TAP Vol 6 Issue 4 by Harborside Press LLC

Gastrointestinal Cancers

4, 12–16

| Oncology Drug Approvals

33, 36–38, 76

| Cancer Documentary to Air on PBS

VOLUME 6, ISSUE 4

MARCH 10, 2015

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

Genitourinary Cancers Symposium

Big Data and the Promise of Precision Medicine in Cancer

Active Surveillance in Intermediate-Risk Prostate Cancer Called Into Question By Alice Goodman

By Peter Paul Yu, MD, FACP, FASCO

new study presented at the 2015 Genitourinary Cancers Symposium calls into question the use of active surveillance in patients with intermediaterisk prostate cancer. Patients with intermediate-risk prostate cancer managed with active surveillance had almost a four times higher risk of prostate cancer– specific death over 15 years compared with low-risk prostate cancer managed with active surveillance.1 This single-center study is the first to analyze longterm outcomes of patients with intermediate-risk prostate cancer on active surveillance.

Surprising Finding The current National Comprehensive Cancer Network (NCCN) Guidelines call for observation (ie, active surveillance) or radiation therapy with or without androgen-deprivation therapy for 4 to 6 months for men with intermediate-risk prostate cancer and a life expectancy of less than 10 years.

The current study suggests that these guidelines should be reconsidered. “This study validates active surveillance for lowrisk patients with prostate cancer. We were surprised by the greater risk of prostate cancer death in the D. Andrew Loblaw, MD intermediate-risk patients assigned to active surveillance,” stated senior author D. Andrew Loblaw, MD, Sunnybrook Health Sciences Center in Toronto. “Caution should be exercised if active surveillance were to be implemented for intermediaterisk patients,” stated lead author Hima Bindu Musunuru, MD, also of Sunnybrook Health Sciences Center. continued on page 3

World Oncology Forum

Addressing the Global Cancer Burden

continued on page 114

Dr. Yu is President of ASCO for 2014–2015 and Director of Cancer Research at Palo Alto Medical Foundation in California.

MORE IN THIS ISSUE

By Ronald Piana ince 1990, the annual global death toll from cancer has risen about 40%, and that number is projected to increase from the current level of approximately 8 million cancer deaths per year to more than 13 million by 2030. The poorer, resource-challenged regions of the world will suffer a disproportionate amount of this growing cancer burden. This lopsided cancer burden on the globe’s low-income populations prompted the European School of Oncology to convene the first World Oncology Forum (WOF) in Lu-

recision medicine—and its promise to revolutionize how we understand disease and care for our patients—is a concept that oncology has understood and embraced for well over a decade. But millions of Americans recently heard about the concept for the first time when President Obama announced a high-profile Precision Medicine Initiative during his annual State of the Union address in January. The President has called on Congress to allocate $215 million in federal funds in the next fiscal year to back this effort. The lion’s share of the funding would be used to establish a new research cohort of a million or more people

gano, Switzerland, on October 12, 2012. The forum was based around a central question: Are we winning the war on cancer?

10-Point Action Plan

The WOF resulted in a 10-point action plan aimed at making government deliver on a commitment it made at the World Health Assembly in May 2012 to have a 25% reduction of preventable deaths from noncommunicable disease by 2025. The 10-point plan covered the following policy headings: prevent preventIn order to launch a global cancer able cancers, treat treatable cancers, support all those fund, similar to the one for AIDS, we living with cancer, accelerneed strong political pressure—and ate finding cures for cancers that are not yet curable, and we are working on that. However, it strengthen policy framewill require concerted and bold action works and health systems. Building on the success at national and international levels. of this forum, the second —Franco Cavalli, MD

Oncology Meetings Coverage Genitourinary Cancers Symposium �� 1, 3 Gastrointestinal Cancers Symposium �� 4, 12–16 World Oncology Forum �� 21 SABCS ��22 ASH Annual Meeting �� 23–25 Mario Sznol, MD, on Renal Cell Cancer �� 31 Direct From ASCO �� 54–57 High-Risk Breast Cancer ��62 In Memoriam: Lee W. Wattenberg, MD �� 108 Alison G. Freifeld, MD, on Measles Risks in Cancer �� 109

continued on page 21

March Is Colorectal and Kidney Cancers Awareness Month

A Harborside Press® Publication

The ASCO Post | MARCH 10, 2015

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PAGE 3

Genitourinary Cancers Symposium Active Surveillance continued from page 1

Study Details

The prospective study included 945 patients managed with active surveillance between 1995 and 2013 at Sunnybrook Health Sciences Center: 237 (23.9%) with intermediate-risk and a median follow-up of 6.9 years and 708 with low-risk prostate cancer and a median follow-up of 6.4 years. The median treatment-free interval

tancy. Further, the risk of prostate cancer–specific death at 15 years was 3.75 times higher for intermediate-risk patients compared with low-risk patients at the same time point: 11.5% vs 3.7%, respectively. The subcategorization of intermediate-risk patients according to molecular and/or clinical markers is an ongoing area of study, said Charles Ryan, MD, ASCO Expert and GU News Planning Team Member. He served as

This study validates active surveillance for low-risk patients with prostate cancer. We were surprised by the greater risk of prostate cancer death in the intermediaterisk patients assigned to active surveillance. —D. Andrew Loblaw, MD

for intermediate-risk patients was 12.3 years. Patients with progressive disease, reflected by a prostate-specific antigen (PSA) doubling time of less than 3 years, were offered radiation or surgery; 86 intermediate-risk patients took advantage of this treatment (mainly radiation, Dr. Loblaw noted). For intermediate-risk patients, 10-year and 15-year overall survival rates were 68.4% and 50.3% vs 83.6% and 68.8% for low-risk patients (P < .0001). The 10- and 15-year cancerspecific survival rates were 95.5% and 88.5% for the intermediate-risk cohort, and 98.2% and 96.3% for the lowrisk patients (P = .006). Dr. Loblaw reported that 61% of the intermediate-risk patients were older than age 70. He noted that active surveillance is typically offered to men with shorter life expectancies and other comorbidities. The risk for dying of any cause was twice as high for intermediate-risk patients compared with low-risk patients, reflecting the selection of intermediate-risk patients with lower life expec-

moderator of a premeeting presscast where these data were presented. Dr. Loblaw agreed that the categorization of intermediate-risk patients

Charles Ryan, MD

needs to be further refined. “We think there may be a subgroup of intermediate-risk patients out there who may be safely managed by active surveillance,” he commented.

Favorable vs Unfavorable Intermediate Risk Intermediate-risk patients are a heterogeneous group of patients. Zumsteg and colleagues have proposed a new risk classification system for therapeutic decision-making for intermediate-risk patients under-

Active Surveillance in Intermediate-Risk Prostate Cancer ■■ Current NCCN Guidelines offer observation as a management strategy for patients with intermediate-risk prostate cancer and a life expectancy of less than 10 years; a study suggests that these guidelines need to be revisited. ■■ At 15 years after diagnosis, men with intermediate-risk prostate cancer were almost four times more likely to die of prostate cancer than men with lowrisk prostate cancer managed with active surveillance.

PROTECT Trial

Jason Efstathiou, MD, PhD

going external-beam radiotherapy.2 They defined favorable intermediate risk as a Gleason score of 3+4 or less, a percentage of positive biopsy cores less than 50%, and, at most, one National Comprehensive Cancer Network (NCCN) determinant of intermediate-risk prostate cancer. The criteria proposed by Zumsteg et al have not been incorporated into official guidelines. Weighing in on the question of whether there may be some intermediate-risk patients who can be safely managed with active surveillance, Jason A. Efstathiou, MD, DPhil, Associate Professor of Radiation Oncology at Massachusetts General Hospital, Harvard Medical School, in Boston, said that management of intermediaterisk patients must be tailored to the individual. “Not all intermediate-risk patients are the same. For example, a patient with 12/12 positive cores, Gleason score of 4+3, and a PSA of 19.9 ng/ mL is not the same as an intermediate-risk patient with < 5% of 1 core involved, Gleason score 3+4, and PSA of 5 ng/mL. Intermediate risk is a spectrum. Some investigators have attempted to stratify intermediate risk based on T stage, Gleason score, percent of cores involved, percent of each core involved, and PSA level,” Dr. Efstathiou said. “There are some intermediate-risk patients who may be appropriate candidates for active surveillance, especially if they have a more limited life expectancy due to age or comorbidities. That being said, intermediaterisk prostate cancer can progress, and the majority of these patients do need definitive therapy aimed with curative intent,” he continued. This prospective study by Loblaw and colleagues will need prospective validation, and there are ongoing trials addressing this question, he noted.

The PROTECT trial, which randomly assigned 250,000 men to PSA screening or not, may provide some clues. The screening arm will be stratified according to low and intermediate risk, and patients will be randomized to receive radical prostatectomy, external-beam radiation with or without androgen-deprivation therapy, or active surveillance. Dr. Efstathiou noted that the availability of genomic and other biomarkers would be ideal in this setting, but in his opinion, a number of standard markers are already available to riskstratify intermediate-risk patients. These include age, comorbidities, life expectancy, stage, grade, number of cores involved, percentage of cores involved, and PSA level. In addition, he said that advances in imaging, such as multiparametric endorectal magnetic resonance imaging, can help determine disease volume and potentially aggressiveness, especially in areas of the prostate not accessible by the biopsy needle. “The totality of data from these clinical factors and assessments can give us a good idea of which intermediate-risk patients are of more favorable risk and which are not,” he stated. n

Disclosure: Dr. Loblaw reported receiving honoraria from Amgen, Astellas Pharma, AstraZeneca, and Sanofi, a consulting or advisory role with Amgen, Astellas Pharma, Janssen Oncology, and Sanofi, research funding (to his institution) from Paladin and Sanofi, and support for travel, accommodations, and expenses from Amgen, Janssen Oncology, and Paladin. In addition, he reported honoraria and/or a consulting/advisory role for an immediate family member from Bristol-Myers Squibb, Elekta, GlaxoSmithKline, Jannssen Oncology, Merck, Novartis, Paladin, Roche, Sanofi. The other study authors reported no potential conflicts of interest.

References 1. Musunuru HB, Klotz L, Vespirini D, et al: Cautionary tale of active surveillance in intermediate-risk patients: Overall and cause-specific survival in the Sunnybrook experience. 2015 Genitourinary Cancers Symposium. Abstract 163. Presented February 26, 2015. 2. Zumsteg ZS, Spratt DE, Pei I, et al: A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing doseescalated external beam radiation therapy. Eur Urol 64:895-902, 2013.

The ASCO Post | MARCH 10, 2015

PAGE 4

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

New Data Reported in Colorectal, Gastric, and Pancreatic Cancers By Caroline Helwick

he 2015 Gastrointestinal Cancers Symposium, held January 15–17 in San Francisco, attracted almost 4,000 attendees, who heard or viewed data from nearly 800 scientific abstracts and lectures. Here are our summaries of some of the many important developments from the meeting.

increase in febrile neutropenia, serious adverse events, or treatment-related deaths. The intensity of FOLFOXIRI precludes its use in all patients, acknowledged Dr. Cremolini, who suggested that it is probably not suitable for those older than age 75 or younger patients with poor performance status.

Bevacizumab Plus Intensive Chemotherapy

High Vitamin D Levels and Survival

Updated results from the Italian phase III TRIBE study indicate that bevacizumab (Avastin) is more effective in metastatic colorectal cancer when combined with the more-intensive FOLFOXIRI regimen (leucovo-

Newly diagnosed colorectal cancer patients with high vitamin D levels prior to treatment lived longer than those with the lowest levels in a prospective analysis of data from a phase III study,2 adding to a growing body of evidence

FOLFOXIRI plus bevacizumab represents a valuable option for the upfront treatment of metastatic colorectal cancer. —Chiara Cremolini, MD

rin, fluorouracil [5-FU], irinotecan, oxaliplatin) than FOLFIRI (leucovorin, 5-FU, irinotecan).1 FOLFOXIRI plus bevacizumab extended overall survival by 4 months and doubled the 5-year survival rate vs bevacizumab plus FOLFIRI, reported Chiara Cremolini, MD, of the Santa Chiara Hospital in Pisa, Italy. The study evaluated 508 patients randomly assigned to bevacizumab plus either FOLFOXIRI or FOLFIRI for 6 months, after which they received maintenance bevacizumab with 5-FU/ leucovorin. After a median follow-up of about 4 years, median overall survival was 29.8 months in the FOLFOXIRI arm vs 25.8 months in the FOLFIRI arm (hazard ratio [HR] = 0.80, P = .030). “Looking at the final part of the shape of the survival curves, we see that the benefit of FOLFOXIRI plus bevacizumab increases over time, and the estimated 5-year survival is 24.9% vs 12.4%, which is double that of FOLFIRI plus bevacizumab,” she said. “Based on these results, FOLFOXIRI plus bevacizumab represents a valuable option for the upfront treatment of metastatic colorectal cancer.” FOLFOXIRI was associated with more grade 3/4 diarrhea, mucositis, neuropathy, and neutropenia but no

that vitamin D has an antitumor effect, said Kimmie Ng, MD, MPD, of DanaFarber Cancer Institute and Harvard Medical School, Boston. “The ultimate goal is to translate this research into an effective intervention for patients,” she said. Dr. Ng and colleagues measured the plasma levels of vitamin D (25-hydroxyvitamin D) in 1,043 patients en-

adjusted for other prognostic factors and healthy behaviors, patients with the highest levels had a median overall survival of 32.6 months, compared with 24.5 months for those in the lowest quintile (HR = 0.67, P = .002), and a longer time to disease progression, 12.2 months vs 10.1 months (HR = 0.80, P = .02). The benefit was seen across the three treatment arms, did not differ by KRAS status, and was not ameliorated after adjustment for other prognostic factors. Dr. Ng acknowledged that the findings do not indicate that raising a low baseline vitamin D level will improve outcomes. Randomized studies are underway to evaluate the benefit of vitamin D supplementation before and after a cancer diagnosis.

Pembrolizumab Active in Gastric Cancer Among metastatic gastric cancer patients treated with the anti–programmed cell death (PD-1) monoclonal antibody pembrolizumab (Keytruda), a trend was observed between level of expression of the programmed death ligand PD-L1 and outcomes, KEYNOTE-012 investigators reported.3 KEYNOTE-012 evaluated the immune checkpoint inhibitor in a variety of solid tumors. The gastric cancer cohort included 39 patients whose tumors expressed PD-L1 (a requirement for eligibility), which comprised 40% of those screened. These patients mostly had received prior chemotherapy. Patients received pembrolizumab at 10 mg/kg every 2 weeks for up to 24 months. The primary endpoint was objective response rate by independent central review. At 8.8 months’ follow-up, there was “strong evidence

Kei Muro, MD

of anticancer activity,” Kei Muro, MD, of Aichi Cancer Center Hospital in Nagoya, Japan, reported. Responses were observed in 22.2% by central review and in 33.3% by investigator review. These eight responses were all partial responses; stable disease was observed in another five patients (and in four patients, response was not determined). Approximately 53% of patients had some degree of tumor shrinkage. “Six of the eight responders were still responding at the time of this analysis,” Dr. Muro noted. The median time to response was “rapid” at 8 weeks, and median response duration was 24 weeks (range, 8 to 33-plus). Median progression-free survival was 1.9 months. At 6 months, the progression-free survival rate was 24% and overall survival rate was 69%. Median overall survival has not been reached. Patients with high PD-L1 expression (staining in the stroma or in ≥ 1% of tumor cells) showed a trend toward improved outcomes (ie, better response rates, progression-free survival, and overall survival). Dr. Muro acknowledged, however, the current trend was “weak” and requires further investigation. The phase II KEYNOTE-059 study of pembrolizumab monotherapy or in combination with cisplatin plus 5-FU for advanced gastric cancer will be initiated early in 2015.

GI Cancers Symposium Briefs Kimmie Ng, MD, MPD

rolling in the Cancer and Leukemia Group B (CALGB) 80405 trial, which evaluated three different first-line treatments for advanced colorectal cancer. Their vitamin D levels ranged from a median low of 8 ng/mL to a median high of 27.5 ng/mL. The median for all patients was 17.2 ng/mL, which is below the recommended healthy range of 20 to 30 ng/mL. Divided into quintiles according to their baseline vitamin D level, and

■■ Updated results from TRIBE showed that bevacizumab is more effective when combined with FOLFOXIRI than with FOLFIRI, for metastatic colorectal cancer. ■■ In a prospective analysis from CALGB 80405, newly diagnosed colorectal cancer patients with high vitamin D levels prior to treatment lived longer than those with the lowest levels. ■■ Activity was shown for the PD-1 inhibitor pembrolizumab in gastric cancer, with a trend for better outcomes in patients whose tumors were expressing the ligand PD-L1. ■■ The addition of MM-398, a nanoliposomal encapsulation of irinotecan, to fluorouracil/leucovorin improved overall survival in metastatic pancreatic cancer patients previously treated with gemcitabine, in an expanded prespecified per-protocol analysis of the NAPOLI-1 trial.

