Valisia LeKae lives in New York.

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The ASCO Post | JANUARY 25, 2015

PAGE 178

Through the Lens of Oncology History

A Century of Progress The text and photographs on these pages represent the establishment of oncology as a viable medical specialty during the mid1800s. The images and captions are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photographic History, by Stanley B. Burns, MD, FACS. To view additional photos from this series of books, visit burnsarchive.com.

The Anesthesia Era 1845-1875 Man With Tumor of the Breast, Albumen Print, Paris, 1873

umors in the male breast, which are relatively rare, have always intrigued physicians. In Revue Médico-Photographique des Hôpitaux de Paris, Volume 6, 1874, an interesting photograph and case history of a breast neoplasm were presented in the section “Surgical Clinics.” Mr. X… entered the Hospital ‘de Santé’ in the service of (Dr.) Demarquay with a diagnosis of tumor of the right breast. Three years prior, the patient had noted a small lump the size of a hazelnut. It was hard and did not change for a year. Suddenly, 2 years ago, the tumor started to develop. In 6 months, it was the size of an egg. It was now soft and mobile. The skin over the area was reddened but without inflammation. A second tumor began to develop next to the first. Both lesions began to grow, and the patient decided to consult Demarquay with the intention of having him remove the tumor. Examination indicated that a third tumor had appeared and the lesions appeared cystic. The ganglions (lymph nodes) in the armpit were not enlarged. On May 19, 1873, at operation, Demarquay examined the protrusion. It was mobile and appeared to have three lobes. It

measured 30 cm in circumference and was elevated 6 cm. The skin was red and firmly adherent to the tumor. A circular incision was made around the lesion and the tumor isolated. The content of the biggest cyst was emptied. Respecting and preserving the pectoralis muscle fibers, he dissected the tumor. Using seven small ligatures he tied off blood vessels. Six sutures closed the skin. A drain

was placed in the wound. Postoperatively the patient did well until June 9. June 7: Everything had gone well, and the drain was removed. June 8: The sutures were removed. June 9: A high fever was noted. The sides of the wound were now reddened. June 10: Erysipelas became apparent, and the patient was treated with quinine sulfate. Dressings of glycerine applied to the wound. June 11: Patient about the same. Glycerine dressings replaced by starch applications. June 14: Erysipelas has now reached the arm. Despite the complications, the incision itself appears to be healing. June 19: The wound is almost healed. June 22: The patient’s fever drops a bit. The erysipelas has almost left the wound.

THE ANTISEPTIC ERA: 1876–1900 Electro-Gynecology, Philadelphia, 1883

n the last half of the nineteenth century, electrotherapy was a popular therapeutic modality. Every conceivable condition was treated with an application of electricity. Although the use of this treatment was often encouraged by the enormous lack of specific therapies for specific diseases, it was often safer than the toxic or narcotic preparations prescribed by the mainstream medicine establishment. Some doctors used these electrical treatments as an alternative to surgery. This choice sometimes helped their patients and other times proved fatal. With the publication in 1889 of Conservative Gynecology and Electro-

June 25: The wound has completely healed. There was no fever. Erysipelas has disappeared from the wound area and only remains in the lumbar region. The patient is now out of danger. Microscopic examination of the tumor indicated that the tumor was not malignant and appeared to be an adenoma. Preoperatively this was suggested by the absence of swollen armpit ganglions. This case illustrates not only a breast tumor occurrence in a male, but the frequent infections that seemed a natural part of surgery. At this time, antiseptic operating principles were known but still not fully accepted. In 1867, Sir Joseph Lister, MD, had described antiseptic techniques, but antisepsis was not generally used in Europe until the late 1870s. German surgeons were the first to adapt the procedure, which ultimately held, and led to their primacy in surgery at the end of the 19th century. n Excerpted from Oncology Tumors & Treatment: A Photographic History, The Anesthesia Era 1845-1875, by Stanley B. Burns, MD, FACS. Photograph courtesy of Stanley B. Burns, MD, and The Burns Archive.

ASCOPost.com | JANUARY 25, 2015

PAGE 179

Through the Lens of Oncology History Therapeutics: A Practical Treatise on the Diseases of Women and Their Treatment by Electricity, Philadelphia gynecologist G. Betton Massey, MD, established the field of electro-gynecology. Dr. Massey, an early opponent of the improper use of surgery, believed electrical stimulation could correct various inflammations and tumors. He treated a variety of diseases with electricity, including breast carcinoma, rectal disease, and even ectopic pregnancies. For uterine disease, he often used a bipolar treatment with the insertion of a negatively charged electrode into the uterus and a positively charged electrode placed on the abdomen. Although most of Dr. Massey’s concepts for the treatment of women’s diseases were ill conceived, there is no question he saved many from surgery and probable death from infection. On the other hand, others died from untreated cancer. His book was so popular that four editions were published until 1905. By the end of the century, however, the advances of surgical techniques, asepsis, and specialized instrumentation made surgery a safer, life-saving procedure. The image on page 178 shows Dr. Massey placing his external electrode on the abdomen, prior to the insertion of the uterine electrode for his treatment of “uterine disease.” Dr. Massey declared, “Application of zinc-mercury cataphoresis offers a most effective method for the destructive sterilization of mammary cancer in its early stages ... without the risk of the infective cells gaining access to the lymphatic spaces, as may happen in a cutting operation.” Dr. Massey details his treatment in the documentation of the following case: Carcinoma of the Left Breast with Extension into the Axillary Glands. - Mrs. N.K. aged 44, was referred by Dr. J. J. Moylan, of Germantown, (Pennsylvania) in April 1899. This patient… presented an instance of acinous carcinoma of the left breast, though but a portion of the outer quadrant was affected. In this case, however, the disease had proceeded to a point of actual infiltration of the skin overlying the disease, and there was one enlarged, movable gland in the axilla, about the size of a horse-chestnut. She had noted the lump one year before. It was now giving pain, and her general condition did not indicate the best of health. The patient was placed under ether April 13, 1899, and major cataphoresis applied, with the assistance of Drs. Hermance and Moylan. A large gold-mercury electrode was inserted, additional mercury injected, and a current of 400 milliam-

peres gradually turned on, encountering some trouble with the pulse again because of what is now understood to have been too rapid increase. Turning it on again more slowly we easily reached a strength of 500 milliamperes. After about a halfhour of steady current flow the whole lump began to soften, which softening included the whole growth at the end of an hour

and twenty minutes. Meantime, a zinc instrument had been substituted for the gold one, as offering quicker results, and another zinc instrument had been made to penetrate the enlarged gland through its overlying skin, the current dividing itself between the two until the condition of the primary growth permitted the instrument in that situation to be removed.

2015

The after-history of the case pursued the usual course, except that the general condition did not improve, and during the frequent postoperative examinations always made in such cases some induration was noticed in the axillary border of the main scar. This should have been destroyed at once, but the patient’s general continued on page 181

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The ASCO Post | JANUARY 25, 2015

PAGE 180

In the News Issues in Oncology

Physicians Need to Maintain Flexibility to Deviate From Treatment Guidelines Without Financial Penalties By Charlotte Bath

ith the provocative headline, “How Medical Care Is Being Corrupted,” an op-ed piece in The New York Times argued that “financial forces largely hidden from the public are beginning to corrupt care and undermine the bond of trust between doctors and patients.”1 The article warned that in-

FASCO, Editor-in-Chief of the Journal of the National Comprehensive Cancer Network (JNCCN), Professor of Medicine at the University of California, San Francisco (UCSF), and Director of the UCSF Pancreas Center. Dr. Tempero is also a past President of ASCO. With those credentials, one might

There is no control over the prices that pharmaceutical companies place on their drugs. We are spending so much time constraining what we do, but, to me, the root of the problem is the cost of the drugs. —Margaret A. Tempero, MD, FASCO

surers, hospital networks, and regulatory groups are proposing or imposing financial rewards and penalties that can influence physicians’ decisions to use specific drugs or follow designated treatment pathways. “This has raised concern in the oncology community because there is considerable debate among experts about what is optimal,” wrote Pamela Hartzband, MD, and Jerome Groopman, MD, of Harvard Medical School. The expert they cited in the article was Margaret A. Tempero, MD,

expect Dr. Tempero to be an advocate and supporter of cancer treatment guidelines, and she is. “I think for the most part, the guidelines should be followed, because they are based both on the degree of evidence available as well as the consensus among thought leaders about what the appropriate approach would be,” Dr. Tempero told The ASCO Post. But in the Times article, in an editorial Dr. Tempero previously wrote for JNCCN,2 and during the interview with The ASCO Post, Dr. Tempero noted that oncologists often see patients for whom

Citing Guidelines May Reassure Patients

hether deviations from treatment guidelines are warranted to provide optimal personalized care, or should be financially penalized for straying from evidence-based care, has raised questions among insurers and physicians and caused a stir in the press. In general, however, patients with cancer are not that aware of the guidelines, Margaret A. Tempero, MD, FASCO, told The ASCO Post. “Or if patients are aware of the guidelines, I don’t think they are checking to see that they are being treated accordingly,” she added. Dr. Tempero is Editor-in-Chief of the Journal of the National Comprehensive Cancer Network, a past ASCO President and Professor of Medicine at the University of California, San Francisco (UCSF), and Director of the UCSF Pancreas Center. “Part of the reason patients are not knowledgeable about treatment guidelines is because many of the guidelines are not available in a patient-friendly format,” Dr. Tempero said, and therefore difficult for patients to interpret. In addition, patients may not be looking for other treatment recommendations. “I still think that patients, especially when they are very sick with cancer, tend to trust their physicians,” Dr. Tempero maintained. Treatment guidelines can be useful and reassuring in describing recommendations and options. “When I am explaining a therapy, I might say, ‘This would be the standard therapy given in any guidelines for care,’” Dr. Tempero noted. n Disclosure: Dr. Tempero reported no potential conflicts of interest.

deviation from treatment guidelines “makes sense.”

Financial vs Moral Incentive “It bothered me that there would be a financial incentive to stick to a guideline, getting paid for doing what is right,” Jerome Groopman, MD Pamela Hartzband, MD Dr. Tempero said. “We ought to have a moral incentive to stick to a FASCO, noted in a letter to the editor guideline, but also have the flexibility, of The New York Times following puband without penalty, to deviate from lication of the op-ed article.3 “Insurers the guideline when it makes sense for a need to allow for this as unexpected deviations from the ‘norm’ may result given patient.” She expressed concern about finan- in equally good—if not better—patient cial rewards for adhering to treatment outcomes,” he continued. Dr. Yu is a guidelines becoming part of the prac- medical oncologist and hematologist tice model. “It seems to me, that would and Director of Cancer Research at Palo be a disincentive to deviate when you Alto Medical Foundation in California. To learn from real-world patient care should deviate,” she stated. “We all agree guidelines are not per- how to improve outcomes for patients, fect; they probably cover 90%-plus of ASCO is developing CancerLinQ. The the patients that we see, but you have “big data initiative” will collect and to be thoughtful about those patients analyze cancer care data from millions for whom—for whatever reason—you of patient visits, together with expert guidance and other evidence to genershould do things a little bit differently.” Dr. Tempero has been very involved ate real-time, personalized assistance in guideline development, having served and quality feedback for physicians, Dr. as Chairperson of the NCCN Guidelines Yu explained. “We are also piloting new physician Panel for Pancreatic Cancer, and was a founding board member of the NCCN. payment models, developed by practic“One of the first decisions we made as ing oncologists, that incentivize highan organization was to develop guide- quality care, while preserving the central lines,” Dr. Tempero said. “Initially, these importance of physicians’ professional guidelines were intended to create some judgment and experience,” he wrote. uniformity among the academic institutions that belonged to the NCCN, but Root of the Problem The driving force behind the recent efthey were really well done, I think, and they became adopted widely by many, forts to impose strict adherence to treatincluding Medicare, as an indication ment guidelines and rein in physician aufor reimbursement. Now some NCCN tonomy is “is the cost of health care and guidelines are even used internationally.” particularly the cost of cancer care,” Dr. Tempero stressed. “There is no control Impact of Targeted Therapies over the prices that pharmaceutical com“Variation in medical treatment is panies place on their drugs. We are spenda necessary part of care … [and] es- ing so much time constraining what we pecially so in cancer, where treatment do, but, to me, the root of the problem is has become increasingly personalized,” the cost of the drugs,” she noted. ASCO President Peter Paul Yu, MD, “There is huge inequity in the cost of drugs as this relates to value. Cost has been set on what the market will bear, and apparently the market has been bearing everything. Now we are in this crisis that is causing us to put fetters on the providers, and Medicare is squeezing payments to physicians to the point where it is bare bones now. Yet [the Centers for Medicare & Medicaid Peter Paul Yu, MD, FASCO

continued on page 181

ASCOPost.com | JANUARY 25, 2015

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In the News Treatment Guidlines continued from page 180

Services] pays huge amounts for these drugs. It doesn’t make sense,” Dr. Tempero commented.