ASCOPost.com | MARCH 10, 2015

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Gastrointestinal Cancers Symposium Nanoliposomal Irinotecan in Metastatic Pancreatic Cancer The addition of MM-398, a nanoliposomal encapsulation of irinotecan, to 5-FU/leucovorin was shown to improve overall survival in metastatic pancreatic cancer patients previously treated with gemcitabine, in an expanded prespecified per-protocol analysis of the NAPOLI-1 trial presented by Li-Tzong Chen, MD, of the National Institute of Cancer Research, National Health Re-

Li-Tzong Chen, MD

search Institutes, Taiwan.4 Investigators had previously reported data from the intent-to-treat population, showing that MM-398 plus 5-FU/leucovorin significantly improved survival.5 “Here, in the per-protocol population, the MM-398 plus 5-FU/leucovorin combination regimen achieved a median overall survival of 8.9 months,

vs 5.1 months with 5-FU/leucovorin alone (HR = 0.47, P = .0018),” Dr. Chen reported. MM-398, liposomal irinotecan injection, contains about 80,000 molecules of irinotecan stably encapsulated in a 100nm liposome, circulates more extensively, and achieves higher levels of the active metabolite, SN-38, in the tumor, compared to conventional irinotecan. The drug has received Fast Track status from the U.S. Food and Drug Administration. With overall survival as the primary endpoint, the open-label study randomly assigned 417 patients to one of these arms: (1) MM-398 (120 mg/m2 every 3 weeks) as a single agent; (2) 5-FU (2,000 mg/m2 over 24 hours) plus leucovorin (200 mg/m2 over 30 min) for 4 weeks followed by 2 weeks off; or (3) MM-398 (80 mg/m2 every 2 weeks) prior to 5-FU (2,400 mg/m2 over 46 hours) and leucovorin (400 mg/m2 over 30 min). The intent-to-treat population included all patients who were randomly assigned to either MM-398–plus– 5‑FU/leucovorin or 5-FU/leucovorin– alone arms (N = 236). The per-protocol population included patients who received at least 80% of the target dose in the first 6 weeks (N = 137); and the non–per-protocol population (N = 99)

were those who did not qualify for perprotocol analysis. While these results in the per-protocol population were anticipated, “what was more surprising,” according to Dr. Chen, was the overall survival benefit in the non–per-protocol population, the combination arm vs the control arm: 4.4 months vs 2.8 months (HR = 0.56, P = .0365). The safety profile of the combination regimen was considered manageable, with the most frequent adverse events being neutropenia, fatigue, diarrhea, and vomiting. n

Disclosure: Dr. Cremolini is a consultant for Roche, Bayer, and Amgen. Drs. Ng and Muro reported no potential conflicts of interest. Dr. Chen has received honoraria from PharmaEngine, Novartis, Merck Serono, TTY, Taiho, Ono, and Five Prime and research medications for investigator-initiated studies from PharmaEngine, Sanofi, Merck Serono, TTY, Taiho, Novartis, and Bayer.

References 1. Cremolini C, Loupakis F, Masi G, et al: FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: Updated survival results of the phase III TRIBE trial by the GONO group. 2015 Gastrointestinal Cancers Symposium. Abstract 657. Presented January 17, 2015.

2. Ng K, Venook AP, Sato K, et al: Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405. 2015 Gastrointestinal Cancers Symposium. Abstract 507. Presented January 17, 2015. 3. Muro K, Bang Y-J, Shankaran V, et al: Relationship between PD-L1 expression and clinical outcomes in patients with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab in KEYNOTE-012. 2015 Gastrointestinal Cancers Symposium. Abstract 3. Presented January 15, 2015. 4. Chen L-T, Von Hoff DD, Li C-P, et al: Expanded analyses of NAPOLI-1: Phase 3 study of MM-398 with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer previously treated with gemcitabinebased therapy. 2015 Gastrointestinal Cancers Symposium. Abstract 234. Presented January 15, 2015. 5. Von Hoff D, Li CP, Wang-Gillam A, et al: NAPOLI-1: Randomized phase 3 study MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer progressed on or following gemcitabine-based therapy (Abstract O-0003). Ann Oncol 25(suppl 2):105106, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Giulio Genovese, PhD, on Clonal Hematopoiesis see page 46

Richard L. Schilsky, MD, FACP, FASCO, on ASCO’s Molecular Oncology Tumor Board Series see page 60

Stephen M. Ansell, MD, PhD, on PD-1 Blockade With Nivolumab in Relapsed/Refractory Hodgkin’s Lymphoma see page 65

Ezekiel J. Emanuel, MD, PhD, on Patient Demands see page 69

Robert I. Haddad, MD, on Head and Neck Cancer Treatment in 2015 see page 71

Carl Freter, MD, PhD, FACP, on Hematologic Malignancies see page 75

Arif Kamal, MD, FACP, on Improving Palliative Care in Oncology see page 83

Barak Goodman and Ken Burns, on PBS Documentary The Emperor of All Maladies see page 92

Visit The ASCO Post online at ASCOPost.com

NOW APPROVED

Indication OPDIVO速 (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. 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.

Select Important Safety Information OPDIVO is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, other adverse reactions; and embryofetal toxicity.

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 | MARCH 10, 2015

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Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Inhibiting the MET Pathway in Gastroesophageal Cancer: Hits and Misses By Caroline Helwick

he MET pathway appears to be important in gastroesophageal cancers, but response to a targeted agent may depend on the class of drugs. A robust response to the novel small-molecule MET inhibitor AMG 337 was observed, but a monoclonal antibody targeting MET fell flat, in studies reported at the 2015 Gastrointestinal Cancers Symposium. The MET signaling pathway is abnormal in a variety of cancers, and aberrant upregulation of MET has been associated with a poor prognosis. MET signaling stimulates cell growth, invasion, and metastasis and promotes resistance to apoptosis, making MET an attractive therapeutic target, speakers said.

Potent Tyrosine Kinase Inhibitor Eunice Kwak, MD, PhD, of Massachusetts General Hospital in Boston, called responses to AMG 337 monotherapy “dramatic” in patients with

MET-amplified gastric, esophageal, and gastroesophageal junction tumors.1 AMG 337 is a potent and highly selective inhibitor of wild-type and some mutated forms of MET. In laboratory studies, cancer cells showing MET gene amplification demonstrated sensitivity to the drug, whereas other cells appeared insensitive. The dose escalation and dose expansion study reported by Dr. Kwak included 90 patients with a variety of advanced solid tumors, who had received a median of two prior lines of therapy. Of this population, 21 had gastric, esophageal, or gastroesophageal junction tumors. Of the 90 patients overall, MET gene amplification was observed in 19 patients (21%).

Outcomes ‘Dramatic’ in MET-Amplified Subset Of the 21 patients with gastric, esophageal, or gastroesophageal junc-

EXPERT POINT OF VIEW

affer A. Ajani, MD, Professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, discussed the two studies. He emphasized the impressive cytoreductive activity of AMG 337. “Granted, it was only 13 patients, but in 13 patients, 8 [responders] is a big number,” he said. “The data with AMG 337 are very compelling,” he observed. “It’s really hard to argue against it…. We can say that the biomarker and the drug are good, and this should be pursued further.” Dr. Ajani tempered his enthusiasm, however, by noting that the risk of resistance to small-molecule inhibitors is real and suggested “we start planning to combine molecules.”

The data with AMG 337 are very compelling. Granted, it was only 13 patients, but in 13 patients, 8 [responders] is a big number. —Jaffer A. Ajani, MD

However, this is little reason to anticipate benefits from onartuzumab or the other anti-MET monoclonal antibody, rilotumumab, he said. “The monoclonal antibodies meant to inhibit the MET receptor have not produced desirable results when MET immunohistochemistry positivity is the enrichment biomarker.” “Here, you can say the antibody is good, but the biomarker is not useful, or the biomarker is good, and the antibody is not useful, or you can say both are not useful,” he said. “There is, perhaps, a solution, and that is to develop an antibody/drug conjugate,” a so-called MET bomb, Dr. Ajani suggested. “This could make the drug better and make the biomarker more relevant,” he predicted. n Disclosure: Dr. Ajani reported no potential conflicts of interest.

All of the patients who achieved a response had some sort of MET abnormality in their tumors. This demonstrates that MET is an oncogenic driver in some of these cancers. —Eunice Kwak, MD

tion tumors, 13 have been treated to date. Of this subset, all of whom had MET-amplified tumors, eight patients responded, for an objective response rate of 62% to single-agent treatment, Dr. Kwak reported, labeling this a “dramatic” response to a single agent. Four patients are still on active treatment; one of these patients has responded for 96 weeks, and another has responded for 155 weeks. Among the 90 patients in the entire population, grade ≥ 3 adverse events were reported in 21%, primarily headache (7.8%). About 50% of patients had headaches of varying degrees of severity. Dr. Kwak emphasized the importance of MET amplification in the population. “All of the patients who achieved a response had some sort of MET abnormality in their tumors,” she said. “This demonstrates that MET is an oncogenic driver in some of these cancers.” MET amplification could prove to be a useful biomarker, she said. “If we have robust biomarkers that tell us we have cancers that are being driven by specific signals, it can change the way we think about treating patients, with the goal being that we can make huge— or at least larger—impacts on patient survival,” she pointed out. The daily maximum tolerated dose has been set at 300 mg, and a twice-daily maximum tolerated dose is still being determined. A dose expansion phase will enroll up to 50 patients with METamplified tumors at the maximum tolerated dose. A phase II study of AMG 337 in patients with MET-amplified gastroesophageal junction, gastric, or esophageal cancer or other MET-amplified solid tumors is currently recruiting patients.

Monoclonal Antibody Falls Flat In contrast, the MET-inhibiting fully humanized monoclonal antibody onartuzumab proved ineffective in a phase II study of the drug in combination with FOLFOX (fluorouracil/leucovorin/ox-

aliplatin) in patients with advanced gastroesophageal adenocarcinoma. MET positivity was defined as ≥ 50% moderate-to-high staining for MET by immunohistochemistry.2 “The addition of onartuzumab to modified FOLFOX6 in metastatic gastroesophageal adenocarcinoma did not improve progression-free survival in either an unselected population or in patients with MET-positive tumors, as defined by immunohistochemistry,” said Manish Shah, MD, of NewYorkPresbyterian Hospital, New York. In the multicenter study presented

Manish Shah, MD

by Dr. Shah, 123 patients with metastatic HER2-negative gastroesophageal adenocarcinoma received FOLFOX alone or with onartuzumab (10 mg/kg every 2 weeks) for 12 cycles, followed by onartuzumab monotherapy until disease progression. The primary endpoint was progression-free survival. In the intent-to-treat population, median progression-free survival was 6.77 months in the onartuzumab arm and 6.97 months with FOLFOX alone (hazard ratio [HR] = 1.06, P = .7149). In the MET-amplified population, median progression-free survival was 5.95 and 6.8 months, respectively (HR = 1.38, P = .4514). The stratified HR for progression-free survival in the MET-negative population was 0.99, Dr. Shah reported. In an exploratory analysis by strength of MET staining, “There was no clear signal that very high MET continued on page 12

The ASCO Post | MARCH 10, 2015

PAGE 12

Gastrointestinal Cancers Symposium Biliary Tract Cancer

Targeting Biliary Tract Cancers Through Genomic Profiling By Caroline Helwick

iliary tract cancers are challenging, but a large genomic profiling study has identified potentially clinically relevant genomic alterations in up to twothirds of patients.1 “The diverse landscape of clinically relevant genomic alterations in biliary tract cancers can serve as targets for therapies for these patients and has the potential to improve outcomes for these aggressive malignancies,” said Jeffrey S. Ross, MD, of Albany Medical College in New York. Dr. Ross is also Medical Director of Foundation Medicine, whose assay was used in this study. At the 2015 Gastrointestinal Cancers Symposium, Dr. Ross presented a report on comprehensive genomic profiling of biliary tract cancers, which revealed tumor-specific differences and genomic al-

for this devastating disease,” he said. Biliary tract cancers—which include intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma—are typically refractory to conventional therapies, including cytotoxic chemotherapy and radiation. The proportion of cancer patients who could benefit from comprehensive genomic profiling varies by tumor type, he said. “We have now profiled more than 35,000 solid tumors and uncovered an unexpectedly high frequency of potential therapy-changing genomic alterations, with some tumor types having significantly higher clinically relevant alteration rates and others having lower rates. In biliary tract cancers, the clinically relevant alteration frequency is quite high, especially for the intrahepatic chol-

The diverse landscape of clinically relevant genomic alterations in biliary tract cancers can serve as targets for therapies and has the potential to improve outcomes for patients with these aggressive malignancies. —Jeffrey S. Ross, MD

terations. Such findings could help to select individualized, targeted treatments for patients, either through mechanismdriven clinical trials of novel agents or off-label treatment of available ones. “Given the limited treatment options and poor prognosis of patients with biliary tract cancers, and the diversity of clinically relevant alterations identified, comprehensive genomic profiling appears to have significant potential to maximize the identification of new treatment paradigms and to meet an unmet clinical need

MET Pathway continued from page 11

staining altered survival” with respect to onartuzumab benefit, he said. At the time of data cutoff, only 50% of patients had died. Median overall survival was approximately 11 months in each arm in the intent-to-treat population and approximately 8.5 months in the MET-positive population. Onartuzumab-specific toxicity included edema and venous thromboembolism. “The question now is how to identify MET-driven tumors? Is it immunohis-

angiocarcinomas.” In the current study, two-thirds of patients harbored genomic alterations that could potentially influence treatment, he said.

Genomic Distributions Differed by Tumor Type From the DNA of 554 biliary tract cancer specimens (primary or metastatic), the researchers performed nextgeneration sequencing of all coding exons of 315 cancer-related genes and 47 introns of 19 genes commonly reartochemistry, amplification, or something else?” Dr. Shah suggested. “That’s the main question with MET inhibition moving forward.” n

Disclosure: Dr. Kwak has received research funding from Amgen (via her institution). Dr. Shah has a consulting or advisory role with Lilly and Sanofi-Aventis and has received research funding from Bayer/Onyx, Genentech, and Sanofi-Aventis (all via his institution).

References 1. Kwak EL, LoRusso P, Hamid O, et al: Clinical activity of AMG 337, an oral MET kinase inhibitor, in adult patients with MET-amplified gastroesophageal junction,

EXPERT POINT OF VIEW

ession moderator Laura A. Dawson, MD, of the University of Toronto, commented on this study by Dr. Ross and colleagues for The ASCO Post: “Moving forward, I think we need to change the way we make treatment decisions, no question. Treatment based on profiling is the way of the future. Dr.

At the end of the day, we still need to do clinical trials. We need to learn, in a prospective setting, how this targeting may change outcomes compared to the standard of care. —Laura A. Dawson, MD

Ross’ results are very exciting, but at the end of the day, my bias is that we still need to do clinical trials. We need to learn, in a prospective setting, how this targeting may change outcomes compared to the standard of care. We need to incorporate profiling into trials.” “Off trials,” she added, “we also need a prospective database or registry, where clinicians can share outcome data about their ‘n of ones.’” Unfortunately, we mainly hear about the success stories. Having an actionable mutation does not guarantee that the patient will respond to a targeted therapy, since there are many factors that may impact outcomes, including nontumor factors.” Dr. Ross agreed that “prospective randomized trials are the final determiner” of the success of this approach. One such trial underway is the Lung-MAP study in advanced squamous cell carcinoma. This trial will sequence up to 1,000 tumors a year using the same assay from this study and will assign patients to second-line treatment based on the genetic profile. Many phase I trials are also using sequencing to identify targets and randomize patients to targeted agents or standard of care. n Disclosure: Dr. Dawson reported no potential conflicts of interest.

ranged in cancer. The aim was to identify clinically relevant genetic alterations that could be targeted with current or novel agents. They examined 412 cases of intrahepatic cholangiocarcinoma, 57 cases of extrahepatic cholangiocarcinoma, and 85 cases of gallbladder carcinoma.

Comprehensive genomic profiling revealed many similarities and differences among the three tumor types. “We saw a wide diversity in type of alteration, and small numbers of alterations in a few patients, which create the continued on page 14

MET Inhibition in Gastroesophageal Cancers ■■ The small molecule MET inhibitor AMG 337, as a single agent, produced responses in 8 of 13 patients with advanced gastric, esophageal, and gastroesophageal function cancers whose tumors were MET-amplified. ■■ The monoclonal antibody onartuzumab, on the other hand, did not improve progression-free or overall survival over chemotherapy alone in a similar population. gastric, or esophageal cancer. 2015 Gastrointestinal Cancers Symposium. Abstract 1. Presented January 15, 2015. 2. Shah MA, Cho JY, Huat ITB, et al: Randomized phase II study of FOLFOX

+/- MET inhibitor, onartuzumab, in advanced gastroesophageal adenocarcinoma. 2015 Gastrointestinal Cancers Symposium. Abstract 2. Presented January 15, 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.

GRANIX® is an option in short-acting G-CSF therapy » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)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 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)1 » Now offering a new presentation for self-administration

Indication » GRANIX 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. » 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. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. » 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. » 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® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40582 January 2015.

The ASCO Post | MARCH 10, 2015

PAGE 14

Gastrointestinal Cancers Symposium Biliary Tract Cancers continued from page 12

landscape of attempted or available targeted therapies,” Dr. Ross said. The total numbers of genomic alterations per patient and clinically relevant (ie, “actionable”) alterations were similar among the tumor types. The three malignancies share genom-

ic alterations in cell cycle (CDKN2B) and chromatin remodeling (ARID1A). Intrahepatic cholangiocarcinoma features FGFR fusions, IDH1/2 substitutions, BRAF substitutions, and MET amplification, with a low KRAS-mutation frequency. KRAS mutations are common in extrahepatic cholangiocarcinoma (though far less common than seen

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 nonmyeloid 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 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 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)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] 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.

in pancreatic ductal carcinoma) and uncommon in gallbladder carcinoma. Extrahepatic cholangiocarcinoma and gallbladder carcinoma harbor ERBB2 amplifications (especially gallbladder carcinoma). PIK3CA/mTOR pathway alterations and ERBB2 amplifications occur in approximately the same proportion of gallbladder carci-

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-USapproved 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. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 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 Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an 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 (AUC) 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. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered 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-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

noma patients as breast and upper gastroesophageal carcinoma patients.

Response to Targeted Therapies The presence of actionable alterations qualified patients for treatment with a targeted agent, with many patients achieving durable stable disease. For example, a 67-year-old with metastatic intrahepatic cholangiocarcinoma and a BRAF mutation had a reduction in a liver lesion, from 3.7 cm at baseline to 1.3 cm at 16 weeks, after treatment with a BRAF inhibitor. A patient with gallbladder carcinoma and an FGFR3-TACC3 fusion became stable on dovitinib. A 64-year-old with recurrent gallbladder carcinoma and an ERBB2 amplification had stable disease with trastuzumab (Herceptin) and chemotherapy.

Next Steps Dr. Ross was asked whether there was concordance between primary and metastatic lesions. Although this information is not available from the current study, he and his team have studied this topic in other series. “We have found that when patients are not treated with a targeted agent, there are very few changes in driver alterations. If patients are treated with a targeted agent— for example, erlotinib if they have EGFR alterations—we later pick up the T790M alteration, which we did not identify at the start of treatment,” he said. “We think that targeted therapy may create genomic stress on the tumor, leading to clonal evolution and resistance mutations.” n

Disclosure: Dr. Ross is a founding strategic advisor and Medical Director of Foundation Medicine, Inc.