A New Paternalism? At the end of The New York Times oped piece, the authors stated that the “past paternalism where doctors imposed their views on the patient” has been replaced by “a new paternalism, largely invisible to the public, diminishing the autonomy of both doctor and patient.” Asked if she agreed that a “new paternalism” is taking root, Dr. Tempero

replied, “In a way, I do, because with the Affordable Care Act, there is going to be a tendency to go to a bundled payment for an episode of care, so you are going to be given only so much money to work with. And that is a form of paternalism. We have not had that kind of a handicap in the past, but I see that coming. When it does, it will be important

to keep practices whole so that we can continue to deliver the quality care our patients deserve.” n

Disclosure: Drs. Hartzband, Groopman, and Tempero reported no potential conflicts of interest.

References 1. Hartzband P, Groopman J: How medical care is being corrupted. The New York

Times. November 18, 2014. Available at www. nytimes.com. Accessed December 17, 2014. 2. Tempero M: Incentive-based oncology: Unintended consequences? J Natl Compr Canc Netw 12:1069, 2014. 3. Yu PP: Financial incentives in health care. The New York Times. November 27, 2014. Available at www.nytimes.com. Accessed December 17, 2014.

JCO:

A LEADER IN REACH, READERSHIP, IMPACT, AND INFLUENCE

Through the Lens of Oncology History continued from page 179

health continuing poor, nothing was done. (The patient had this area treated by another physician with application of caustic paste. She died from metastatic disease soon afterward.) It is amazing to note in reviewing several of Dr. Massey’s breast cases that he does not follow his own protocol for choosing cases and that although he is also proud of a patient’s results for the first 2 months or so, all his cancer patients died. He established a very large practice not only from physician referrals but also from direct appeals from patients who had had other surgeons recommend mastectomies. It is understandable that a patient would perhaps seek “alternative or quack therapy” that does not require a major procedure. The treatment of cancer has always required drastic therapy and some patients in every era seek a shortcut to healing. A large number of physicians continued to refer cancer patients to Dr. Massey well into the early 1900s. This was a decade after the preferred treatment of radical mastectomy had been established by William S. Halsted, MD, and the development of radiation therapy. In this era it was normal for women to be subject to clitorectomies and a wide variety of genital and reproductive system procedures for social reasons and psychiatric conditions. Hysterectomies were still controversial in recent times because the various reasons expounded for performing this procedure are not always medically sound. n Excerpted from Oncology: Tumors & Treatment, A Photographic History, The Antiseptic Era 1876-1900 by Stanley B. Burns, MD, FACS. Photograph courtesy of Stanley B. Burns, MD, and The Burns Archive.

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The ASCO Post | JANUARY 25, 2015

PAGE 182

In the Literature

Emerging Clinical Data on Cancer Management RECTAL CANCER AJCC Cancer Staging System Is Most Accurate Measuring Response to Chemoradiation in Locally Advanced Rectal Cancer When classifying response to chemoradiation among patients with locally advanced rectal cancer, the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (7th edition) system “is most accurate and should be adopted as the standard,” Attaphorn Trakarnsanga, MD, and colleagues at Memorial Sloan Kettering Cancer Center concluded after comparing several published classification schemes. The comparisons of the predictive accuracies of these schemes were published in the Journal of the National Cancer Institute. Currently, there are several different systems for tumor regression grade, a measure of histopathologic response of rectal cancer to neoadjuvant chemoradiation that is associated with outcomes. “A single measure of rectal cancer response would assist in comparing results across institutions and in designing future rectal cancer studies,” the researchers wrote. “Review of a prospective database identified 563 patients with locally advanced rectal cancer (T3/4 and/or N1) treated between 1998 and 2007 with long-course chemoradiation and total mesorectal excision. Tumor regression grade was determined by measuring the proportion of tumor mass replaced by fibrosis,” the investigators explained.

Patients were classified into tumor regression grade schemes: AJCC (4-tier), system, the Mandard (five-, three-tier), Dowrak/Rödel (five-, three-tier), Memorial Sloan Kettering Cancer Center (MSKCC, 3-tier). The schemes were compared by analyzing association with tumor recurrence and survival using concordance index. Although all tumor regression grade systems were predictive of tumor recurrence, the AJCC system more accurately predicted recurrence than the three-tier Mandard (P = .002) or Dowrak/Rödel (P = .006) and had a higher concordance index than the three-tier MSKCC scheme, although this did not reach statistical significance (P = .068), the researchers reported. Higher concordance numbers denote better prediction, and the AJCC system had the highest number, 0.694. Concordance indices for the other systems were 0.683 for the MSKCC, 0.665 for the Mandard, and 0.653 for the Dowrak/ Rödel. “Tumor regression grade may provide a valuable tool for clinical decision making for patients with rectal cancer who undergo neoadjuvant chemoradiation and surgery. The data from Trakarnsanga et al provide guidance as to which of the tumor regression grade systems is most predictive for recurrence following preoperative chemoradiation and surgery for rectal cancer,” noted an accompanying editorial by Bruce D. Minsky, MD, of the University of Texas MD Anderson Cancer Center, Houston, and Claus Rodel, MD,

University Cancer Center University Hospital, Frankfurt Germany. Despite several caveats, including tumor regression grade systems not accounting for possible involvement of pelvic lymph nodes and dependence on the expertise and dedication of the pathologist, “the four-tier AJCC tumor regression grade system appears to be a good choice,” Drs. Minsky and Rodel wrote. However, this classification system needs to be prospectively tested on multiple datasets to validate its reproducibility in the broader setting.” Trakarnsanga A, et al: J Natl Cancer Inst 106(10):dju248, 2014. Minsky BD, Rodel C: J Natl Cancer Inst 106(10):dju285, 2014.

LEUKEMIA Patients With Chronic Lymphocytic Leukemia Who Progress After Front-line Treatment May Be Candidates for Novel Noncytotoxic Therapies Although patients who relapse within 3 years of front-line fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) therapy have poor survival when treated with conventional salvage regimens, these patients may be candidates for novel noncytotoxic therapies, according to an analysis of extended results from the phase II FCR study at the University of Texas MD Anderson Cancer Center in Houston. To define optimal salvage strategy and identify patients who are not suitable for retreatment with FCR, Constantine S. Tam, MBBS, MD, and colleagues, of the University of Texas MD Anderson Cancer Center in Houston and the Peter MacCallum Cancer Center and the University of Melbourne in Australia, examined the survival and treatment outcome of 300 patients. At a median follow-up of 142 months, 156 patients had developed progressive chronic lymphocytic leukemia, with a median survival of 51 months following disease progression. “During the study period, there was no protocol-mandated salvage strategy for patients who progressed following FCR, and patients were offered standard or investigational therapy at MD Anderson or treated locally, according to individual clinical status and physician discretion. To consolidate disparate salvage strategies, patients who received

similar therapies were grouped together if the treatment outcomes of the individual salvage regimens were found to be similar on survival analysis,” the investigators explained. Salvage therapies were grouped into these six categories: FCRbased (n = 60), rituximab-based (n = 31), alemtuzumab (Campath)-based (n = 15), lenalidomide (Revlimid)-based (n = 8), intensive chemotherapy (n = 12), and other therapies (n = 10). “The duration of first remission was a key determinant of survival following disease progression and first salvage,” the researchers wrote. “Patients with a short first remission (< 3 years) had short survival irrespective of salvage therapy received; these patients have a high unmet medical need and are good candidates for investigation of novel therapies. In patients with a long first remission (≥ 3 years), salvage treatment with either repeat FCR or lenalidomide-based therapy results in a subsequent median survival exceeding 5 years; for these patients, FCR rechallenge represents a reasonable standard of care.” The authors pointed out that “significant therapeutic advances have occurred since the patients on this study received their first salvage regimen.” They include the tyrosine kinase inhibitors ibrutinib (Imbruvica) and idelalisib (Zydelig), novel anti-CD20 antibodies, bcl2 inhibitors, and chimeric antigen receptor T cells. “These agents all show promising activity in chronic lymphocytic leukemia but are associated with considerable costs and are not affordable in many health-care systems if applied broadly across large numbers of patients with chronic lymphocytic leukemia. To responsibly and effectively progress the development of these promising new therapies, they should be targeted specifically to groups where they can make the greatest contribution, such as those not suitable for FCR retreatment. Our experience and that of others suggest that an expanded ultra-high risk category including (1) patients with TP53 aberrations and (2) those with early (< 3 years) FCR failure represents an effective and practical way to identify such patients,” the researchers wrote. “Finally, patients with significant marrow failure and thrombocytopenia had very poor treatment outcomes in our series, largely due to poor tolerance of chemotherapy and exclusion from therapeutic trials. The nonmyelosuppressive nature of many of the novel agents provides an

ASCOPost.com | JANUARY 25, 2015

PAGE 183

In the Literature

opportunity to offer these patients effective salvage.” Tam CS, et al: Blood 124:3059-3064, 2014.

GLIOMA Ten Best-Practice Measures Improve Quality of Care During Perioperative Period for Patients With Glioma Ten best-practice measures identified by a multidisciplinary team at the Norris Cotton Cancer Center (NCCC) at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, were used to improve the care provided to patients with glioma during the perioperative period. “Using a plando-study-act framework,” the team assessed current process performance, developed and implemented improvement interventions, and created a plan for sustaining the new process, Natalie B. V. Riblet, MD, MPH, and colleagues explained in the Journal of Oncology Practice. The specific aims of the multiphase quality improvement project are to improve the quality of care for patients with glioma, reduce process variation, and maximize patient safety. The current report covers the first phase, which focuses on the time from initial diagnosis to entry into the surgical pathway and first visit with neuro-oncology to establish care. The multidisciplinary team included physicians, a physician’s assistant, nursing staff, schedulers, and a social worker, with members representing disciplines such as neuro-oncology, neurosurgery, radiation oncology, and care management as well as cancer center leadership. The team was organized into three groups: entry into the neuro-oncology microsystem, surgical care, and postoperative care. “Before beginning this quality improvement work, we reviewed the literature, and except for guidelines directing chemotherapy, surgery, and radiation treatment, we found limited information on which measures are associated with improved outcomes in the glioma population,” the team members explained. “On the basis of scant evidence and brainstorming, we proposed 10 objective measures that reflected timely and comprehensive care.”

10 Best-Practice Measures The 10 best practices follow: (1) The Neuro-Oncology Program is notified preoperatively of new admissions by the neurosurgery service; (2) The Neuro-Oncology Program evaluates a

patient during hospital admission; (3) Standard postoperative orders are used; (4) Appropriate use of corticosteroids; (5) Appropriate use of antiepileptic drugs; (6) Patients are evaluated by the social worker within 2 weeks of admission; (7) Follow-up appointment is scheduled with neuro-oncology prior to hospital discharge; (8) Patients are

evaluated by radiation-oncology within 2 weeks of discharge; (9) Patients are presented at tumor board; (10) Tumor board within 2 weeks of surgery. During the retrospective assessment phase of the quality improvement project, a manual medical record review for 43 patients with a diagnosis of glioma showed that compliance with 10 best-

practice measures ranged from 23% to 100%. “Several factors contributed to less-than-ideal process performance, including poor communication among disciplines and lack of familiarity with the larger system of care,” the authors noted. “After implementing improvement interventions, performance was continued on page 184