Reference 1. Ross JS, Wang K, Catenacci DVT, et al: Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and genomic alterations. 2015 Gastrointestinal Cancers Symposium. Abstract 231. Presented January 16, 2015.

Genomic Profiling for Biliary Tract Cancers ■■ Comprehensive genomic profiling revealed that approximately two-thirds of patients with biliary tract cancers harbor genomic alterations that could potentially be targeted. ■■ The genetic landscape of three biliary tract malignancies was diverse, but the total number of clinically relevant mutations per patient was similar for each type.

ASCOPost.com | MARCH 10, 2015

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Gastrointestinal Cancers Symposium Gastrointestinal Cancer

Lanreotide Evaluated in Pancreatic Neuroendocrine Subgroup By Caroline Helwick

he somatostatin analog lanreotide (Somatuline) depot extended the time to disease progression in patients with pancreatic neuroendocrine tumors, in a planned subgroup analysis of the CLARINET trial, Alexandria T. Phan, MD, of The Houston Methodist Hospital in Texas, reported at the 2015 Gastrointestinal Cancers Symposium.1 “Treatment options in advanced pancreatic neuroendocrine tumors are limited, and the optimal front-line therapy has not been defined by existing prospective studies,” Dr. Phan indicated. The CLARINET trial reinforces earlier findings that suggest a somatostatin analog can have antiproliferative activity. The PROMID trial established an antiproliferative benefit for octreotide, but this drug is currently approved for symptom management in functional neuroendocrine tumors (ie, symptom relief) and not as an anticancer agent. PROMID included only patients with midgut, primarily grade 1, tumors and hepatic volumes of mostly 0% to 10%. CLARINET included patients with gastroenteropancreatic neuroendocrine tumors–neuroendocrine tumors (midgut, hindgut, pancreas) with grade 1 and 2 tumors, more than one-third of whom had hepatic volumes greater than 25%. “These findings support lanreotide

as the first and only somatostatin analog approved by the U.S. Food and Drug Administration (FDA) as an antitumor treatment to improve progression-free survival in patients with unresectable, well- or moderately differentiated, unresectable locally advanced/metastatic gastroenteropancreatic neuroendocrine tumors,” Dr. Phan said.

These data offer reassurance that age is not a clinically significant factor when considering lanreotide for the treatment of pancreatic neuroendocrine tumors. Both younger and older groups achieved antitumor effects, without tolerability issues.

CLARINET Details CLARINET is a phase III multicenter, randomized, double-blind, placebo-controlled 96-week randomized trial in which 204 patients received lanreotide depot 120 mg or placebo, by deep subcutaneous injection, every 28 days. Treatment with lanreotide significantly prolonged progression-free survival (hazard ratio [HR] = 0.47, P < .001); median progres-

—Alexandria T. Phan, MD

sion-free survival was not reached in the lanreotide arm and was 18.0 months in the placebo arm.2 Based on its findings, on December 15, 2014, lanreotide was approved by the FDA. Subgroup analyses were done to investigate the consistency of treatment effects.

Update on Lanreotide in Pancreatic Neuroendocrine Tumors ■■ The somatostatin analog lanreotide showed a trend toward improved progression-free survival in the subgroup of patients with pancreatic neuroendocrine tumors treated in the phase III CLARINET trial. ■■ Risk of disease progression was reduced by 42%, vs observation; the median progression-free survival was not reached in the lanreotide arm and was 12.1 months in the observation arm. ■■ Lanreotide was recently approved as an antiproliferative agent for locally advanced or metastatic, unresectable, moderately or well-differentiated gastroenteropancreatic neuroendocrine tumors.

The pancreatic neuroendocrine tumors subgroup included 91 patients with nonfunctional grade 1 or 2 tumors, representing about half of the broader CLARINET population. In this subgroup, 37% had hepatic tumor loads greater than 25%, 95% had stable disease at baseline, 38% had undergone surgery, and 77% had received no previous medical treatment. The median progression-free survival was not reached in patients with pancreatic neuroendocrine tumors treated with lanreotide but was 12.1 months in the placebo arm (95% confidence interval [CI]: 9.4–18.3). This yielded a HR for progressive disease or death of 0.58 (95% CI: 0.32–1.04), which was not statistically significant but indicated a “favorable trend,” Dr. Phan said. continued on page 16

EXPERT POINT OF VIEW

agan Kennecke, MD, Associate Professor, University of British Columbia at the British Columbia Cancer Agency, said in an interview, “It was important to see the detailed sub-

activity may vary among subtypes. Pamela L. Kunz, MD, Assistant Professor of Medicine/Oncology at Stanford University School of Medicine, also an expert in neuroendocrine

It was important to see the detailed subgroup analysis for pancreatic neuroendocrine tumors, because that is a major patient population we treat, and it was not included in the PROMID study.

Pamela L. Kunz, MD

—Hagan Kennecke, MD

group analysis for pancreatic neuroendocrine tumors, because that is a major patient population we treat, and it was not included in the PROMID study. You cannot automatically assume that all (neuroendocrine) tumors respond the same,” since somatostatin-receptor

tumors, noted that the two somatostatin analogs have “very similar mechanisms of action and affinity for the somatostatin receptors 2 and 5, and the National Comprehensive Cancer Network (NCCN) guidelines use them interchangeably.” She said their

George Fisher, MD, PhD

antiproliferative benefits are “likely a class effect, but lanreotide has the FDA label [as an antiproliferative].” George Fisher, MD, PhD, Profes-

sor of Medicine (Oncology) at Stanford University Medical Center and Director of the Oncology Clinic, who moderated the session, said he would view the two somatostatin analogs as “interchangeable,” unless additional data reveal differences between them. He maintained that many asymptomatic patients, as were enrolled in CLARINET, do not need treatment but can be followed. “There is nothing you lose by observing asymptomatic patients with small-volume disease,” he said. “If a subsequent scan shows stable disease, then therapy with a somatostatin analog may have been unnecessary, and if it shows progressive disease, therapy could safely be initiated at that point,” he said. n Disclosure: Drs. Kennecke and Fisher reported no potential conflicts of interest. Dr. Kunz is on the advisory boards of Ipsen and Novartis and has received research funding from Genentech, Merck, Advanced Accelerator Applications, Lexicon, and Pharm Olam.

The ASCO Post | MARCH 10, 2015

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Gastrointestinal Cancers Symposium Lanreotide Trial continued from page 15

There were 18 events in the lanreotide arm, compared with 31 events in the placebo arm. In the lanreotide arm, 16 patients completed treatment without events, compared with 9 in the placebo arm. “The lanreotide treatment arm had more patients with disease control,” she said. Although the mean exposure time was longer for lanreotide—62 weeks vs 56 weeks for the placebo arm— the incidence of adverse events (any events plus the most common events) was similar across the treatment arms. Adverse events were reported by 88% in each arm, and serious adverse events were reported by 29% in the lanreotide arm and 43% in the placebo arm (only three were treatment-related). The most common side effect was diarrhea, reported in 43% and 37%, respectively.

Consistent Across Age Groups Dr. Phan also presented a prespecified exploratory analysis based on age, showing a consistent treatment effect of lanreotide 120 mg across age groups, with similar tolerability and safety.3 “These data offer reassurance that age is not a clinically significant factor when considering lanreotide for the treatment of pancreatic neuroendocrine tumors,” Dr. Phan said. “Both younger

and older groups achieved antitumor effects, without tolerability issues.” In the analysis of 115 patients younger than 65 and 89 patients aged 65 or older, the median progressionfree survival was not reached with lanreotide in either age group and was 18.1 months in patients up to age 65 (HR = 0.51) and 12.1 months in those older than age 65 (HR = 0.38). n

Disclosure: The CLARINET study was supported by a research grant from Ipsen, and Dr. Phan was one of the principal investigators. She is on advisory boards for Novartis and Ipsen; speakers bureaus for Novartis, Genentech, Lilly, and Celgene; and has received other research funding to her institution from Incyte, Novartis, Lexicon, and GSK.

References 1. Phan AT, Caplin ME, Pavel ME, et al: Effects of lanreotide autogel/depot in pancreatic neuroendocrine tumors: A subgroup analysis from the CLARINET study. 2015 Gastrointestinal Cancers Symposium. Abstract 233. Presented January 16, 2015. 2. Caplin ME, Pavel M, Cwikla JB, et al: Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371:224-233, 2014. 3. Phan AT, Caplin ME, Pavel ME, et al: Effects of lanreotide autogel/depot in patients with neuroendocrine tumors age 65 or younger versus older than age 65: Subgroup analyses from the CLARINET study. 2015 Gastrointestinal Cancers Symposium. Abstract 367. Presented January 16, 2015.

Views from 2015 Gastrointestinal Cancers Symposium

Chiara Cremolini, MD, U.O. Oncologia Medica II, Azienda Ospedaliero-Universitaria Pisana Istituto Toscano Tumori, presenting the poster for abstract 657, “FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of metastatic colorectal cancer: Updated survival results of the phase III TRIBE trial by the GONO group”, during General Poster Session C at the Gastrointestinal Cancers Symposium 2015. Photo by © ASCO/Todd Buchanan 2015.

Sabine Tejpar, MD, PhD, University of Leuven, KUL speaking, receiving award plaque from George Fisher, MD, PhD, of Stanford University Medical Center, during her Keynote Lecture: Molecular Characterization of Colorectal Cancer at the Gastrointestinal Cancers Symposium 2015. Photo by © ASCO/Todd Buchanan 2015.

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

BECAUSE YOU CAN’T DO THIS TO FL…

THERE’S ZYDELIG

A first-in-class selective inhibitor of PI3Kδ, a protein that is expressed in normal and malignant B cells

ZYDELIG is a PI3Kδ inhibitor indicated for Relapsed FL after ≥2 systemic therapies The FL indication was granted accelerated approval based on ORR; improvement in patient survival or disease-related symptoms has not been established. FL=follicular B-cell non-Hodgkin lymphoma; ORR=overall response rate; PI3Kδ=phosphatidylinositol 3-kinase delta.

IMPORTANT SAFETY INFORMATION BOXED WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, AND INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended • Fatal and serious pneumonitis can occur. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended • Fatal and serious intestinal perforation can occur in ZYDELIG-treated patients. Discontinue ZYDELIG for intestinal perforation

Please see the following pages for additional Important Safety Information and Brief Summary of full Prescribing Information, including BOXED WARNING.

IMAGINE WHAT’S POSSIBLE

FDA approved in relapsed FL after ≥2 systemic therapies

Imagine what’s possible: ZYDELIG®—A first-in-class PI3Kδ inhibitor ZYDELIG is the FIRST AND ONLY

KINASE INHIBITOR APPROVED IN FL.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) RECOMMEND IDELALISIB MONOTHERAPY AS AN OPTION for appropriate patients with relapsed/refractory FL.1*

ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCCN®=National Comprehensive Cancer Network®. *Please see the complete version of the NCCN Guidelines® for Non-Hodgkin’s Lymphomas available on NCCN.org for specific recommendations.

IMPORTANT SAFETY INFORMATION (cont'd) Contraindications • History of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis (TEN) Warnings and Precautions • Hepatotoxicity: Findings were generally observed within the first 12 weeks of treatment and reversed with dose interruption. Upon rechallenge at a lower dose, ALT/AST elevations recurred in 26% of patients. In all patients, monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, and every 1 to 3 months thereafter. If ALT/AST is >3× upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5× ULN, withhold ZYDELIG and monitor ALT/AST and total bilirubin weekly until resolved. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use with other hepatotoxic drugs • Severe diarrhea or colitis: Grade 3+ diarrhea can occur at any time and responds poorly to antimotility agents. Avoid concurrent use with other drugs that cause diarrhea • Pneumonitis: Evaluate for pneumonitis in patients presenting with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or oxygen saturation decline by ≥5% • Intestinal perforation: Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting • Severe cutaneous reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (grade ≥3) cutaneous reactions have been reported. Monitor patients for the development

of severe cutaneous reactions and discontinue ZYDELIG if a reaction occurs • Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported. Discontinue ZYDELIG permanently and institute appropriate supportive measures if a reaction occurs • Neutropenia: Treatment-emergent grade 3-4 neutropenia occurred in 31% of ZYDELIG-treated patients in clinical trials. In all patients, monitor blood counts ≥every 2 weeks for the first 3 months. In patients with neutrophil counts <1.0 Gi/L, monitor weekly • Embryo-fetal toxicity: ZYDELIG may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking ZYDELIG and to use effective contraception during and at least 1 month after treatment with ZYDELIG Adverse Reactions • Most common adverse reactions (incidence ≥20%; all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash • Most frequent serious adverse reactions (SAR) were pneumonia (15%), diarrhea (11%), and pyrexia (9%); SAR were reported in 50% of patients and 53% of patients discontinued or interrupted therapy due to adverse reactions • Most common lab abnormalities (incidence ≥30%; all grades) were neutrophils decreased and ALT/AST elevations

Median time— the first follow-up, per protocol

Powerful efficacy, chemotherapy free 0

1.9

months 1

Demonstrated single-agent efficacy in an open-label, pivotal, phase 2 trial2† Range=1.6 to 8.3 months ZYDELIG in FL (n=72)

ORR

Response (%)

POWER of response

(95% CI, 42%-66%) 8% CR, 46% PR

Median DoR

Not reached

DURATION of response 0

Range=0.0+ to 14.8+ months CI=confidence interval; CR=complete response; DoR=duration of response; PR=partial response. †Results of a single-arm, open-label trial of ZYDELIG (150 mg, twice daily) in patients with FL who failed to respond or relapsed after ≥2 prior therapies (which must have included both rituximab and an alkylating agent). Primary end point was ORR, as assessed by an independent review committee. ORR was defined as the proportion of subjects who achieved CR or PR. Secondary end point was DoR. DoR was measured from the onset of first documented response (CR or PR) to disease progression or death.2

• Most common adverse reactions (incidence ≥20%; all grades) were diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash; 53% of patients discontinued or interrupted therapy due to adverse reactions Drug Interactions • CYP3A inducers: Avoid coadministration with strong CYP3A inducers • CYP3A inhibitors: When coadministered with strong CYP3A inhibitors, monitor closely for ZYDELIG toxicity • CYP3A substrates: Avoid coadministration with CYP3A substrates Dosage and Administration • Adult starting dose: One 150 mg tablet twice daily, swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The safe dosing regimen for patients who require treatment longer than several months is unknown • Dose modification: Consult the ZYDELIG full Prescribing Information for dose modification and monitoring recommendations for the following specific toxicities: pneumonitis, ALT/AST elevations,

bilirubin elevations, diarrhea, neutropenia, and thrombocytopenia. For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce the dose to 100 mg, twice daily, upon resuming treatment. If severe or life-threatening toxicities recur upon rechallenge, ZYDELIG should be permanently discontinued Please see the following pages for Brief Summary of full Prescribing Information, including BOXED WARNING. VISIT ZYDELIG.COM

IMAGINE WHAT’S POSSIBLE

S:9.5” ZYDELIG® (idelalisib) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only. WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION • Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and/or serious and severe diarrhea or colitis occurred in 14% of ZYDELIG-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and serious pneumonitis can occur in ZYDELIG-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue ZYDELIG as recommended [See Dosage and Administration, Warnings and Precautions]. • Fatal and serious intestinal perforation can occur in ZYDELIGtreated patients. Discontinue ZYDELIG for intestinal perforation [See Warnings and Precautions]. INDICATIONS AND USAGE: • ZYDELIG is indicated in combination with rituximab for the treatment of adults with relapsed chronic lymphocytic leukemia (CLL) for whom rituximab alone would be considered appropriate therapy due to other comorbidities. • ZYDELIG is indicated for the treatment of adults with relapsed follicular B-cell non-Hodgkin lymphoma (FL) who have received ≥2 prior systemic therapies. • ZYDELIG is indicated for the treatment of adults with relapsed small lymphocytic lymphoma (SLL) who have received ≥2 prior systemic therapies. • Accelerated approval was granted for FL and SLL based on overall response rate. An improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

See Warnings and Precautions, Adverse Reactions, and Use in Specific Populations for additional information. Adult Starting Dose: One 150 mg tablet taken orally twice daily (BID), swallowed whole with or without food. Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who required treatment longer than several months is unknown.

Severe diarrhea or colitis (≥Grade 3) occurred in 14% of ZYDELIG-treated patients across clinical trials. ZYDELIG-induced diarrhea can occur at any time and responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month following ZYDELIG interruption with or without enteric or systemic corticosteroids. Avoid concurrent use of ZYDELIG with drugs that cause diarrhea. [See Dosage and Administration]. Fatal and serious pneumonitis occurred in ZYDELIG-treated patients. Patients taking ZYDELIG who present with pulmonary symptoms (e.g., cough, dyspnea, hypoxia, interstitial infiltrates, >5% decrease in oxygen saturation) should be evaluated for pneumonitis. If pneumonitis is suspected, withhold ZYDELIG until etiology of pulmonary symptoms has been determined. Patients thought to have ZYDELIG-induced pneumonitis were treated with ZYDELIG discontinuation and corticosteroids. Fatal and serious intestinal perforation occurred in ZYDELIG-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Permanently discontinue ZYDELIG in patients who experience intestinal perforation. Severe Cutaneous Reactions: One case of TEN occurred in a study of ZYDELIG in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions (dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, exfoliative rash, skin disorder) have been reported. Monitor patients for severe cutaneous reactions and discontinue ZYDELIG. Anaphylaxis: Serious allergic reactions including anaphylaxis have been reported in ZYDELIG-treated patients. Permanently discontinue ZYDELIG and institute appropriate supportive measures in patients who develop serious allergic reactions. Neutropenia: Treatment-emergent neutropenia (Grade 3 or 4) occurred in 31% of ZYDELIG-treated patients across clinical trials. Monitor blood counts every 2 weeks for the first 3 months, and weekly when neutrophils are <1 Gi/L [See Dosage and Administration]. Embryo-fetal Toxicity: Idelalisib is teratogenic in rats and may cause fetal harm. Women who are or become pregnant while taking ZYDELIG should be apprised of the potential hazard to the fetus. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after treatment [See Use in Specific Populations]. ADVERSE REACTIONS: See BOXED WARNING and Warnings and Precautions for additional serious adverse reactions.