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PAGE 184

In the Literature Emerging Clinical Data

Study Findings

continued from page 183

Among 316,114 patients with stage 0 to II breast cancer who underwent initial breast-conservation surgery, 241,597 patients (76.4%) had a single lumpectomy, and 74,517 (23.6%) underwent at least one additional operation. Among those having an additional operation, 46,250 (62.1%) underwent a completion lumpectomy, and 28,267 (37.9%) underwent a mastectomy. “The proportion of patients undergoing repeat surgery decreased slightly during the study period, from 25.4% to 22.7% (P < .001),” the researchers reported. “Independent predictors of repeat surgeries were age, race, insurance status, comorbidities, histologic subtype, estrogen receptor status, pathologic tumor size, node status, tumor grade, facility type and location, and volume of breast cancer cases. Age was inversely associated with repeat surgery, decreasing from 38.5% in patients 18 to 29 years old to 16.5% in those older than 80 years (P < .001). In contrast, larger tumor size was linearly associated with a higher repeat surgery rate (P < .001).” Repeat surgeries were most common at facilities in the Northeast region (26.5%) compared with facilities in the Mountain region (18.4%, P < .001). The rate for repeat surgeries was 26% at academic or research facilities vs 22.4% at community facilities (P < .001). “At the root of the variability in repeat surgery rates for breast-conservation surgery is the lack of standardization of an acceptable margin width. The tumor margin width that will provide the lowest local recurrence rate has not been established in a randomized clinical trial setting,” the authors stated.

measured in 96 consecutive patients with glioma. The proportion of patients who met criteria for the 10 practice measures significantly improved (pre-quality improvement work, 63%; post-quality improvement work, 85%; P = .003). The largest improvement was observed in the measure assessing for preoperative notification of the neuro-oncology program (pre-quality improvement work, 39%; post-quality improvement work, 97%; P < .001).” The team members concluded that “the timeliness and consistency of care provided to patients with glioma in the perioperative period can be improved through the use of quality improvement principles. Involving clinical leaders, developing a system for ongoing measurement, and reporting of system performance are important for sustaining the gains of quality improvement work.” The next phase of the quality improvement initiative is currently underway and focuses on the delivery of acute care. The final phase will be to examine and postulate best-practice measurements for the chronic and palliative care of patients with glioma. Riblet NB, et al: J Oncol Pract 10:365370, 2014.

BREAST CANCER About 25% of Patients Who Undergo Breast-Conservation Surgery for Stage 0 to II Carcinoma Have Subsequent Surgery “Approximately one-fourth of all patients who undergo initial breastconservation surgery for breast cancer will have a subsequent operative intervention,” concluded a study published online by JAMA Surgery. “The rate of repeat surgeries varies by patient, tumor, and facility factors,” reported Lee G. Wilke, MD, of the University of Wisconsin, and colleagues. Using the National Cancer Database, the researchers identified patients who were diagnosed with breast cancer at a Commission on Cancer–accredited center from January 1, 2004, through December 31, 2010. Patients who had an excisional biopsy were excluded, “because this cohort would be expected to have a higher-than-average repeat surgery rate,” the authors explained. “Patients who underwent neoadjuvant therapy were also excluded because of the variability in response to neoadjuvant therapy that could influence surgical choice.”

Consensus Guidelines The data from their study can, the authors concluded, “be used to further support the vitally important adoption of guidelines regarding re-excision after initial breast-conservation surgery. Standard definitions of adequate margins, as set forth in the consensus guidelines by the Society of Surgical Oncology and the American Society for Radiation Oncology, and the indications for re-excision will decrease the wide variation in repeat surgery rates.” Those consensus guidelines encourage “adoption of ‘no tumor on ink’ as the standard definition of a negative margin for invasive stage I and II breast cancer,” as noted in an accompanying editorial. Wilke et al “were unable to obtain exact pathologic margin width, but more than 92% of the patients had negative margins, indicating that a sig-

nificant percentage of those undergoing additional operations had margins that were ‘negative on ink,” noted Julie A. Margenthaler, MD, of Washington University School of Medicine in St. Louis, and Aislinn Vaughan, MD, of Sisters of St. Mary’s Breast Care, St Charles, Missouri. Calling for rapid adoption of the consensus guidelines, Drs. Margenthaler and Vaughn, stated: “We have robust evidence that additional operations for close, but negative, margins do not result in better outcomes. However, additional operations increase health-care costs, misuse of resources, patient anxiety, and delay in adjuvant therapy. With more than 200,000 new invasive breast cancers diagnosed each year, a staggering number of women are undergoing procedures that are unnecessary and simply wasteful.” n Wilke LG, et al: JAMA Surg. November 12, 2014 (early release online). Margenthaler JA, Vaughan A: JAMA Surg. November 12, 2014 (early release online).

Mammographic Density Is Highly Heritable, Possibly Explaining the Familial Aggregation of Breast Cancer Using a fully automated method to ascertain volumetric mammographic density, a study conducted by the Karolinska Mammography (KARMA) project for risk prediction of breast cancer in Sweden confirmed the high heritability of mammographic density, although estimates were weaker for absolute than for percent dense volume of breast tissue. “These data support the notion that mammographic density is a risk factor under strong genetic influence that may partially explain the familial aggregation of breast cancer,” Judith S. Brand, PhD, of the Karolinska Institutet in Stockholm, and colleagues wrote in the Journal of the National Cancer Institute. “Mammographic density, which reflects the amount of fibroglandular or radiodense tissue in the breast, is a strong determinant of breast cancer risk,” the authors explained. “Although the exact mechanisms underlying the association between mammographic density and breast cancer are not completely understood, both traits share several risk factors, including nulliparity, late age at first birth, and hormone replacement therapy. Apart from an overlap in environmental risk factors, there is also evidence of a shared genetic basis.” Previous studies to investigate the genetic basis of mammographic density have relied on either qualitative or semi-

automated measures. “The main disadvantage of these measures is that they are reader-dependent and do not acknowledge the three-dimensional structure of the breast,” the researchers wrote. “Fully automated measures of volumetric mammographic density may provide more accurate measures, as they incorporate information on breast thickness.”