Dose Modifications:

Subjects with Relapsed CLL:

• Pneumonitis: discontinue ZYDELIG for any symptomatic pneumonitis

The safety assessment of ZYDELIG 150 mg BID + rituximab (up to 8 doses) is based on data from 110 adult subjects with relapsed CLL (Study 1). The median duration of exposure to ZYDELIG was 5 months.

• Hepatotoxicity: – ALT/AST >3 to 5x ULN or bilirubin >1.5 to 3x ULN: maintain ZYDELIG dose; monitor weekly until ≤1x ULN – ALT/AST >5 to 20x ULN or bilirubin >3 to 10x ULN: withhold ZYDELIG; monitor weekly until ≤1x ULN then resume ZYDELIG 100 mg BID – ALT/AST >20x ULN or bilirubin >10x ULN: permanently discontinue ZYDELIG • Diarrhea: – Moderate (increase of 4-6 stools/day over baseline): maintain ZYDELIG dose; monitor weekly until resolved – Severe (increase of ≥7 stools/day over baseline) or hospitalization: withhold ZYDELIG; monitor weekly until resolved then resume ZYDELIG 100 mg BID – Life-threatening: permanently discontinue ZYDELIG • Neutropenia: – ANC 1 to <1.5 Gi/L: maintain ZYDELIG dose – ANC 0.5 to <1 Gi/L: maintain ZYDELIG dose; monitor weekly – ANC <0.5 Gi/L: withhold ZYDELIG; monitor weekly until ≥0.5 Gi/L then resume ZYDELIG 100 mg BID • Thrombocytopenia: – Platelets 50 to <75 Gi/L: maintain ZYDELIG dose – Platelets 25 to <50 Gi/L: maintain ZYDELIG dose; monitor weekly – Platelets <25 Gi/L: withhold ZYDELIG; monitor weekly until ≥25 Gi/L then resume ZYDELIG 100 mg BID • For other severe or life-threatening toxicities, withhold ZYDELIG until toxicity is resolved and reduce dose to 100 mg BID if resuming treatment. Permanently discontinue ZYDELIG if severe or life-threatening toxicities recur upon rechallenge. CONTRAINDICATIONS: History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis (TEN). WARNINGS AND PRECAUTIONS: Fatal and/or serious hepatotoxicity occurred in 14% of ZYDELIG-treated patients. ALT or AST >5x ULN have occurred, usually within the first 12 weeks of treatment and were reversible with dose interruption. Upon resuming

• Adverse Reactions: Most common (≥2%) serious adverse reactions reported in 49% of subjects were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%). Most common adverse reactions (incidence ≥5% and occurring at ≥2% higher incidence in ZYDELIG-treated subjects; all Grades) were pyrexia (35%), nausea (25%), pneumonia (23%), diarrhea (21%), chills (21%), rash (18%), vomiting (13%), headache (10%), sepsis (8%), sinusitis (8%), pain (7%), arthralgia (7%), GERD (6%), stomatitis (6%), bronchitis (6%), nasal congestion (5%), and urinary tract infection (5%). Most common adverse reactions leading to dose reductions in 15% of subjects were elevated transaminases, diarrhea or colitis, and rash. Most common adverse reactions leading to discontinuation in 10% of subjects were hepatotoxicity and diarrhea/colitis. • Laboratory Abnormalities: Treatment emergent laboratory abnormalities (incidence ≥10% and occurring at ≥5% higher incidence in ZYDELIG-treated subjects; all Grades) were decreased neutrophils (60%), hypertriglyceridemia (56%), hyperglycemia (54%), increased ALT (35%), increased GGT (26%), increased lymphocytes (25%), increased AST (25%), decreased lymphocytes (20%), hyponatremia (20%), and hypoglycemia (11%). Subjects with Indolent Non-Hodgkin Lymphoma (iNHL):

• Laboratory Abnormalities: Treatment emergent laboratory abnormalities (all Grades) were decreased neutrophils (53%), increased ALT (50%), increased AST (41%), decreased hemoglobin (28%), and decrease platelets (26%). DRUG INTERACTIONS: • CYP3A Inducers: Strong CYP3A inducers decreased idelalisib AUC by 75%. Avoid coadministration with strong CYP3A inducers (e.g., rifampin, phenytoin, St. John’s wort, carbamazepine). • CYP3A Inhibitors: Strong CYP3A inhibitors increased idelalisib AUC 1.8-fold. Monitor for signs of ZYDELIG toxicity during coadministration and follow dose modifications for adverse reactions [See Dosage and Administration]. • CYP3A Substrates: ZYDELIG is a strong CYP3A inhibitor. Avoid coadministration with CYP3A substrates as AUC of sensitive CYP3A substrates increased 5.4-fold when coadministered. USE IN SPECIFIC POPULATIONS: Pregnancy: ZYDELIG is Pregnancy Category D and may cause fetal harm. In pregnant rats, embryo-fetal toxicities were observed, including decreased fetal weights, external malformations (short tail), skeletal variations (delayed ossification and/or unossification of the skull, vertebrae and sternebrae), urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, microphthalmia/anophthalmia). Women who are or become pregnant during ZYDELIG treatment should be apprised of the potential hazard to the fetus [See Warnings and Precautions]. Nursing Mothers: It is not known whether idelalisib 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 ZYDELIG, a decision should be made whether to discontinue nursing or ZYDELIG, taking into account the importance of ZYDELIG to the mother. Pediatric Use: Safety and effectiveness of ZYDELIG in children <18 years of age have not been established. Geriatric Use: In clinical trials of ZYDELIG in patients with FL, SLL, and CLL, 63% of patients were ≥65 years old; no major differences in effectiveness were observed. • In patients with iNHL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (28% vs. 20%), serious adverse reactions (64% vs. 37%), and death (11% vs. 5%). • In patients with CLL: Compared to younger patients, older patients (≥65 years) had higher incidences of discontinuation due to adverse reaction (11% vs. 5%), serious adverse reactions (51% vs. 43%), and death (3% vs. 0%). Contraception in Females of Reproductive Potential: ZYDELIG may cause fetal harm. Advise females of reproductive potential to avoid pregnancy during treatment and to use effective contraception during and for ≥1 month after taking the last dose of ZYDELIG. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking ZYDELIG [See Warnings and Precautions]. Renal Impairment: No dose adjustment of ZYDELIG is necessary for patients with creatinine clearance ≥15 mL/min. Hepatic Impairment: Idelalisib AUC increased up to 1.7-fold in subjects with ALT, AST, or bilirubin >ULN compared to healthy subjects with normal ALT, AST, or bilirubin. Safety and efficacy data are not available in patients with baseline ALT or AST >2.5x ULN or bilirubin >1.5x ULN as these patients were excluded from Studies 1 and 2. Monitor patients with baseline hepatic impairment for signs of ZYDELIG toxicity and follow dose modifications for adverse reactions [See Warnings and Precautions, Dosage and Administration]. 205858-GS-000-PI July 2014

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.1.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed January 7, 2015. 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. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-1018.

The safety assessment of ZYDELIG 150 mg BID is based on data from 146 adult subjects with iNHL. The median duration of exposure to ZYDELIG was 6.1 months (range: 0.3 to 26.4 months). • Adverse Reactions: Most common serious adverse reactions reported in 50% of subjects were pneumonia (15%), diarrhea (11%), and pyrexia (9%). Most common adverse reactions (incidence ≥10%; all Grades) were diarrhea (47%), fatigue (30%), cough (29%), nausea (29%), pyrexia (28%), abdominal pain (26%), pneumonia (25%), rash (21%), dyspnea (17%), decreased appetite (16%), vomiting (15%), upper respiratory tract infection (12%), asthenia (12%), night sweats (12%), insomnia (12%), headache (11%), and peripheral edema (10%). Most common adverse reactions leading to dose interruption or discontinuation in 53% of subjects were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).

Gilead, the Gilead logo, and ZYDELIG are trademarks of Gilead Sciences, Inc., or one of its related companies. All other trademarks referenced herein are the property of their respective owners. © 2015 Gilead Sciences, Inc. All rights reserved. ZYDP0068 02/2015

S:13”

DOSAGE AND ADMINISTRATION:

treatment at a lower dose, 26% of patients had recurrence of ALT and AST elevations. Discontinue ZYDELIG for recurrent hepatotoxicity. Avoid concurrent use of ZYDELIG with hepatotoxic drugs. In all patients, monitor ALT and AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. If ALT or AST >3x ULN, monitor weekly until elevation resolves; if ALT or AST >5x ULN, withhold ZYDELIG and monitor AST, ALT and total bilirubin weekly until elevation resolves [See Dosage and Administration].

ASCOPost.com | MARCH 10, 2015

PAGE 21

World Oncology Forum Global Cancer Burden continued from page 1

WOF was held in Lugano in October 2014, with the central theme of treating the treatable, which appealed to governments, international agencies, and policymakers wishing to expand access to early detection and care and to address problems in the global cancer ecosystem that hinders faster progress in the discovery and development of promising new therapies. The WOF assembled 127 of the world’s leading cancer experts including ASCO Chief Medical Officer Richard L. Schilsky, MD, who noted that the central focus of the second WOF was to follow-up on one of the two main recommendations from the first WOF, which was to treat the treatable.

Important Steps

T:13.75”

“The discussions at the WOF basically went in two different directions. One had to do with outlining the steps that governments need to take in order to develop the infrastructure necessary to deliver cancer care in resource-challenged regions—thus achieving the goal of treating the treatable,” said Dr. Schilsky. Dr. Schilsky explained that the cancer therapies that they recommended were the basic oncologic tools. “We urged the deployment of known effective therapies such as fundamental radiation therapy services as well as access to about 15 generic cancer chemotherapies that are proven to be effective in treating nearly 75% of the most common malignancies, without having to venture into costly targeted therapies,” said Dr. Schilsky. Along with infrastructure development and deploying treatments, Dr. Schilsky said that another important step was educating populations, especially in the developing world, about cancer risk factors and early detection. “Education could go a long way in reducing the incidence of cancers, which will be the focus of the next WOF: prevent the preventable. The other prong of our ‘treat the treatable’ initiative is to find ways to ensure that all patients who need pain control have access to analgesics, such as morphine. Right now, many countries have little or no morphine with which to treat the cancer patient’s pain, which borders on the inhumane. That’s definitely an area we will address,” noted Dr. Schilsky. “The other major issue of discussion [the second of the two directions referred to above],” continued Dr. Schilsky, “had to do with how to accelerate the discovery, development, and deployment of new cancer therapies. We concluded that there needed to be

greater partnerships between academic research and the pharmaceutical sector to bring new agents into clinical testing and ultimately the global market. Moreover, as a cancer community we need to set the expectation bar higher, so we should no longer devote resources to developing cancer drugs that produce only small, incremental advances. Instead, those resources should be redirected into further discovery work in the laboratory.”

Need for Pragmatism Dr. Schilsky stressed that spending $150 million on a phase III clinical trial for a drug that gives 6 weeks of improved survival is not adding dollar value to the system. “We need to be able to learn about new drugs through the continuum of their life cycles, from the regulatory system that approves a drug’s indication and the reimbursement system that makes a drug affordable, by using valuebased metrics that base reimbursement levels on how the drug performs in its various indications,” he said. Dr. Schilsky concluded by emphasizing that the wide-reaching goals set by the WOF must be tempered by pragmatism. “We need to face the fact that

Franco Cavalli, MD, presented the idea of a global cancer fund to reduce cancer incidence and lessen the overall economic burden the disease places on the developing world. Credit: © 2014 Luca Sangiorgi

Economic Burden of Cancer Following the WOF, the Union for International Cancer Control organized the World Cancer Leaders Summit to discuss the economic issues of global cancer. The figures are staggering. When the adjusted monetary loss of output from patients with cancer is added to the costs of their treatment, it amounts to more than $3 trillion of the world’s economy annually—equiv-

As a cancer community, we need to set the expectation bar higher, so we should no longer devote resources to developing cancer drugs that produce only small, incremental advances. Instead, those resources should be redirected into further discovery work in the laboratory. —Richard L. Schilsky, MD

treating the treatable is a populationspecific goal. We must use the resources that are available and cost-effective and can be deployed fairly efficiently, without worrying about holding the standards of care that we have in the United States and other wealthy industrialized nations to resource-challenged regions.” He continued, “To that end, we discussed the development of resourceappropriate clinical practice guidelines. We can’t expect poor countries without efficient infrastructures to use the same guidelines that we do. Guidelines are an important tool in standardizing care, especially when the tools and expertise are limited. So the development of region-specific practice guidelines is an important part of the ‘treat the treatable’ initiative.”

alent to around 1.5% of global gross domestic product. Franco Cavalli, MD, Director of Oncology at the Oncology Institute of Southern Switzerland in Bellinzona, and one of the prominent leaders of the first and second WOFs, was invited to the World Economic Forum in Davos, Switzerland, to discuss the economics of cancer. Based on a proposal formulated at the World Cancer Leaders Summit, Dr. Cavalli presented the idea of creating a global cancer fund to reduce cancer incidence and lessen the overall economic burden that the disease places on the developing world. “We need to draw on lessons learned from impressive progress in tackling cancer that has been achieved in recent years in countries such as Thailand and

Brazil, as well as the successes of global initiatives in other disease areas, including the Global Alliance for Vaccines and Immunizations (GAVI) and the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM),” said Dr. Cavalli. Dr. Cavalli and his associate, Rifat Atun, MD, Professor of Global Health Systems at the Harvard School of Public Health, Boston, recently published a commentary centering on the global cancer fund in The Lancet Oncology.1 Dr. Cavalli said that the priorities of the global cancer fund would be the development of cancer registries for cervical and breast cancers and pediatric oncology as well as investment in cancer prevention, treatment, and care to alleviate needless suffering and to realize significant health and economic benefits in low-income countries. Asked if he felt optimistic about the chances of a global cancer fund being realized, Dr. Cavalli responded, “I have mixed feelings about how the oncology community’s concerns over the growing incidence of cancer in the developing world were received. The representatives from the oncology community were in agreement, but there was opposition to our initiatives from some very powerful people who felt that global cancer was way down on the priority list. In order to launch a global cancer fund, similar to the one for AIDS, we need strong political pressure—and we are working on that. However, it will require concerted and bold action at national and international levels.” n

Disclosure: Drs. Schilsky, Cavalli, and Atun reported no potential conflicts of interest.

Reference 1. Cavalli F, Atun R: Towards a global cancer fund. Lancet Oncol 16:133-134, 2015.

The ASCO Post | MARCH 10, 2015

PAGE 22

San Antonio Breast Cancer Symposium Breast Cancer

PI3K Inhibition in Hormone Receptor–Positive Breast Cancer ‘Not Ready for Prime Time’ By Alice Goodman

nterest is high in studying the PI3K pathway in hormone receptor–positive breast cancer, but it is not clear which of the PI3K inhibitors under development—if any—will be a “home run.” The phase II FERGI study, reported at the 2014 San Antonio Breast Cancer Symposium, failed to meet its primary endpoint with the PI3K inhibitor pictilisib but did provide hints of activity and areas for further investigation of this drug.1 In the FERGI trial, the addition of pictilisib to fulvestrant (Faslodex) did not significantly improve progression-free survival in women with estrogen receptor– positive metastatic breast cancer resistant to previous aromatase inhibitor therapy. However, in an exploratory analysis of the trial, pictilisib extended progression-free survival in women with both estrogen receptor–positive and progesterone receptor–positive metastatic breast cancer. “When we considered only women with metastatic breast cancer positive for both the estrogen receptor and progesterone receptor, adding pictilisib resulted in a doubling of progression-free survival in an exploratory analysis. We plan to inves-

Ian Krop, MD, PhD

tigate whether the benefit of pictilisib for women with estrogen receptor–positive and progesterone receptor–positive breast cancer holds true in an additional cohort of patients within this study,” stated lead author Ian Krop, MD, PhD, Director of Clinical Research for the Breast Oncology Program at the Dana-Farber Cancer Institute in Boston. “We saw enough activity in the combination arm to investigate this class of drugs further in the setting of metastatic breast cancer. Whether pictilisib is the right drug remains to be seen. There are ongoing studies of other more potent PI3K inhibitors that may ultimately have better results,” said study coauthor Eric Winer, MD, of Dana-Farber Cancer Institute. PI3K mutations are present in 40% to 45% of cases of estrogen receptor–positive breast cancers, and PI3K/mTOR signal-

ing is a suspected resistance mechanism to antiestrogen therapy. Pictilisib is an oral potent, pan-class I selective PI3K inhibitor, and there was interest in determining the effect of adding this agent to fulvestrant in patients resistant to aromatase inhibitor therapy.

The [PI3K] pathway is clearly activated in breast cancer, [but] the modest 1- to 2-month advantage with pictilisib was not impressive.

Study Details and Findings The phase II FERGI trial included 168 postmenopausal women with advanced or metastatic breast cancer previously treated with an aromatase inhibitor as adjuvant or metastatic therapy. The women were randomly assigned 1:1 to receive treatment with fulvestrant plus pictilisib vs fulvestrant plus placebo and treated until disease progression, at which time patients receiving placebo could cross over to pictilisib. The median age of patients was about 62 years, and more than one-third of patients were older than age 65. About 40% of patients in both arms had PIK3CA mutations. In the pictilisib arm, 65% were progesterone receptor–positive, and 24% were progesterone receptor–negative; in the placebo arm, 73% were progesterone receptor–positive, and 18% were progesterone receptor–negative. The progesterone receptor status was unknown for the remaining patients in both arms. All patients were estrogen receptor–positive. Safety of the combination was consistent with single-agent phase I experience. No treatment-related deaths were reported. Adverse events of grade 3 or higher in the combination arm included diarrhea (7%), rash (17%), and fatigue (6%). “These effects were not overly severe in the vast majority of patients. On the other hand, there were more dose adjustments and discontinuations due to adverse events with combination therapy,” Dr. Winer said. A modest improvement in progression-free survival was observed in an

—Jennifer Litton, MD

Investigational alpha-selective PI3K inhibitors may turn out to be more effective than pictilisib in breast cancer. —Eric Winer, MD

intent-to-treat analysis of the entire study population: a median of 6.6 months for the combination vs 5.1 months for the placebo. However, in the subgroup of patients with both estrogen receptor–positive and progesterone receptor–positive disease, an unplanned subset analysis showed a median progression-free survival of 7.4 months vs 3.7 months. “Although we had hoped the combination would be somewhat more active, the subgroup data are worth exploring further, and ongoing studies will look at this,” Dr. Winer said. One surprise was that patients with PIK3CA mutations did not seem to have an increased benefit from combination therapy. However, testing for PIK3CA mutations should be done only in the context of a clinical trial, Dr. Winer stated. “It is likely that the field is going toward more selective PI3K inhibitors, such as alpha-selective agents,” he noted.

PI3K Inhibitors in Metastatic Breast Cancer ■■ Pictilisib, a PI3K inhibitor, added to fulvestrant did not significantly extend progression-free survival in estrogen receptor–positive advanced or metastatic breast cancer resistant to aromatase inhibition, according to the results of the FERGI trial. ■■ However, the signal was much stronger for the benefit of this combination in estrogen receptor–positive/progesterone receptor–positive breast cancer in an exploratory analysis, and this subgroup will be studied further. ■■ This study does not dampen enthusiasm for pursuing the PI3K pathway in hormone receptor–positive breast cancer, because other more selective PI3K inhibitors may be more effective.

Dr. Krop said that an additional 60 patients would be entered in this study.

Glass Half Empty? At the press conference, moderator Jennifer Litton, MD, of MD Anderson Cancer Center in Houston, said evidence shows that targeting the PI3K pathway continues to be important in hormone receptor–positive breast cancer. “The pathway is clearly activated in breast cancer. The modest 1- to 2-month advantage with pictilisib was not impressive,” she said. “Also, this therapy has toxicity.” In addition, in this study, PI3K mutations were not a reliable biomarker. Both she and Dr. Winer agreed that pictilisib would not turn out to be the PI3K inhibitor “most likely to succeed,” and both said that perhaps investigational alpha-selective PI3K inhibitors may turn out to be more effective than pictilisib in breast cancer. n

Disclosure: Drs. Krop and Winer have received research funding from Genentech/Roche. Dr. Litton has received uncompensated research funding from BioMarin Pharmaceutical, Novartis, and BMS.

Reference 1. Krop I, Johnston S, Mayer IA, et al: The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER-positive, aromatase inhibitor-resistant advanced or metastatic breast cancer: Part I results. 2014 San Antonio Breast Cancer Symposium. Abstract S2-02. Presented December 10, 2014.

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.

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 | MARCH 10, 2015

PAGE 23

ASH Annual Meeting Hematology

From ASH 2014: What’s New in the Myeloma Treatment Arsenal? By Caroline Helwick

t the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, attendance at many multiple myeloma sessions outnumbered the room size, as data from studies of novel agents, such as the monoclonal antibodies, and from key trials, such as ASPIRE, drew crowds. The ASCO Post covered these key developments, but our coverage did not end there. Here is our roundup of other newsworthy presentations about antimyeloma drugs.

Sequencing or Alternating Bortezomib and Lenalidomide Outcomes are comparable, whether bortezomib (Velcade)– and lenalidomide (Revlimid)–based regimens are alternated or sequenced, according to a study by the Spanish Myeloma Group comparing these approaches in newly diagnosed elderly patients.1 The investigators hypothesized that an alternating scheme would be more efficacious and less toxic; however, this hypothesis was not confirmed, said Maria-Victoria Mateos, MD, of the University Hospital of Salamanca in Spain. “So far, both schemes yielded similar results,” she said.

plete responses were also similar, approximately 41%. The median progression-free survival was 32 months in the sequential arm and 34 months in the alternating arm. Overall survival at 3 years was 73% and 71%, respectively, and toxicity profiles were also similar. “This fixed total therapy (18 cycles) regimen, including VMP and Rd, resulted in impressive results in those patients who completed the 18 planned cycles,” Dr. Mateos indicated.

Pomalidomide Activity as Single Agent or in Combination In reportedly the largest study yet in a heavily pretreated relapsed/refractory myeloma population, the European phase IIIb STRATUS (MM-010) trial evaluated single-agent pomalidomide

Meletios A. Dimopoulos, MD

Clinic, Rochester, Minnesota.3 “Patients with high- or intermediate-risk disease were just as likely to respond as patients with low-risk disease…. PVD is a highly attractive option for patients with relapsed and refractory myeloma,” Dr. Lacy said. She reported these findings in 47 patients who had received up to four prior regimens and were resistant to

Patients with high- or intermediaterisk disease were just as likely to respond as patients with low-risk disease…. PVD [pomalidomide/ bortezomib/dexamethasone] is a highly attractive option for patients with relapsed and refractory myeloma. —Martha Q. Lacy, MD

Maria-Victoria Mateos, MD

The GEM2010MAS65 trial of 250 patients evaluated a “total therapy” approach that included bortezomib/ melphalan/prednisone (VMP) and lenalidomide/low-dose dexamethasone (Rd). Patients were treated with both regimens. One cohort received them in an alternating fashion—one cycle with one, one with another, and so on for 18 cycles. The other received the regimens sequentially, with one given for nine cycles and then the next for nine cycles. The investigators predicted, she said, that the alternating scheme would offer less probability of cell-tumor escape and lower cumulative toxicity, but after a median of 18 cycles, the overall response rate was 77% in the sequential arm and 80% in the alternating arm. Rates of complete and near-com-

(Pomalyst) with low-dose dexamethasone according to the current indication—ie, after failure with both an immunomodulatory drug and a proteasome inhibitor.2 The overall response rate was 35%, which was maintained in patients refractory to both lenalidomide and bortezomib. The median progression-free survival was 4.2 months. The safety profile was consistent with previous studies. The most frequent grade 3/4 adverse events were hematologic, but there was a low incidence of febrile neutropenia or discontinuation of treatment. The efficacy in STRATUS confirmed the clinical benefit observed in previous trials, said Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece. A regimen of pomalidomide/ bortezomib/dexamethasone (PVD) achieved a response rate of 85% and a 12-month event-free survival of 94% in patients refractory to lenalidomide, in a small phase II trial reported by Martha Q. Lacy, MD, of the Mayo

lenalidomide. They received a median of eight cycles of PVD and were followed for a median of 12 months. Of 40 patients who responded, 21 had very good partial responses or better. The median progression-free survival was 10.7 months, and the median duration of response was 13.7 months.

Weekly Dosing for Carfilzomib Weekly administration of carfilzomib (Kyprolis) may be equivalent to the current practice of twice-weekly injections, according to Antonio Palumbo, MD, of the University of Turin, Italy, who presented data from a phase I/II study in elderly newly diagnosed patients.4

Antonio Palumbo, MD

“With weekly injections, treatment becomes more feasible, and we can keep patients on treatment longer. That translates into efficacy,” Dr. Palumbo said in an interview. To evaluate once-weekly carfilzomib, Dr. Palumbo and colleagues enrolled 12 patients in a dose-finding phase, then added 18 patients for phase II. Escalating doses started at 45 mg/ m2, with a maximal planned dose of 70 mg/ m2. Carfilzomib was given along with oral cyclophosphamide and oral dexamethasone on days 1, 8, and 15. Of 30 patients, 21 patients received the maximum tolerated dose (70 mg/ m2). After completion of nine cycles, patients received 28-day maintenance cycles with carfilzomib at the maximum tolerated dose until disease progression or intolerance. “Grade 3/4 adverse events were very rare, very low,” he said, with once-weekly higher-dose carfilzomib and were not increased over what has been observed with twice-weekly dosing. Dose reductions also appeared to be required less frequently (10%) than with twiceweekly dosing (21%). Grade 3/4 hematologic events were observed in 23% of patients in this study, compared with 27% in studies of twice-weekly (36 mg/m2) carfilzomib. Grade 3/4 nonhematologic events were seen in 30% and 29%, respectively. The overall response rate was 86%, with 64% having at least a very good partial response and 41% achieving at least a near-complete response. By cycle 9, a very good partial response or better was achieved by 91% receiving weekly carfilzomib, compared with 77% receiving the drug twice-weekly in prior studies. Dr. Palumbo indicated that response rates would continue to improve over time.

Panobinostat Used With a Triplet Regimen Jatin Shah, MD, of the University of Texas MD Anderson Cancer Center, presented data for panobinostat in combination with bortezomib, lenalidomide, and dexamethasone (VRD).5 The study in 31 newly diagnosed transplant-eligible patients was the first experience reported with panobinostat in combination with subcutaneous bortezomib and offered the first data in combination with these three drugs, he indicated. continued on page 24

The ASCO Post | MARCH 10, 2015

PAGE 24

ASH Annual Meeting Myeloma Treatment continued from page 23

“The combination was highly active, with a high depth of response and rapid disease control after four cycles,” he said. The maximum tolerated doses were determined to be 10 mg for panobinostat, 25 mg for lenalidomide, and 1.3 mg/m2 for bort-

Jatin Shah, MD

ezomib. The combination was “very well tolerated,” with limited grade 3/4 toxicity. The rate of grade 3/4 diarrhea/constipation was 6%. Of the 22 patients who completed 4 cycles at the time of analysis, the overall response rate was 95%, of which 50% were complete responses or nearcomplete responses. This is much higher than the historic complete response rate of 10% to 20% for VRD alone after three to four cycles, according to Dr. Shah.

Novel Therapies: Ibrutinib, CAR T-Cell Therapy Could a targeted agent that works in leukemia become a blockbuster in myeloma as well? Perhaps, according to a phase II study of the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).6 Ravi Vij, MD, of Washington University School of Medicine, St. Louis, presented preliminary results for 69 relapsed/refractory patients who received escalating doses of ibrutinib with or without dexamethasone. In the highest dose cohort (840 mg orally daily), a clinical benefit rate of 25% was observed, and another 25% of patients had stable disease. The median progression-free survival was 5.6 months in this latter group. Some patients had prolonged remissions, even after having received at least four prior treatments. Since the time of analysis, further responses have been observed, Dr. Vij said. Severe adverse events were observed

Ravi Vij, MD

in 57% of patients, and 22% required dose modifications; 10% discontinued treatment. Major hematologic adverse events were limited to grades 1 and 2. Ibrutinib will be studied in combination with proteasome inhibitors and immunomodulatory drugs. At a special symposium on chimeric antigen receptor (CAR) T-cell therapy, Carl June, MD, of the University of Pennsylvania, described four latestage myeloma patients treated with

References 1. Mateos M-V, Martinez-Lopez J, Hernandez M-T, et al: Comparison of sequential vs alternating administration of bortezomib, melphalan, prednisone and lenalidomide plus dexamethasone in elderly patients with newly diagnosed multiple myeloma: GEM2010MAS65 trial. 2014 ASH Annual Meeting. Abstract 178. Presented December 7, 2014. 2. Dimopoulos MA, Palumbo A, Weisel K, et al: Safety and efficacy in the Stratus (MM-010) trial, a single-arm phase 3b study evaluating pomalidomide + low-dose dexamethasone in patients with refractory or relapsed and refractory multiple myeloma. 2014 ASH Annual Meeting. Abstract 80. Presented December 7, 2014. 3. Lacy MQ, LaPlant BR, Laumann KM, et al: Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide refractory multiple myeloma. 2014 ASH Annual Meeting. Abstract 304. Presented December 8, 2014. 4. Palumbo A, Rossi D, Bringhen S, et

al: Weekly carfilzomib, cyclophosphamide, and dexamethasone in newly diagnosed multiple myeloma patients: A phase I-II study. 2014 ASH Annual Meeting. Abstract 175. Presented December 7, 2014. 5. Shah JJ, Feng L, Manasanch EE, et al: Phase I/Ib trial of the efficacy and safety of combination therapy with lenalidomide/ bortezomib/dexamethasone and panobinostat in transplant-eligible patients with newly diagnosed multiple myeloma. 2014 ASH Annual Meeting. Abstract 33. Presented December 6, 2014. 6. Vij R, Huff CA, Bensinger WI, et al: Ibrutinib, single agent or in combination with dexamethasone, in patients with relapsed or relapsed/refractory multiple myeloma: Preliminary phase 2 results. 2014 ASH Annual Meeting. Abstract 31. Presented December 6, 2014. 7. June C: Therapeutic efficacy of chimeric antigen receptor T cells. 2014 ASH Annual Meeting. Special Scientific Symposium on Chimeric Antigen Receptor T-Cell Therapy. Presented December 7, 2014.

Images in Oncology Carl June, MD

CTL019, which has been used primarily in chronic and lymphocytic leukemias.7 In this pilot study, three of four patients achieved at least a very good partial response to CTL019, and two patients have achieved a stringent complete response. n Disclosure: Dr. Mateos has received honoraria from and is a member of an entity’s Board of Directors or advisory committees for Celgene and Janssen. Dr. Dimopoulos has served as a consultant for and received honoraria from Janssen, Onyx, and Celgene. Dr. Lacy has received research funding from Celgene. Dr. Palumbo has served as a consultant for and received honoraria from Celgene, Janssen-Cilag, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Amgen, Genmab A/S, and Bristol-Myers Squibb; he also has received honoraria from Array BioPharma and Sanofi. Dr. Shah has served as a consultant to and received research funding from Onyx Pharmaceuticals, Celgene, Millennium Pharmaceuticals, Novartis, and Array. Dr. Vij reported no potential conflicts of interest. Dr. June has received royalties and research funding from Novartis.

Human T Cell: Scanning electron micrograph of a human T lymphocyte (T cell) from the immune system of a healthy donor. Source: National Institute of Allergy and Infectious Diseases (NIAID). Send your image to editor@ASCOPost.com. Please include your name and a caption for the photo.

ASCOPost.com | MARCH 10, 2015

PAGE 25

ASH Annual Meeting Hematology

HIV-Related Lymphoma Can Be Safely Treated With Transplant By Alice Goodman

uman immunodeficiency virus (HIV)-positive patients with relapsed/refractory lymphoma can safely undergo autologous hematopoietic cell transplantation, according to results of a phase II multicenter trial presented at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition in San Francisco.1 At many centers, HIV-positive patients with lymphoma are currently excluded from this potentially curative treatment due to concerns

Our study shows that exclusion from clinical trials on the basis of HIV infection alone is no longer justified. In fact, in clinical practice, patients with controlled HIV infection—with emphasis on the word “controlled”—should be receiving transplants as standard of care,” said lead study author Joseph Alvarnas, MD, Associate Clinical Professor and Director of Medical Quality at City of Hope, Duarte, California. “Now that we have effective therapies

Our study shows that exclusion from clinical trials on the basis of HIV infection alone is no longer justified. —Joseph Alvarnas, MD

about increased risk of infection in these immunocompromised patients. In the phase II trial, autologous hematopoietic cell transplantation achieved an estimated 1-year overall survival of 86.6% and progression-free survival of 82.3% in patients with HIV-related lymphoma who failed to respond to prior therapy. The estimated rate of disease progression at 1 year was 12.5%, and the estimated mortality was 5%.

Exclusion Unjustified “Chemotherapy-sensitive patients with relapsed/refractory HIV-related lymphoma may successfully undergo [autologous hematopoietic cell transplantation] with favorable outcomes.

for AIDS, we tend to trivialize it as a risk factor for lymphoma, but it is still a considerable risk factor. We have excellent treatment for patients with lymphoma, yet HIV infection remains an exclusion criterion for most [transplant] therapeutic trials. We conducted this study to see whether we could extend [autologous hematopoietic cell transplantation] to HIV-infected patients with lymphoma at nonspecialty centers,” he told an audience at a press conference held during the ASH meeting. The single-arm, multi-institutional trial was conducted jointly by the Blood and Bone Marrow Transplant Clinical Trials Network and the AIDS Malignancy Clinical Trials Consor-

Role of Transplant in HIV-Related Lymphoma ■■ Patients with HIV-related lymphoma are currently often excluded from clinical trials of autologous hematopoietic cell transplantation, a potentially curative therapy. ■■ A single-arm study found that transplant can be safely delivered to patients with HIV-related lymphoma, provided their HIV infection is controlled. ■■ This study should impact clinical trial design and clinical practice.

EXPERT POINT OF VIEW

“T

he National Cancer Institute (NCI) sees a real need for additional study of treatment options for human immunodeficiency virus (HIV)-infected patients with malignancies. The results of this trial make us confident that exclusion from autologous transplant studies on the basis of HIV serostatus is no longer justified,” said Richard Little, MD, Head of Hematologic, HIV, and Stem Cell Therapeutics at NCI, regarding the Richard Little, MD presentation by Alvarnas et al at the 2014 American Society of Hematology (ASH) Annual Meeting and Exposition. “This study is important. Even well controlled HIV infection increases the risk of lymphoma. In many centers, HIV infection is an exclusion criterion for the only potentially curative treatment we have for lymphoma. This study will change standard practice at centers that currently exclude patients with HIV infection [from transplant],” stated Brad S. Kahl, MD Brad S. Kahl, MD, ASH press conference moderator and Associate Professor of Medicine at the University of Wisconsin School of Medicine and Public Health, Madison. n Disclosure: Drs. Little and Kahl reported no potential conflicts of interest.

tium. The 16 transplant centers included in the study do not necessarily specialize in HIV/AIDS treatment, therefore making it possible to duplicate the treatment at a broader number of nonspecialized centers, noted the authors.

Study Details Study results were based on 40 HIV-infected patients with relapsed or refractory lymphoma. All underwent autologous hematopoietic cell transplantation, receiving a modified BEAM regimen (carmustine [BiCNU], etoposide, cytarabine, melphalan), and blood stem cell grafts. Antiretroviral therapy for HIV infection was withheld during the preparative regimen and resumed after the resolution of gastrointestinal toxicities. All patients received standard institutional supportive care posttransplant. “Patients had no problem mobiliz-

ing stem cells,” Dr. Alvarnas said. Dr. Alvarnas said that a historical case-control study of 151 matched non– HIV-infected patients with lymphoma who underwent autologous hematopoietic cell transplantation showed no significant differences in overall mortality compared with the HIV-infected patients in his team’s study. n

Disclosure: The National Cancer Institute provided funding for the trial as part of the Cancer Therapy Evaluation Program to expand access to clinical trials for HIV-infected people with cancer. Dr. Alvarnas reported no potential conflicts of interest.