Study Details and Clinical Implications Heritability of volumetric mammographic density was estimated with a variance component model in a sample of 955 pairs of full or half sisters. For the breast cancer single nucleotide polymorphism analysis, researchers chose a separate independent sample of 4,025 unrelated women who were genotyped. Associations with 82 established breast cancer loci were assessed using linear models, adjusting for age, body mass index, and menopausal status. “Single nucleotide polymorphism analyses were performed in cancer-free women, reducing the likelihood of artificial associations because of confounding by breast cancer,” the researchers noted. Both study populations had a mean age of 54 years at study entry and a mean body mass index of 25 kg/m2. “After multivariable adjustment, heritability estimates (standard error) for percent dense volume, absolute dense volume, and absolute nondense volume were 0.63 (0.06) and 0.43 (0.06) and 0.61 (0.06), respectively (all P < .001),” the authors reported. Percent and absolute dense volumes were associated with two single nucleotide polymorphisms, associations with the absolute dense volume observed in two others, and absolute nondense volume in two additional single nucleotide polymorphisms. “The breast cancer single nucleotide polymorphisms that have been identified to date explain only little of the variation in mammographic density, but the observed associations with individual single nucleotide polymorphisms are relevant, as they provide more insight into the biological mechanisms leading to breast cancer in women with highly dense breasts,” the authors stated. “In addition, the observed breast cancer single nucleotide polymorphism associations with the absolute nondense volume indicate that the shared genetic component with breast cancer is not restricted to dense tissues only.” n Brand JS, et al: J Natl Cancer Inst 106(12):dju334, 2014. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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Perspective Chandrakanth Are, MBBS, MBA, FRCS, FACS continued from page 1

Faulty Communication? We are told that we do not know how to communicate. It must require a highly sophisticated set of skills for someone to cleverly navigate through college/medical school and residency/ fellowship without mastering any communication skills. It is expected that how we communicate needs to evolve to suit the evolving sociocultural fabric of the society. And, yes, some people are not good at communication no matter how much they are taught. But to say that all physicians cannot communicate at all is either a fallacious overreach or a sad testament to the years of rigorous education that now supposedly leaves us incommunicado.

Lack of Teamwork? We are told that we do not work enough in teams. But the field of Medicine is steeped in history, and I do not recall Dr. William Stewart Halsted performing operations by himself. He needed an effective team to function. Nor do I recall Dr. William Osler rounding all by himself. Instead, every picture of those yesteryears depicts a team of people with the physician. We continue to work in teams that include physicians, nurses, nonphysician providers, physiotherapists, pharmacists, occupational therapists, and so on. Yes, teamwork has a different connotation today, with the development of ambulatory services, skilled facilities, visiting nursing services, other out-ofhospital services, and health-care redesign. Yes, there can be more integration such as having nurses, pharmacists, and others joining the ward rounds. That said, physicians continue to work with teams of people in nearly every aspect of what they do, except when they have to fumble with the electronic medical record system. The suggestion that physicians work in a blissful alley of solitariness can be easily dispelled by walking into any operating room or joining any ward rounds where there are more people than we need.

Inappropriate Dress? We are told that we do not dress appropriately. Recently we have been receiving feedback to suggest that our signature white coat is more a haven for filth rather than a picture of health. In point of fact, studies have shown that white coats are good sources and carriers of microorganisms. This has led to demands that we re-

move our white coats as well as the last item of fashion for men—ties. This is based on the presumption that the civilian clothes underneath our white coats are presumably free of microorganisms. I don’t recall any physician sending their civilian clothes to the sterilizer, but should anyone dare question the sterility of our civilian clothes, the consequences may not be particularly appealing.

Lack of Compassion? We are told that we are not compassionate enough. But physicians enter the field because of a burning passion to do something good by healing the sick. Mark Twain once said, “A proficiency in billiards is a sign of misspent youth.” To paraphrase that quip, I would suggest, “A proficient physician is a sign of wasted youth.” Most physicians spend the better part of their youth toiling through 80hour workweeks (and more, in the past) and training to become compassionate

sick. It may be possible to teach physician leaders the required new skill sets, but they need to be taught by the right people with the right background for the right reasons. The current environment of nonphysicians—including football coaches, CEOs of businesses unrelated to health care, and health-care economists who are not physicians—exhorting us and doling out advice on how the medical profession should be run is unprecedented in its scope and scale. Unless this situation is altered, we will indeed be perceived as people without leadership skills, and the profession will be in the control of people who know less about it than physicians do.

Declining Likability? We are told that patients do not like us. A Gallup poll in December 2013 placed doctors fourth on a rating of honesty and ethical standards, behind nurses, pharmacists, and grade-school teachers.1 In

We have been made to believe that nothing we do is going well. But strange as it may sound to those who complain, the medical profession is littered with many successes, even when taken on a conservative scale. —Chandrakanth Are, MBBS, MBA, FRCS, FACS

physicians. It is the joy of nurturing the sick to health that drives physicians to toil beyond what is expected of them. It is the joy of building good physicianpatient relationships that is unique to the profession. Nevertheless, compassion can be hard to come by when physicians are compelled to dedicate no more than 20 minutes per patient, to introduce a computer between themselves and the patient, and to constantly worry about the sword of Damocles known as malpractice hanging over their heads.

Inadequate Leadership? We are told that we do not possess leadership skills. To the contrary, we may have more leaders than we need. Witness the numerous medical societies that have been in existence for several decades and the new ones that pop up on a regular basis. It is likely that we may not have the right type of leadership skills that are required for the present health-care environment, which sometimes is more about business than about treating the

several other polls, physicians continue to be in the top 3 to 5 ranks of the most liked and respected professions. Yes, patients do not like that they have to navigate hospitals that are now like small cities. They do not like the complexity of the bills they receive or that they have to decipher complex insurance regulations. Patients may not particularly like many aspects of the health-care system, but overall, they continue to rate the individual physician highly. These same surveys have shown that members of Congress and lobbyists fall at the bottom of honesty and ethics polls. Ironically, these people thought to be lowest on the honesty and ethics ladder have considerable control over what we do in our profession at the top of the ladder.

Another Perspective In recent times, we have been made to believe that nothing we do is going well. But strange as it may sound to those who complain, the medical profession is littered with many successes, even when taken on a conservative scale.