Reference 1. Alvarnas J, Le Rademacher, Wang Y, et al: Autologous hematopoietic stem cell transplant (AHCT) in patients with chemotherapy-sensitive relapsed/refractory human immunodeficiency virus (HIV)associated lymphoma. 2014 ASH Annual Meeting. Abstract 674. Presented December 8, 2014.

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PAGE 30

JCO Spotlight Genitourinary Oncology

Nivolumab Shows Activity in Previously Treated Metastatic Renal Cell Carcinoma By Matthew Stenger

n a randomized phase II trial reported in the Journal of Clinical Oncology, Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues found that the programmed cell death protein-1 (PD-1) immune checkpoint inhibitor antibody nivolumab (Opdivo) was associated with antitumor activity and manageable toxicity at three dose levels in patients with metastatic renal cell carcinoma who had previously received vascular endothelial growth factor (VEGF) inhibitor therapy.1 No doseresponse effect in progression-free survival (the primary outcome measure) was observed.

Study Details In the study, 168 patients with clear cell metastatic renal cell carcinoma previously treated with VEGF inhibitors from 39 sites in the United States, Canada, Finland, and Italy were randomly assigned between May 2011 and January 2012 to receive intravenous nivolumab at 0.3 mg/kg (n = 60), 2 mg/kg (n = 54), or 10 mg/kg (n = 54) once every 3 weeks. The primary objective was to evaluate doseresponse relationship measured by progression-free survival. Overall, patients had a median age of 61 years; 72% were male; Memorial Sloan Kettering Cancer Center risk group was favorable for 33%, intermediate for 42%, and poor for 25%; Karnofsky performance status was 70 or 80 in 46% and 90 or 100 in 54%; and 82% had at least two evaluable sites. Sites of lesions included lungs in 74%, lymph nodes in 58%, liver in 28%, skin/soft tissue in 24%, and adrenals in 22%; 36% had received prior radiotherapy; 98% had received prior surgery; the number of prior systemic therapies in the metastatic setting was one for 30%, two for 37%, and more than two for 33%; and the number of prior systemic antiangiogenic therapies in the metastatic setting was one for 62%, two for 33%, and three for 5%. The most common prior systemic therapies in the metastatic setting were sunitinib (74%), everolimus (Afinitor, 34%), pazopanib (Votrient, 27%), interleukin-2 (Proleukin, 23%), and sorafenib (Nexavar, 19%). Overall, 118 patients (70%) had received more than one prior systemic regimen. In total,

107 patients (64%) had quantifiable PD-ligand–1 (PD-L1).

Progression-Free Survival Median progression-free survival in the 0.3-, 2-, and 10-mg/kg groups was 2.7 months (80% confidence interval [CI] = 1.9–3.0 months), 4.0 months (80% CI = 2.8–4.2 months), and 4.2 months (80% CI = 2.8–5.5 months), respectively, with no dose-response relationship observed (P = .9 for trend). An exploratory analysis showed median immune-response progression-free survival of 4.3, 5.4, and 6.9 months (P = .6 for trend).

Response Rates Objective response rates were 20%, 22%, and 20% (P = 1.0). Median time

Nivolumab in Kidney Cancer ■■ Median progression-free survival ranged from 2.7 to 4.2 months, with no dose-response relationship observed. ■■ Many patients remained in response after 24 months. ■■ Median overall survival ranged from 18.2 to 25.5 months.

in the 2-mg/kg group and 0.9 (80% CI = 0.6–1.2) in the 10-mg/kg group. Overall survival reflected Memorial Sloan Kettering risk group and was better in patients with one line of prior therapy than in those with more than one line.

Analysis by PD-L1 Expression Exploratory analysis according to PD-L1 expression status showed that median progression-free survival was 4.9 months among patients with PD-

These efficacy and safety results in [metastatic renal cell carcinoma] support study [of nivolumab] in the phase III setting. —Robert J. Motzer, MD, and colleagues

to response was 2.8 months (range, 1.3–5.6 months), 3.0 months (range, 1.4–6.9 months), and 2.8 months (range, 1.2–10 months). Median duration of response was not reached in the 0.3-mg/kg group and the 2-mg/ kg group and was 22.3 months in the 10-mg/kg group. Among responders, 75% (9/12), 50% (6/12), and 45% (5/11) had ongoing response at the time of analysis. Overall, 40% (14/35) remained in response after 24 months and 7 were still in response that had not yet reached 24 months.

Overall Survival Median overall survival was 18.2 months (80% CI = 16.2–24.0 months), 25.5 months (80% CI = 19.8–28.8 months), and 24.7 months (80% CI = 15.3–26.0 months). According to the authors, the median overall survival values were numerically higher than those reported in pivotal phase III trials in metastatic renal cell carcinoma. Compared with the 0.3-mg/kg group, hazard ratios were 0.8 (80% CI = 0.6–1.1)

L1 expression ≥ 5% (n = 29) and 2.9 months among those with expression < 5% (n = 78), response rates were 31% vs 18%, and median overall survival was not reached vs 18.2 months. Median progression-free and overall survival and response rate were similar between PD-L1–positive (n = 43) and PD-L1–negative (n = 64) patients when an expression cutoff of ≥ 1% for positivity was used.

Adverse Events Treatment-related adverse events of any grade occurred in 75%, 67%, and 78% of patients in the 0.3-, 2-, and 10-mg/kg groups; the most common were fatigue (24%, 22%, and 35%), nausea (10%, 13%, and 13%), and pruritus (10%, 9%, and 11%). Overall skin-related adverse events occurred in 22%, 22%, and 28%. Hypersensitivity (all grade 1 or 2) occurred in 17% of patients in the 10-mg/kg group, compared with 2% of patients in each of the lower-dose groups. Treatment-related grade 3 or 4 adverse events occurred in 5%, 17%, and

13% of patients, with no individual adverse event occurring in > 2% of patients in any group. No grade 3 or 4 pneumonitis was reported. Systemic corticosteroids were used for management of adverse events in 15%, 19%, and 33% of patients. Treatment-related adverse events led to discontinuation of the study drug in 7%, 2%, and 7% of patients, with reasons including elevated serum aspartate transaminase level, cardiac disorder, endocrine disorder, nervous system disorder, and respiratory/thoracic disorder. There were no treatment-related deaths. Based on findings in the current study and analyses of safety and efficacy across tumor types in a large phase I study, nivolumab at 3 mg/kg every 2 weeks has been selected as the monotherapy regimen to be used in further study. The investigators concluded: “Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in [metastatic renal cell carcinoma]. No dose-response relationship was detected as measured by [progression-free survival]. These efficacy and safety results in [metastatic renal cell carcinoma] support study in the phase III setting.”

A phase III trial comparing nivolumab and everolimus in patients with metastatic renal cell carcinoma previously treated with antiangiogenic therapy and a phase III trial evaluating the combination of nivolumab and ipilimumab (Yervoy) in first-line treatment of metastatic renal cell carcinoma are underway. n

Disclosure: The study was supported by Bristol-Myers Squibb and Ono Pharmaceutical Company. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Motzer RJ, Rini BI, McDermott DF, et al: Nivolumab for metastatic renal cell carcinoma: Results of a randomized phase II trial. J Clin Oncol. December 1, 2014 (early release online).

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Perspective

Nivolumab in Previously Treated Metastatic Renal Cell Cancer By Mario Sznol, MD

he approval of multiple inhibitors of either the VEGF or mTOR pathway provided an incremental advance in the treatment of metastatic clear cell renal cancer. However, the agents have several important limitations: For example, the optimal clinical effect appears to be dependent on chronic administration, chronic drug toxicity can impact quality of life in many patients, and almost all patients eventually develop resistance and succumb to the disease. High-dose interleukin (IL)-2 can produce long and unmaintained remissions in approximately 5% to 10% of selected patients with metastatic renal cancer and remains an important option for treat-

received two or more prior therapies. In the latter population, in which additional treatment with other VEGFR or mTOR inhibitors produced at best temporary benefit, the activity of nivolumab (Opdivo), particularly the durable objective responses, appeared particularly striking. Accrual to a phase III trial of nivolumab vs everolimus (Afinitor) in patients progressing on a prior antiangiogenic agent was recently completed and will eventually address the impact of nivolumab on progression-free and overall survival more definitively. Even prior to the availability of the phase III data, it could be argued that the activity and safety profile observed by Motzer et al pro-

Multiple other immunotherapy combinations merit exploration in metastatic renal cancer, with or without the inclusion of a PD-L1/ PD-1 antagonist. —Mario Sznol, MD

ment of the disease. However, multiple approaches to improve on IL-2 activity or to combine it with other agents either have failed or have met with limited success. New effective therapies are desperately needed for both clear cell and non– clear cell metastatic renal cancers.

PD-1/PD-L1 Antagonists In multiple trials, including the recently reported study by Motzer et al reviewed in this issue of The ASCO Post, antibody antagonists of the immune regulatory checkpoint PD-1 (programmed cell death protein 1) or its ligand PD-L1 demonstrated clinically meaningful activity in metastatic clear cell renal cancer.1,2 Objective response rates have been in the range of 20%, and responses can persist for long periods in a subset of patients. Moreover, PD-1/PD-L1 antagonists were generally well tolerated in the clinical trials, with a favorable risk/benefit profile. In the Motzer et al trial, all enrolled patients progressed on a prior systemic antiangiogenic agent, and 70% had Dr. Sznol is Professor of Internal Medicine at Yale Cancer Center in New Haven, Connecticut.

vide sufficient evidence of clinical benefit to consider nivolumab as a second-line treatment option in patients with metastatic clear cell renal carcinoma.

In Combination With Immunotherapy Although substantial time and resources will be expended to refine predictive biomarkers for single-agent PD-1/PD-L1 antagonists and to debate the best sequence for immunotherapy vs targeted therapy or the relative roles of IL-2 vs the PD-1/PD-L1 antagonists, the most important clinical need is to develop even more effective immunologic agents and combinations. At the 2014 ASCO Annual Meeting, Hammers et al reported an overall objective response rate of 45% among 44 patients with metastatic clear cell renal carcinoma treated with one of two dose/ schedules of nivolumab combined with ipilimumab (Yervoy).3 Eighty percent had received a prior therapy and 57%, a prior antiangiogenic agent. Follow-up was short, but 16 of 20 responders had ongoing response at the time of analysis. The rate of grade 3 to 4 adverse events was high, but the adverse events were manageable, as shown in prior studies

of the combination in melanoma. If the activity is confirmed in a planned phase III trial vs sunitinib (Sutent), the combination of ipilimumab and nivolumab could be an important treatment advance for patients with advanced clear cell renal carcinoma. Multiple other immunotherapy combinations merit exploration in metastatic renal cancer, with or without the inclusion of a PD-L1/PD-1 antagonist. The highest priority will likely be given to combinations of active cytokines such as interferon alfa (Roferon-A, Intron A) or IL-2 with a PD-1/PD-L1 antagonist, combinations of inhibitors of immunosuppressive pathways, and combinations of immune costimulatory antibodies with PD-1/PD-L1 antagonists. It seems likely that other highly active and tolerable combinations will be discovered, although the challenge will be to select the best combination for each individual patient. Evaluation of all the potential combinations exceeds the capacity of the clinical trials system, and the best endpoints for go/no-go decisions beyond the initial trials remain unclear.

More Combinations Under Study Promising clinical data were also recently presented for combinations of PD-1/PD-L1 antagonists with antiangiogenic agents. The mechanisms by which these two classes of agents could interact to produce improved antitumor activity are unknown but could be related to potential beneficial effects of the antiangiogenic agents on the immune tumor microenvironment or on traffic of lymphocytes into tumor. At the 2014 ASCO Annual Meeting, Amin et al reported the results of a trial combining nivolumab with either sunitinib or pazopanib (Votrient).4 Objective response rates were high for both combinations, from 45% to 52%, which included patients who had progressed on a prior VEGFR tyrosine kinase inhibitor. Rates of grade 3 to 4 toxicity were high in both arms, and therefore, further adjustments in dose and schedule may be necessary to define an optimal regimen. At the 2014 ESMO Meeting, early encouraging data were also presented by McDermott et al for the combination of bevacizumab (Avastin) with the anti–PD-L1 agent MPDL3280A.5 Among the 10 evaluable patients, 4

met criteria for objective response, and another 4 achieved stable disease for at least 24 weeks. The MPDL3280A/bevacizumab combination was well tolerated, with a low rate of grade 3 adverse events. A phase II randomized trial of MPDL3280A with or without bevacizumab vs sunitinib will complete accrual soon, and phase III trials are likely to follow. It remains to be seen whether responses to combinations of immunotherapies with antiangiogenic agents will persist beyond discontinuation of the VEGF pathway inhibitor. Overall, the immune checkpoint inhibitors, and particularly the PD-1/ PD-L1 inhibitors, represent an important new class of agents for treatment of metastatic renal cancer. We observed significant tumor regression in a patient with non–clear cell renal cancer treated with anti–PD-L1, suggesting that trials in non–clear cell renal cancer should also be pursued. n

Disclosure: Dr. Sznol is a paid consultant for Genentech/Roche, Bristol-Myers Squibb, Astra-Zeneca/Medimmune, Pfizer, Novartis, Kyowa-Kirin, Merus, Seattle Genetics, Immune Design, Prometheus, Anaeropharma, AstellasAgensys, Immunova, Nektar, Neostem, and Pierre-Fabre and is on the advisory board of Symphogen, Lion Biotechnologies Amphivena, and Adaptive Biotechnologies.

References 1. Motzer RJ, Rini BI, McDermott DF, et al: Nivolumab for metastatic renal cell carcinoma: Results of a randomized phase II trial. J Clin Oncol. December 1, 2014 (early release online). 2. 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. 3. Hammers HJ, Plimack ER, Infante JR, et al: Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma. 2014 ASCO Annual Meeting. Abstract 4504. 4. Amin A, Plimack ER, Infante JR, et al: Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients with metastatic renal cell carcinoma. 2014 ASCO Annual Meeting. Abstract 5010. 5. McDermott DF, Sznol M, Sosman JA, et al: Immune correlates and long term follow up of a phase Ia study of MPDL3280A, an engineered PD-L1 antibody, in patiens with metastatic renal cell carcinoma (mRCC). 2014 Annual ESMO Conference. Abstract 809O.

The ASCO Post | MARCH 10, 2015

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In the Clinic Thyroid Cancer

Lenvatinib in Advanced Radioiodine-Refractory Differentiated Thyroid 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 February 13, 2015, lenvatinib (Lenvima) was approved for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine–refractory differentiated thyroid cancer.1,2

Supporting Trial Approval was based on the finding of increased progression-free survival for lenvatinib vs placebo in a double-blind trial in which 392 patients with disease progression within the prior 12 months were randomly assigned to lenvatinib at 24 mg per day in 28-day cycles (n = 261) or placebo (n = 131).2,3 Patients in the placebo group could receive lenvatinib following independent radiologic confirmation of disease progression. Among all patients, median age was 63 years (40% > 65 years), 51% were male, 79% were white, 54% had Eastern Cooperative Oncology Group performance status of 0, and 24% had received one prior vascular endothelial growth factor (VEGF)/ VEGF receptor–targeted therapy. Metastases were present in 99%, including in lungs in 89%, lymph nodes in 52%, bone in 39%, liver in 18%, and brain in 4%. Histologic diagnoses were papillary in 66% and follicular in 34%; of those with follicular histology, 44% had Hürthle cell and 11% had clear cell subtypes. No iodine uptake on any radioiodine scan was observed in 67% of patients in the lenvatinib group and 77% in the placebo group. Median progression-free survival was 18.3 months (95% confidence interval [CI] = 15.1 months to not estimable) in the lenvatinib group vs 3.6 months (95% CI = 2.2–3.7 months) in the placebo group (hazard ratio [HR] = 0.21, P < .001). Objective response rates were 65% (complete response in 2%) vs 2% (P < .001). Median overall survival was not reached in either group (HR = 0.73, P = .10). At disease progression, 109 placebo patients (83%) received open-label lenvatinib.

How It Works Lenvatinib is a receptor tyrosine kinase inhibitor that inhibits the kinase activities of VEGF receptors 1, 2, and 3.

It also inhibits other receptor tyrosine kinases implicated in pathogenic angiogenesis, tumor growth, and cancer progression as well as normal cellular functions, including fibroblast growth factor (FGF) receptors 1, 2, 3, and 4, plateletderived growth factor (PDGF) receptor α, KIT, and RET.

How It Is Given The recommended dose of lenvatinib is 24 mg/d, continued until disease progression or unacceptable toxicity. In patients with severe renal impairment or severe hepatic impairment, the recommended dose is 14 mg/d. Treatment should be interrupted for grade 4 clinical adverse events; at present, there are no recommendations on resumption of dosing in patients with grade 4 reactions that resolve. In general, for persistent and intolerable grade 2 adverse events, grade 3 adverse events, and grade 4 laboratory abnormalities, treatment should be interrupted until resolu-

tinued depending on the severity and persistence of the reaction. For proteinuria ≥ 2 g/24 hours, treatment should be withheld and can be resumed at a reduced dose when proteinuria is < 2 g/24 hours; treatment should be discontinued for nephrotic syndrome. Lenvatinib should be discontinued for gastrointestinal perforation or lifethreatening fistula. Treatment should be withheld for grade ≥ 3 QT-interval prolongation and can be resumed at a reduced dose when QT prolongation resolves to grade 0 or 1 or baseline status. Lenvatinib should be withheld for reversible posterior leukoencephalopathy syndrome until complete resolution; it can be resumed at a reduced dose or discontinued depending on the severity and persistence of neurologic symptoms.

Safety Profile In the randomized trial, median treatment duration was 16.1 months in the lenvatinib group and 3.9 months in the

Lenvatinib in Thyroid Cancer ■■ Lenvatinib (Lenvima) was approved for the treatment of patients with locally recurrent or metastatic, progressive, radioiodine-refractory differentiated thyroid cancer. ■■ The recommended dose of lenvatinib is 24 mg/d, continued until disease progression or unacceptable toxicity.

tion to grade 0 or 1 or baseline status and resumed at doses of 20, 14, and 10 mg/d for successive interruptions. With regard to specific adverse reactions, lenvatinib should be withheld for grade 3 hypertension that persists despite optimal antihypertensive therapy and resumed at a reduced dose when hypertension is controlled to grade ≤ 2. Treatment should be discontinued for life-threatening hypertension. In addition, treatment should be discontinued for grade 4 cardiac dysfunction or hemorrhage; it should be withheld for grade 3 events until improvement to grade 0 or 1 or baseline status and can be resumed at a reduced dose or discontinued depending on the severity and persistence of the reaction. Lenvatinib should be discontinued after an arterial thrombotic event. Lenvatinib should be discontinued for hepatic failure. For grade 3 or 4 renal failure/impairment or hepatotoxicity, it should be withheld until resolution to grade 0 or 1 or baseline status and can be resumed at a reduced dose or discon-

placebo group. The most common adverse events of any grade in the lenvatinib group occurring at an incidence ≥ 5% higher vs the placebo group were hypertension (73% vs 16% in the placebo group), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), decreased weight (51% vs 15%), nausea (47% vs 25%), and stomatitis (41% vs 8%). The most common grade 3 or 4 adverse events were hypertension (44% vs 4%), decreased weight (13% vs 1%), fatigue (11% vs 4%), proteinuria (11% vs 0%), and diarrhea (9% vs 0%). The most common grade 3 or 4 laboratory abnormalities were hypocalcemia (9% vs 2%), hypokalemia (6% vs 1%), increased aspartate aminotransferase levels (5% vs 0%), increased alanine aminotransferase levels (4% vs 0%), and increased lipase (4% vs 1%). The most common serious adverse events in lenvatinib patients were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse events led to dose reductions in 68% of lenvatinib recipients vs 5% of placebo recipients, with the most

OF NOTE Lenvatinib carries warnings/precautions for hypertension, cardiac failure, arterial thrombotic events, hepatotoxicity, proteinuria, renal impairment, gastrointestinal perforation, and fistula formation, among other toxicities.

common causes in lenvatinib recipients being hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%). Adverse events led to discontinuation of treatment in 18% vs 5%, with the most common cause in lenvatinib patients being hypertension (1%) and asthenia (1%). Lenvatinib carries warnings/precautions for hypertension, cardiac failure, arterial thrombotic events, hepatotoxicity, proteinuria, renal failure and impairment, gastrointestinal perforation and fistula formation, QT-interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroidstimulating hormone suppression, and embryofetal toxicity. Patients must have blood pressure controlled prior to treatment and should have blood pressure, liver function tests, and proteinuria monitored prior to and regularly during treatment. Patients should be monitored for clinical symptoms or signs of cardiac decompensation. Electrolytes should be monitored in all patients and abnormalities corrected. Blood calcium levels should be monitored at least monthly, with calcium replacement as necessary. Thyroid-stimulating hormone levels should be monitored monthly and thyroid replacement medication adjusted as needed. Patients should be advised regarding potential fetal risk and effective contraception. n References 1. U.S. Food and Drug Administration: Lenvatinib (Lenvima). Available at http:// www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm434347.htm. Accessed February 19, 2015. 2. Lenvatinib (LenvimaTM) capsules prescribing information. Esai Inc, February 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf. Accessed February 19, 2015. 3. Schlumberger M, Tahara M, Wirth LJ, et al: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621-630, 2015.

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FDA Update

FDA Approves Palbociclib in Combination With Letrozole for Advanced Breast Cancer

he U.S. Food and Drug Administration has granted accelerated approval to palbociclib (Ibrance) in combination with letrozole for the treatment of postmenopausal women with estrogen receptor–positive, HER2-negative metastatic breast cancer who have not yet received an endocrine-based therapy. Palbociclib is an inhibitor of cyclindependent kinase (CDK) 4 and 6. In vitro palbociclib reduced cellular proliferation of estrogen receptor–positive breast cancer cell lines by blocking progression of cells from the G1 into the S phase of the cell cycle. “The addition of palbociclib to letrozole provides a novel treatment option to women diagnosed with metastatic breast cancer,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Clinical Trial Results The approval was based on the results of a randomized, multicenter, open-label trial in 165 postmenopausal women with

estrogen receptor–positive, HER2-negative, locally advanced or metastatic breast cancer who had not received previous systemic treatment for advanced disease. Patients were randomly assigned to receive either palbociclib (125 mg/d for 21 days, followed by 7 days off treatment) plus letrozole (2.5 mg/d continuously throughout the 28-day cycle) or letrozole alone. Among the 165 patients, 43% had received chemotherapy and 33% had received antihormonal therapy as a neoadjuvant or adjuvant treatment; 49% of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had metastatic disease. Participants treated with palbociclib plus letrozole had a median progressionfree survival of 20.2 months (95% confidence interval [CI] = 13.8–27.5), compared to about 10.2 months (95% CI = 5.7–12.6) in patients receiving only letrozole (hazard ratio [HR] = 0.488, 95% CI = 0.319–0.748). The treatment effect

of the combination on progression-free survival was also supported by a retrospective radiographic independent review (HR = 0.621, 95% CI = 0.378–1.109). The overall response rate in patients with measurable disease was higher in the palbociclib-plus-letrozole arm compared to the letrozole-alone arm (55.4% vs 39.4%). Information on overall survival is not available at this time. The most common side effects of the drug were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse reactions in patients receiving the combination were pulmonary embolism (4%) and diarrhea (2%). Health-care professionals should inform patients of these risks. It is recommended that treatment begin with a 125-mg dose for 21 days, followed by 7 days without treatment.

Health-care professionals are advised to monitor complete blood cell count prior to the start of therapy and at the beginning of each cycle, as well as on day 14 of the first two cycles, and as clinically indicated.

Approval History The FDA granted palbociclib Breakthrough Therapy designation in April 2013 based on preliminary evidence of clinical activity in this patient population. It also received a priority review, which provides for an expedited review of drugs intended to provide a significant improvement in safety or effectiveness in the treatment of a serious condition or meet an unmet medical need. Palbociclib is being approved more than 2 months ahead of the prescription drug user fee goal date of April 13, 2015. This accelerated approval is based on demonstration of an improvement in progression-free survival. See page 85 in this issue of The ASCO Post for a comprehensive overview of palbociclib in combination with letrozole for advanced breast cancer. n

FDA Grants Cobimetinib Priority Review for Use in Combination With Vemurafenib in Advanced Melanoma

he U.S. Food and Drug Administration (FDA) has accepted and granted Priority Review for Genentech’s New Drug Application (NDA) for cobimetinib in combination with vemurafenib (Zelboraf) for the treatment of people with

positive unresectable locally advanced or metastatic melanoma who had not previously been treated for advanced disease. Patients were randomly assigned to receive vemurafenib every day on a 28-day cycle plus either cobimetinib or placebo on days 1 to 21. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-

BRAF V600 mutation–positive advanced melanoma. The FDA will make a decision on approval by August 11, 2015. Cobimetinib is designed to selectively block the activity of MEK, one of a series of proteins make up a signaling pathway that helps regulate cell division and survival. Cobimetinib binds to MEK while vemurafenib binds to mutant BRAF, another protein on the pathway, to interrupt abnormal signaling that can cause tumors to grow.

FDA Grants Breakthrough Therapy Designation to MPDL3280A for Non–Small Cell Lung Cancer

Phase III coBRIM Study The NDA is based on results of the phase III coBRIM study, which evaluated the safety and efficacy of cobimetinib plus vemurafenib vs vemurafenib alone in 495 patients with BRAF V600 mutation–

he U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to Genentech’s investigational cancer immunotherapy MPDL3280A for the treatment of PD-L1–positive non–small cell lung cancer (NSCLC) that has progressed during or after platinum-based chemotherapy (and an appropriate targeted therapy for those with an EGFR mutation–positive or ALK-positive tumor). MPDL3280A (also known as anti– PD-L1) is an investigational mono-

assessed progression-free survival. Cobimetinib plus vemurafenib reduced the risk of disease worsening or death by half in people who received the combination (hazard ratio = 0.51, 95% confidence interval = 0.39–0.68, P < .0001). The median progression-free survival was 9.9 months for cobimetinib plus vemurafenib compared to 6.2 months with vemurafenib alone.

clonal antibody designed to interfere with a protein called programmed death ligand 1 (PD-L1). MPDL3280A is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, MPDL3280A may enable the activation of T cells, restoring their ability to effectively detect and attack tumor cells. This Breakthrough Therapy designation is based on early results of MP-

The safety profile was consistent with a previous study of the combination. The most common grade 3 or higher adverse events in the combination arm included liver lab value abnormalities, elevated creatine phosphokinase, and diarrhea. The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity, and lab value abnormalities. n

DL3280A in patients whose NSCLC was characterized as PD-L1–positive by an investigational test being developed by Roche. All studies of MPDL3280A are prospectively evaluating PD-L1 expression. Some studies will evaluate the medicine regardless of a tumor’s PD-L1 status; other studies are evaluating the medicine only in people whose tumors are characterized as PD-L1–positive. MPDL3280A previously received Breakthrough Therapy designation for metastatic bladder cancer in 2014. n

First-line Treatment for CLL ARZERRA® (ofatumumab) is indicated, in combination with chlorambucil, for previously untreated patients with CLL for whom ﬂudarabine-based therapy is considered inappropriate

An Effective Combination to Extend PFS*

*Assessed by a blinded Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute–sponsored Working Group (NCI-WG) guidelines (2008). CLL=chronic lymphocytic leukemia; PFS=progression-free survival; AR=adverse reaction; IR=infusion reaction.

Indications

Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in ARZERRA (ofatumumab) is indicated: fulminant hepatitis, hepatic failure and death, has occurred • In combination with chlorambucil, for the treatment of previously in patients treated with ARZERRA. Cases have been reported untreated patients with chronic lymphocytic leukemia (CLL) for in patients who are hepatitis B surface antigen (HBsAg) positive whom fludarabine-based therapy is considered inappropriate and also in patients who are HBsAg negative but are hepatitis B • For the treatment of patients with CLL refractory to core antibody (anti-HBc) positive. Reactivation also has occurred fludarabine and alemtuzumab in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface Important Safety Information for ARZERRA antibody [anti-HBs] positive). WARNING: HEPATITIS B VIRUS REACTIVATION AND HBV reactivation is defined as an abrupt increase in HBV PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously • Hepatitis B Virus (HBV) reactivation can occur in HBsAg negative and anti-HBc positive. Reactivation of HBV patients receiving CD20-directed cytolytic antibodies, replication is often followed by hepatitis, ie, increase in including ARZERRA, in some cases resulting in transaminase levels and, in severe cases, increase in bilirubin fulminant hepatitis, hepatic failure, and death levels, liver failure, and death. [see Warnings and Precautions (5.2)]. • Progressive Multifocal Leukoencephalopathy (PML) Screen all patients for HBV infection by measuring HBsAg and resulting in death can occur in patients receiving anti-HBc before initiating treatment with ARZERRA. For CD20-directed cytolytic antibodies, including ARZERRA patients who show evidence of hepatitis B infection (HBsAg [see Warnings and Precautions (5.4)]. positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing Infusion Reactions hepatitis B regarding monitoring and consideration for HBV ARZERRA can cause serious, including fatal, infusion reactions antiviral therapy. manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, Monitor patients with evidence of current or prior HBV cardiac events (eg, myocardial ischemia/infarction, acute coronary infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment syndrome, arrhythmia, bradycardia), back pain, abdominal pain, with ARZERRA. HBV reactivation has been reported for at least pyrexia, rash, urticaria, angioedema, cytokine release syndrome, 12 months following completion of therapy. and anaphylactoid/anaphylactic reactions. Infusion reactions In patients who develop reactivation of HBV while receiving occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment. ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate Administer ARZERRA in an environment where facilities to treatment. Resumption of ARZERRA in patients whose HBV adequately monitor and treat infusion reactions are available. reactivation resolves should be discussed with physicians with Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication. expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who Interrupt infusion with ARZERRA for infusion reactions of any develop HBV reactivation. severity. Institute medical management for severe infusion Hepatitis B Virus Infection reactions including angina or other signs and symptoms Fatal infection due to hepatitis B in patients who have not been of myocardial ischemia. If an anaphylactic reaction occurs, previously infected has been observed with ARZERRA. Monitor immediately and permanently discontinue ARZERRA and patients for clinical and laboratory signs of hepatitis. initiate appropriate medical treatment. ®

ARZERRA Plus Chlorambucil Demonstrated a Median PFS of 22.4 Months vs 13.1 Months With Chlorambucil Alone1 Probability of Progression-free Survival

1.0

ARZERRA + chlorambucil (n=221) Chlorambucil (n=226)

0.9 0.8

(HR 0.57 [95% CI: 0.45, 0.72] P<0.001)

0.7

22.4

0.6

13.1

0.4

• 67% incidence of IRs (all grades), including Grade ≥3, serious, or those that led to interruption or discontinuation; majority were Grade 1-2 and decreased after Cycle 1

Months

0.3 0.2 0.1 0.0 0

Number at risk ARZERRA plus 221 192 169 Chlorambucil 173 130 Chlorambucil 226

• 10% incidence of Grade ≥3 IRs; occurred most frequently during Cycle 1 — 6% on Day 1 — 3% on Day 8

Months

0.5

The Most Common ARs (≥10%) Were IRs and Neutropenia1

Time of Progression-free Survival (Months) 148

125

104

ARZERRA in combination with chlorambucil vs chlorambucil alone was studied in a randomized, open-label, parallel-arm, multicenter trial of 447 patients with previously untreated CLL for whom ﬂudarabine-based therapy was considered inappropriate. The population for safety analysis comprised 444 patients.1 HR=hazard ratio; CI=conﬁdence interval.

Important Safety Information for ARZERRA (cont’d) Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

— 56% on Day 1 — 23% on Day 8 • No patients in the chlorambucilalone arm experienced IRs • 3% of IRs led to discontinuation of ARZERRA • 27% incidence of neutropenia with ARZERRA plus chlorambucil vs 18% with chlorambucil alone

Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the previously untreated CLL clinical trial, the most common adverse reactions (≥10%, all grades) were infusion reactions (67% for ARZERRA plus chlorambucil vs 0% for chlorambucil) and neutropenia (27% vs 18%). In the single-arm refractory CLL clinical trial, the most common adverse reactions (≥10%, all grades) were neutropenia, pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation. Laboratory Abnormalities In the previously untreated CLL clinical trial, post-baseline hematologic laboratory abnormalities (all grades) occurring with ≥5% incidence in patients receiving ARZERRA plus chlorambucil and also ≥2% more than patients receiving chlorambucil were leukopenia (67% for ARZERRA plus chlorambucil vs 28% for chlorambucil), neutropenia (66% vs 56%), and lymphopenia (52% vs 20%). Reference: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GSK; 2014.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for ARZERRA on the following pages.

ARZERRA J-Code: J9302 To learn more, please visit www.ARZERRAhcp.com.

The ASCO Post | MARCH 10, 2015

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FDA Update

FDA Approves Lenvatinib for Progressive Radioiodine-Refractory Differentiated Thyroid Cancer

he U.S. Food and Drug Administration (FDA) has granted approval to lenvatinib (Lenvima) to treat patients with progressive, differentiated thyroid cancer whose disease progressed despite

receiving radioactive iodine therapy. Lenvatinib is a tyrosine kinase inhibitor that binds to multiple sites involved in angiogenesis and proliferation. “The development of new therapies

BRIEF SUMMARY ARZERRA® (ofatumumab) Injection, for intravenous infusion The following is a brief summary only; see full prescribing information, including Boxed Warning, for complete product information. WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA®, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)]. • Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.1 Previously Untreated Chronic Lymphocytic Leukemia ARZERRA (ofatumumab) is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate [see Clinical Studies (14.1) of full prescribing information]. 1.2 Refractory CLL ARZERRA is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab [see Clinical Studies (14.2) of full prescribing information]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment [see Adverse Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing information]. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3) of full prescribing information]. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment. 5.2 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have 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 also has 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 ARZERRA. 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 ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately

to assist patients with refractory disease is of high importance to the FDA,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evalu-

discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA 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 ARZERRA in patients who develop HBV reactivation. 5.3 Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis. 5.4 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. 5.6 Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA [see Adverse Reactions (6.1)]. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. 5.7 Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Infusion Reactions [see Warnings and Precautions (5.1)] • Hepatitis B Virus Reactivation [see Warnings and Precautions (5.2)] • Hepatitis B Virus Infection [see Warnings and Precautions (5.3)] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.4)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.5)] • Cytopenias [see Warnings and Precautions (5.6)] Previously Untreated CLL: The most common adverse reactions (≥10%) were infusion reactions and neutropenia (Table 1). Refractory CLL: The most common adverse reactions (≥10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections (Table 3). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation. 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 with rates in the clinical trials of another drug and may not reﬂect the rates observed in practice. Previously Untreated CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 1) in 444 patients with previously untreated CLL. Patients were randomized to receive either ARZERRA as an intravenous infusion every 28 days in combination with chlorambucil (n = 217) or chlorambucil as a single agent (n = 227). In both arms, patients received chlorambucil 10 mg/m2 orally on Days 1 to 7 every 28 days. The infusion schedule for ARZERRA was 300 mg administered on Cycle 1 Day 1, 1,000 mg administered on Cycle 1 Day 8, and 1,000 mg administered on Day 1 of subsequent 28-day cycles. The median number of cycles of ARZERRA completed was 6. The data described in Table 1 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 2 includes relevant hematologic laboratory abnormalities.

(cont’d)

ASCOPost.com | MARCH 10, 2015

PAGE 37

FDA Update

ation and Research. “Today’s approval gives patients and health-care professionals a new therapy to help slow the progression of differentiated thyroid cancer.”