For example, the 5-year survival rates for cancers of all sites increased from 49% (1975–1977) to 68% (2002–2008), with some cancers (eg, breast) demonstrating rates of nearly 90%.2 Several diseases considered incurable in the past are now curable or close to it. The introduction of minimal-access surgery has benefitted countless millions of people. The average life span of American citizens has also increased over the decades. While new diseases and challenges will always remain, the successes of the past should not be forgotten. Considering all of these achievements, it is not surprising that there is such a large degree of disenchantment with the aforementioned complaints in the physician community.

Call a Spade a Spade To add to these woes, we are now told that we are not even physicians, but rather, providers. I don’t think any of us remembers going to a provider school. I recall going to a medical school (and a good one at that) to train to be a physician. I may be a provider who cares for the sick, but I am still a physician. Coming closer to home, the surgeons among us have been told recently that we are not surgeons but proceduralists (which even the autocorrect option on this word-processing program does not recognize). Procedures are of many kinds, and many people perform them, but it is surgical training that makes a surgeon. Sometimes it is better to call a spade a spade instead of calling it a “manual earth restructuring implement.” So instead of calling physicians something else, let us just address them as physicians. That is what patients want and need to know as well. The next time you see a physician, address him or her as just that—a physician. You will witness a sense of sublime but potent external pride that emanates from a deeply seated internal passion for the profession. If you don’t sense that, you may want to return to another decades-long amnestic spell and try your luck the next time you wake up. n

Disclosure: Dr. Are reported no potential conflicts of interest.

References 1. Gallup: Honesty/ethics in professions. Conducted December 5–8, 2013. Available at www.gallup.com/poll/1654/ honesty-ethics-professions.aspx. Accessed July 14, 2014. 2. American Cancer Society: Cancer Facts & Figures 2013. Available at www. cancer.org. Accessed July 14, 2014.

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The ASCO Post | JANUARY 25, 2015 AVASTIN® (bevacizumab)

Letters to the Editor

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

Better Studies Needed to Dispel Confusion Over When to Refer a Patient to Hospice

read the article on “Private Payer and Academic Center Data Capture Inappropriate Use of End-of Life Care” (The ASCO Post, December 15, 2014, page 11). The data highlight Dr. Deborah Schrag’s notion that there is “ample evidence of overuse of intensive care at the end of life.” However, there is a flaw in the argument that there is overuse of intensive care at the end of life. In real life, we never know when a patient will die or live on in response to a therapeutic intervention. Studying retrospective data that includes only deceased

will live to survive many months to years. By counting only the patients who died and not counting those who survived in the data, you do an injustice to the survivors, health-care workers, and future potential survivors. We need better-designed studies before we continue to propagate the notion that any cancer patient who suffers a drawback during therapy should immediately be referred to hospice. Clearly, there are situations when the patient should be referred to hospice. Until we have better studies to

Until we have better studies to identify when it’s the right time to refer a patient to hospice, I believe it’s best to let the patient and her doctor make that decision. —Armando Armas, MD

individuals and deriving conclusions from this information are not statistically or ethically valid. To prove that there is “ample evidence of overuse of intensive care at the end of life,” you need to do a prospective study looking at whether or not intensive care of a critically ill population of similarly matched cancer patients vs hospice care yields worse results as measured by endpoints of quality of life and extension of life-years. The problem is that given the broad spectrum of tumor heterogeneity, it’s difficult to predict which patients with cancer will respond favorably to therapy. As often is the case, these patients are immunocompromised and often become septic. Many will die despite intensive care, but many

identify when it’s the right time to refer a patient to hospice, I believe it’s best to let the patient and her doctor make that decision. Flooding the journals with skewed studies and constantly second-guessing health-care providers are only adding to the confusion families and patients experience every day and could lead many otherwise hopeful patients to throw in the towel prematurely. It may also cause patients to lose faith in their providers. n —Armando Armas, MD Valley View Hospital Glenwood Springs, Colorado Disclaimer: This letter represents the views of the authors and may not necessarily represent the views of ASCO.

ASCO Announces Major Steps in Development of CancerLinQ™

he American Society of Clinical Oncology (ASCO) announced that its wholly owned subsidiary, CancerLinQ LLC, will use the SAP HANA® platform in the development of ASCO’s CancerLinQ™. CancerLinQ is a groundbreaking health information technology platform that will harness Big Data to deliver high-quality care to patients with cancer. It is one of the only major cancer data initiatives being developed and led by physicians with the primary purpose of improving patient care. SAP HANA is a flexible, multipurpose, in-memory data

management and application platform. By providing advanced capabilities, such as predictive text analytics, spatial processing, and data virtualization on the same architecture, it further simplifies application development and processing across big-data sources and structures. This makes SAP HANA a highly suitable platform for building and deploying next-generation, realtime applications and analytics. The first version of CancerLinQ is scheduled for release in late 2015. For more information, visit CancerLinQ.org. n

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 3.2%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occur up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 1.5 Persistent, Recurrent, or Metastatic Carcinoma of the Cervix Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix. [See Clinical Studies (14.6).] 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations and Fistulae Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 3.2% across clinical studies. [See Adverse Reactions (6.1).] From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in <1% of Avastin‑treated patients. The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin. Permanently discontinue Avastin in patients with gastrointestinal perforation. In Avastin clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer but were also reported less commonly in patients with other types of cancer. In a cervical cancer trial (Study 9), the incidence of gastrointestinal‑vaginal fistulae was 8.2% in Avastin‑treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Non‑Gastrointestinal Fistulae Serious and sometimes fatal fistula formation involving tracheo‑ esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. Uncommon (<1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post‑marketing experience. Most events occurred within the first 6 months of Avastin therapy. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), 1.8% of Avastin‑treated patients and 1.4% of control patients were reported to have had non‑gastrointestinal vaginal, vesical, or female genital tract fistulae. Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.3 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).] 5.4 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 0.4 to 6.9 %. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑ squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

AVASTIN® (bevacizumab) In clinical studies in non−small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%−5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3−4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Venous Thromboembolic Events Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade ≥ 3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. Permanently discontinue Avastin in patients with life‑threatening (Grade 4) VTE, including pulmonary embolism. [See Dosage and Administration (2.4), Adverse Reactions (6.1).] 5.7 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.8 Posterior Reversible Encephalopathy Syndrome (PRES) PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of PRES. Discontinue Avastin in patients developing PRES. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing PRES is not known. [See Dosage and Administration (2.4).] 5.9 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).] Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] 5.10 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.11 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations and Fistulae [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Non-Gastrointestinal Fistulae [See Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Venous Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Posterior Reversible Encephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.9).] • Infusion Reactions [See Dosage and Administration (2.4), Warnings and Precautions (5.10)] • Ovarian Failure [See Warnings and Precautions (5.11), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4817 patients with CRC, non‑squamous NSCLC, glioblastoma, mRCC, or cervical cancer, including controlled (Studies 1, 2, 4, 5, 8 and 9) or uncontrolled, single arm trials (Study 6) treated at the recommended dose and schedule for a median of 6 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 59 years), 44% male and 85% White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of

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Arm 1 IFL+ Placebo (n = 396) NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

AVASTIN® (bevacizumab) and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo Preferred terma (n = 304) Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Arm 2 IFL+ Avastin (n = 392)

74%

87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) 55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

26% 1%

32% 6%

40% 32% 25% 6% 6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/ embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and PRES (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). Persistent, Recurrent, or Metastatic Carcinoma of the Cervix All grade adverse reactions were collected in Study 9. Grade 1‑4 adverse reactions occurring where the incidence difference is ≥ 5% in patients receiving Avastin plus chemotherapy compared to chemotherapy alone are presented in Table 4. Table 4 NCI‑CTC Grades 1‑4 and 3‑4 Adverse Reactions in Study 9 (Incidence Difference of ≥ 5% Between Treatment Arms in Chemo + Avastin vs. Chemo Alone) Grade 1‑4 Grade 3‑4 reactions reactions Chemo Chemo+ Chemo Chemo+ Alone Avastin Alone Avastin (n=222) (n=218) (n=222) (n=218) Metabolism and Nutrition Disorders Decreased Appetite 26% 34% Hyperglycemia 19% 26% Hypomagnesemia 15% 24% Hyponatremia 10% 19% Hypoalbuminemia 11% 16% General Disorders and Administration Site Conditions Fatigue 75% 80% Edema Peripheral 22% 15% Investigations Weight Decreased 7% 21% Blood Creatinine Increased 10% 16% Infections and Infestations Urinary Tract Infection 14% 22% Infection 5% 10% Vascular Disorders Hypertension 6% 29% 0.5% 11.5% Thrombosis 3% 10% 2.7% 8.3% Nervous System Disorders Headache 13% 22% Dysarthria 1% 8% Gastrointestinal Disorders Stomatitis 10% 15% Proctalgia 1% 6% Anal Fistula — 6% Blood and Lymphatic System Disorders Neutropenia 6% 12% Lymphopenia 5% 12% Psychiatric Disorders Anxiety 10% 17% Reproductive System and Breast Disorders Pelvic Pain 8% 14% Respiratory, Thoracic and Mediastinal Disorders Epistaxis 1% 17% Renal and Urinary Disorders Proteinuria 3% 10% Grade 3 or 4 adverse reactions occurring at a higher incidence ( ≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone were abdominal pain (11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%), proctalgia (2.8% vs. 0%), urinary tract infection 8.3% vs. 6.3%), cellulitis (3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%), hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8% vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic pain (5.5% vs. 1.4%). There were no Grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, PRES, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort

AVASTIN® (bevacizumab) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.11), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients. 17 PATIENT COUNSELING INFORMATION Advise patients: • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated. • To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting. • Of increased risk of wound healing complications during and following Avastin. • Of increased risk of an arterial thromboembolic event. • Of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following last dose of Avastin. • Of the increased risk for ovarian failure following Avastin treatment.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

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Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

T:13"

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.11), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized,

AVASTIN® (bevacizumab) double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

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AVASTIN® (bevacizumab) 9 doses of Avastin, 337 mRCC patients who received a median of 16 doses of Avastin, and 218 cervical cancer patients who received a median of 6 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, and 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. There were no patients with Grade 5 VTE. [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%. Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.9).]

Now Approved in Cervical Cancer for women with persistent, recurrent, or metastatic disease Avastin plus chemotherapy demonstrated a statistically significant increase in median OS vs chemotherapy alone in the GOG 240 study (16.8 vs 12.9 months)1

3.9-month increase

1.0

in median OS (HR=0.74 [95% CI, 0.58–0.94], P=0.0132)

Proportion Surviving

0.8 0.6

Avastin plus chemotherapy (n=227) Chemotherapy alone (n=225)

0.4 0.2 0

Months Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. OS=overall survival; HR=hazard ratio; CI=confidence interval.

Indication

Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix.

Most common adverse events

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 3.2% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 6.9% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — GI fistulae (up to 2%) — Non-GI fistulae (≤1.8%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — GI-vaginal fistulae occurred in 8.2% of patients in a cervical cancer trial — Venous thromboembolism (grade 3–4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with Avastin — Hypertension (grade 3–4, 5%–18%) — Posterior reversible encephalopathy syndrome (PRES) (<0.5%)

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

AVA0002613100

Printed in USA.

(08/14)

Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In CC, grade 3 or 4 adverse reactions in study GOG 240, occurring at a higher incidence (≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone, were abdominal pain (11.9% vs 9.9%), diarrhea (5.5% vs 2.7%), anal fistula (3.7% vs 0%), proctalgia (2.8% vs 0%), urinary tract infection (8.3% vs 6.3%), cellulitis (3.2% vs 0.5%), fatigue (14.2% vs 9.9%), hypertension (11.5% vs 0.5%), thrombosis (8.3% vs 2.7%), hypokalemia (7.3% vs 4.5%), hyponatremia (3.7% vs 1.4%), dehydration (4.1% vs 0.5%), neutropenia (7.8% vs 4.1%), lymphopenia (6.0% vs 3.2%), back pain (5.5% vs 3.2%), and pelvic pain (5.5% vs 1.4%). There were no grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. CC=persistent, recurrent, or metastatic cervical cancer. Reference: 1. Avastin Prescribing Information. Genentech, Inc. August 2014.