Clinical Trial Details Lenvatinib’s efficacy was demonstrated in a phase III trial of 392 participants with progressive, radioiodine-refractory

differentiated thyroid cancer who were randomly assigned to receive either the study drug or a placebo. Study results showed lenvatinib-treated participants had a median progression-free survival of 18.3 months, compared to a median of 3.6 months for participants who received a placebo. Additionally, 65% of participants treated with lenvatinib saw a reduction in

Table 1. Adverse Reactions With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil and Also ≥2% More Than Patients Receiving Chlorambucil ARZERRA Plus Chlorambucil (N = 217)

Chlorambucil (N = 227)

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

Infusion reactionsa

Neutropenia

Asthenia

Headache

Lower respiratory tract infection

Arthralgia

Adverse Reactions

Leukopenia Herpes simplex

Upper abdominal pain

Adverse Events The most common side effects of lenvatinib were hypertension, fatigue, diar-

Table 3. Incidence of All Adverse Reactions Occurring in ≥5% of Patients and in the Fludarabine- and Alemtuzumab-refractory Subset

Total Population (N = 154) Adverse Reaction Pneumoniaa

Fludarabine- and Alemtuzumabrefractory (N = 59)

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

Pyrexia

Cough

Diarrhea

Anemia

Fatigue

Dyspnea

Rashb

Bronchitis

Nausea

Upper respiratory tract infection

Edema peripheral

Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, ﬂushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria. b Includes oral herpes, herpes, herpes virus infection, genital herpes, and herpes simplex. Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil and Also ≥2% More Than Patients Receiving Chlorambucil

Leukopenia

continued on page 38

and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were white.

ARZERRA Plus Chlorambucil (N = 217)

rhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmarplantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. Lenvatinib may cause serious side effects, including cardiac failure, arterial thromboembolic events, hepato-

tumor size, compared to the 2% of participants who received a placebo. A majority of participants randomly assigned to receive the placebo were treated with lenvatinib upon disease progression.

Chlorambucil (N = 227)

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

Neutropenia

Lymphopenia

Infusion Reactions: Overall, 67% of patients who received ARZERRA in combination with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal). Infusion reactions that were either Grade 3 or greater, serious, or led to treatment interruption or discontinuation occurred most frequently during Cycle 1 (56% on Day 1 [6% were Grade 3 or greater] and 23% on Day 8 [3% were Grade 3 or greater]) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients. Neutropenia: Overall, 3% of patients had neutropenia as a serious adverse event, reported up to 60 days after the last dose. One patient died with neutropenic sepsis and agranulocytosis. Prolonged neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 4% of patients receiving chlorambucil. Late-onset neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 1% of patients receiving chlorambucil alone. Refractory CLL: The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 2 [n = 154]) or 3 doses (Study 3 [n = 27]). The data described in Table 3 and other sections below are derived from 154 patients in Study 2. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA

Back pain

Chills

Nasopharyngitis

Sepsisc

Urticaria

Insomnia

Headache

Herpes zoster

Hyperhidrosis

Hypertension

Hypotension

Muscle spasms

Sinusitis

Tachycardia

Includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. b Includes rash, rash macular, and rash vesicular. c Includes sepsis, neutropenic sepsis, bacteremia, and septic shock. a

Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the ﬁrst infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 or greater infections, of which 19 (12%) were fatal. The proportion of fatal infections in the ﬂudarabine- and alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 or greater neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 300 patients with CLL were tested during and after treatment for antibodies to ARZERRA. (cont’d)

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PAGE 38

FDA Update Lenvatinib continued from page 37

toxicity, renal failure and impairment, gastrointestinal perforation or fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhage, risks to an unborn child if a patient becomes pregnant during

treatment, and impairing suppression of the production of thyroid-stimulating hormone. Lenvatinib was reviewed under the FDA’s Priority Review program, which provides for an expedited review of drugs that, if approved, would provide significant improvement in safety or effectiveness in the treatment

There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA 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 ARZERRA. 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. Infusion-related Cardiac Events: Cardiac arrest. Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda. 7 DRUG INTERACTIONS Coadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or wellcontrolled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older. Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see Adverse Reactions (6.1)]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients [see Clinical Studies (14.1) of full prescribing information]. In refractory CLL, clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted. 10 OVERDOSAGE No data are available regarding overdosage with ARZERRA. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

of a serious condition. The drug also received Orphan Product designation because it is intended to treat a rare disease. Lenvatinib is being approved approximately 2 months ahead of the prescription drug user fee goal date of April 14, 2015. See page 32 in this issue for a comprehensive overview of lenvatinib. n

13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the maximum human dose (2,000 mg) of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the ﬁnal dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15% to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared with control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared with the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared with control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared with the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological signiﬁcance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals. 17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1), Adverse Reactions (6.1)] • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.2, 5.3)] • New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.4)] • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.6)] • Signs of infections including fever and cough [see Warnings and Precautions (5.6), Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Monitoring and possible need for treatment if they have a history of hepatitis B infection (based on the blood test) [see Warnings and Precautions (5.2)] • Periodic monitoring for blood counts [see Warnings and Precautions (5.6)] • Avoiding vaccination with live viral vaccines [see Warnings and Precautions (5.7)] ARZERRA is a registered trademark of the GSK group of companies. Manufactured by: GLAXO GROUP LIMITED Brentford, Middlesex, TW8 9GS, United Kingdom U.S. License 1809 Distributed by:

GlaxoSmithKline Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved. Revised: 04/2014 ARZ:8BRS ©2014 GSK group of companies. All rights reserved. Printed in USA. AZA522R0 October 2014

Human Reovirus Formulation Gets Orphan Drug Designation in Ovarian and Pancreatic Cancer

he U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation for Oncolytics Biotech’s proprietary formulation of the human reovirus (Reolysin) for the treatment of ovarian and pancreatic cancer. The reovirus’s primary mode of activity is to infect and selectively target tumors with activating Ras pathway mutations and/or overexpressions of Ras pathway elements including EGFR, BRAF, and KRAS. Oncolytics has supported two sponsored clinical studies assessing the reovirus in the treatment of ovarian cancer. The first was a phase I/ II clinical trial (OSU-07022) for patients with metastatic ovarian, perito-

neal, and fallopian tube cancers using concurrent intravenous and intraperitoneal administration of the human reovirus that provided evidence of viral targeting and replication in peritoneal and ovarian cancer cells. The second study is an ongoing randomized phase II trial (GOG186H) of weekly paclitaxel vs weekly paclitaxel with the reovirus in patients with persistent or recurrent ovarian, fallopian tube or primary peritoneal cancer. The second trial completed enrollment in September 2014. n

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication

ASCOPost.com | MARCH 10, 2015

PAGE 39

Journal Spotlight Thoracic Oncology

First-Line Crizotinib Improves Progression-Free Survival vs Chemotherapy in ALK-Positive NSCLC By Matthew Stenger

n a phase III trial (PROFILE 1014) reported in The New England Journal of Medicine, Benjamin J. Solomon, MB, BS, PhD, of Peter MacCallum Cancer Centre, Melbourne, and colleagues found that the ALK inhibitor crizotinib (Xalkori) improved progression-free survival vs standard chemotherapy in first-line treatment of advanced ALK-positive non–small cell lung cancer (NSCLC).1 Crizotinib was associated with significant improvements in patient-reported outcomes. The median overall survival had not been reached in either group. Dr. Solomon and Tony Mok, MD, of Chinese University of Hong Kong, contributed equally to The New England Journal of Medicine article.

In patients with previously untreated ALK-positive NSCLC, crizotinib treatment was superior to pemetrexedplus-platinum chemotherapy with respect to progression-free survival, objective response rate, reduction of lung cancer symptoms, and improvement in quality of life. —Benjamin J. Solomon, MB, BS, PhD, Tony Mok, MD, and colleagues

Study Details In this open-label international trial, 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease were randomized between January 2011 and July 2013 to receive oral crizotinib 250 mg twice daily (n = 172) or intravenous chemotherapy (n = 171) consisting of pemetrexed (Alimta) 500 mg/m2 plus either cisplatin 75 mg/ m2 or carboplatin area under the curve of 5 to 6 mg/mL/min every 3 weeks for up to 6 cycles. Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) performance status, Asian or non-Asian race, and presence or absence of brain metastases. Crossover to crizotinib after disease progression was permitted. The primary endpoint was progression-free survival assessed by independent radiologic review. The crizotinib and chemotherapy groups were generally balanced for age (median 52 and 54 years), gender (60% and 63% female), race (53% and 50% white, 45% and 47% Asian), smoking status (never for 62% and 65%, former for 33% and 32%, and current for 6% and 3%), histology (adenocarcinoma in 94% in both), ECOG performance status (0 or 1 in 94% and 95%), extent of disease (locally advanced in 2% in both, metastatic in

98% in both), brain metastases (26% and 27%), and time since initial diagnosis (median 1.2 months in both). Among evaluable intravenous chemotherapy patients, 91 received pemetrexed-cisplatin and 78 received pemetrexed-carboplatin.

Progression-Free Survival At the time of data cutoff, the median duration of follow-up for overall survival was 17.4 months in the crizotinib group and 16.7 months in the chemotherapy group. The median duration of treatment was 10.9 months (range, 0.4–34.3 months) in the crizotinib group (median of 16 cycles started) and 4.1 months (range, 0.7–6.2 months) in the chemotherapy group (median of 6 cycles of chemotherapy started). Progression-free survival was significantly longer with crizotinib than with chemotherapy (median 10.9 vs 7.0 months, hazard ratio [HR] = 0.45, P < .001). Subgroup analysis showed that HRs significantly favored crizotinib in almost all stratification and baseline characteristic subgroups, including Asian (HR = 0.44) and non-Asian patients (HR = 0.53), age < or ≥ 65 years, gender, never and current/ former smokers, and presence or absence of brain metastases.

Crizotinib in ALK-Positive NSCLC ■■ Crizotinib was associated with improved progression-free survival vs standard chemotherapy in first-line treatment of advanced ALK-positive NSCLC. ■■ Response rate and quality-of-life outcomes were also significantly better with crizotinib treatment.

Response Rates, Overall Survival Objective response rates were 74% (including complete response in 2%) vs 45% (including complete response in 1% [P < .001]), and the median duration of response was 11.3 vs 5.3 months. Median overall survival was not reached in either group (HR = 0.82, P = .36), likely reflecting the low rate of all-cause mortality in the population (26%) and the fact that 70% of patients in the chemotherapy group crossed over to crizotinib treatment. The probability of 1-year survival was 84% vs 79% with chemotherapy. After adjustment for crossover with a rank-preserving structural failure time model, the HR for death with crizotinib was 0.60 (95% confidence interval = 0.27–1.42). Among patients in the crizotinib group, 74 of 89 (83%) with disease progression continued to receive crizotinib for a median of 3.0 months (range, 0.7–22.6 months); 21 crizotinib patients (12%) subsequently received platinum-based chemotherapy.

Adverse Events The most common adverse events of any grade with a frequency ≥ 5% in the crizotinib group were vision disorder (71% vs 9%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), and constipation (43% vs 30%); the most common adverse events with a frequency ≥ 5% in the chemotherapy group were fatigue (38% vs 29%), anemia (32% vs 9%), and neutropenia (30% vs 21%). The most common grade 3 or 4 adverse events were elevated to aminotransfer-

ases (14%) and neutropenia (11%) in the crizotinib group and neutropenia (15%), anemia (9%), and thrombocytopenia (7%) in the chemotherapy group. Adverse events led to treatment discontinuation in 12% of the crizotinib group and 14% of the chemotherapy group; events leading to treatment discontinuation in the crizotinib group included hepatic events in four patients and interstitial lung disease in two patients. One case of fatal pneumonitis occurred in a patient who crossed over to crizotinib and was considered related to crizotinib treatment.

Patient-Reported Outcomes Patient-reported outcomes were assessed by the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life core questionnaire (QLQ-C30) and corresponding lung cancer module (QLQ-LC13) and the EuroQol Group 5-Dimension SelfReport Questionnaire (EQ-5D). Crizotinib treatment was associated with greater overall improvement from baseline in global quality of life (P < .001); overall improvement in physical, social, emotional, and role-functioning domains (P < .001); and overall reduction in the symptoms of pain, dyspnea, and insomnia assessed by QLQ-C30 and in dyspnea, cough, chest pain, arm or shoulder pain, and pain in other parts of the body assessed by QLQ-LC13 (P < .001 for all comparisons). The crizotinib group also had a significantly greater delay in worsening of lung cancer symptoms (HR = 0.62, P = .002), with an estimated probability of being event-free at 6 months of 38% vs 22%, and a greater improvement in EQ5D general health status scores (P = .002). The investigators concluded: “[I]n patients with previously untreated ALKpositive NSCLC, crizotinib treatment was superior to pemetrexed-plus-platinum chemotherapy with respect to progression-free survival, objective response rate, reduction of lung cancer symptoms, and improvement in quality of life.” n

Disclosure: This study was funded by Pfizer. For full disclosures of the study authors, visit www. nejm.org.

Reference 1. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-2177, 2014. See commentary by Justin F. Gainor, MD, on page 40.

The ASCO Post | MARCH 10, 2015

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Perspective Thoracic Oncology

Crizotinib Crosses Another Finish Line in Lung Cancer By Justin F. Gainor, MD

reatment of anaplastic lymphoma kinase (ALK)–positive lung cancer has been one of the great success stories in oncology in the past decade. First discovered in lung cancer in 2007, ALK rearrangements are found in 3% to 5% of patients and define a distinct molecular subgroup of the disease with characteristic clinical and pathologic features.1 Most notably, ALK-rearranged tumors are oncogene-addicted and exhibit marked sensitivity to ALK inhibition. Indeed, the initial single-arm studies of the ALK inhibitor crizotinib (Xalkori) demonstrated high objective response rates (~60%) and median progression free-survival of 7 to 10 months in ALK-positive patients.2,3 Importantly, these studies validated ALK as a therapeutic target and culminated in the accelerated approval of crizotinib by the U.S. Food and Drug Administration (FDA) in August 2011—just 4 years after the initial discovery of ALK rearrangements in non–small cell lung cancer (NSCLC). This was followed by full regulatory approval of crizotinib in November 2013.

Among 343 ALK-positive patients, crizotinib produced significant improvements in median progression free-survival compared with che-

motherapy (10.9 vs 7.0 months, P < .001). Crizotinib was also associated with a superior objective response rate (74% vs 45%, hazard ratio [HR] =

0.45, P < .001), greater improvement in global quality of life, and significant reduction in lung cancer symptoms compared with chemotherapy.

A New Chapter in the Story As reviewed in this issue of The ASCO Post, Solomon and colleagues have recently added an important new chapter in the story of crizotinib.4 They reported the results of PROFILE 1014, an ongoing, global, randomized phase III trial comparing crizotinib with first-line cytotoxic chemotherapy (platinumpemetrexed [Alimta]) in previously untreated ALK-positive lung cancer. It should be noted that participants randomized to the chemotherapy arm of this study received a maximum of six cycles of platinumpemetrexed, but maintenance pemetrexed was not permitted, as this was not considered standard of care at the time of the study design. The primary endpoint of this study was progression free-survival. Dr. Gainor is Instructor, Department of Medicine, Harvard Medical School and Assistant in Medicine, Department of Medicine, Massachusetts General Hospital, Boston.

ASCOPost.com | MARCH 10, 2015

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Perspective

Perhaps not surprising, the PROFILE 1014 investigators did not observe differences in overall survival among ALK-positive patients receiving crizotinib compared with chemotherapy. The median overall survival was not reached in either group, and the probability of 1-year survival was

84% with crizotinib and 79% with chemotherapy. The lack of a survival benefit in this study likely reflects the fact that 70% of patients initially randomized to chemotherapy crossed over to crizotinib upon disease progression, likely confounding the overall survival analysis.

Impact of First-Line Crizotinib Although it is always difficult to make cross-trial comparisons, one intriguing aspect of the PROFILE 1014 data is that both the objective response rate and the median progression freesurvival for patients treated with crizotinib in the first-line setting appeared

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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.

greater than those seen in previous studies of crizotinib, including a previous randomized study (PROFILE 1007) that compared second-line crizotinib with single-agent chemotherapy (docetaxel or pemetrexed).5 One potential explanation is that treatment-naive, ALK-rearranged tumors may theoretically be more sensitive to ALK inhibition. Alternatively, there may have been subtle differences in patient populations across trials. For example, although the PROFILE 1007 and 1014 studies generally enrolled similar patient populations, one important distinction is that PROFILE 1014 required treatment of all brain metastases prior to study entry. In contrast, patients with stable, untreated brain metastases were still eligible for participation in PROFILE 1007. As the central nervous system is a frequent site of relapse in ALK-positive patients, this may have affected response rates and progression freesurvival in these trials.

Remaining Challenges The PROFILE 1014 study is important for several reasons. First and foremost, it solidifies the role of crizotinib as a standard of care in the treatment of ALK-positive lung cancer. Furthermore, it again highlights the value of tumor genotyping in the management of lung cancer while also reinforcing the targeted therapy paradigm that was initially established in the treatment of EGFR-mutant lung cancer. Nevertheless, several important questions and challenges remain. Despite the impressive efficacy of crizotinib in ALK-positive NSCLC, resistance to therapy almost invariably develops—typically within 1 year. Efforts are now underway to elucidate the molecular mechanisms of resistance to crizotinib. To date, resistance mutations in the ALK kinase domain, ALK fusion gene amplification, and upregulation of bypass signaling pathways have all been identified as mechanisms of resistance to crizotinib.6,7 Still, in approximately one-third of crizotinibresistant tumors, mechanisms of resistance remain unknown. In addition to understanding the molecular underpinnings of acquired drug resistance, another major obstacle has been to identify continued on page 42

The ASCO Post | MARCH 10, 2015

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Perspective

Justin F. Gainor, MD continued from page 41

approaches to overcome resistance. In ALK-positive NSCLC, current strategies have centered on the use of more potent, structurally distinct ALK inhibitors. To date, at least eight different nextgeneration ALK inhibitors are currently in development. One of these agents, ceritinib (LDK378, Zykadia), recently received accelerated approval by the FDA, whereas two other compounds (alectinib and AP26113) have

sequential ALK inhibition (ie, crizotinib followed by a next-generation ALK inhibitor)? Moving forward, prospective trials comparing different ALK inhibitors will be important. To that end, the ALEX study (NCT02075840) was recently launched. ALEX is a phase III randomized trial comparing crizotinib with the next-generation ALK inhibitor alectinib in treatment-naive, ALK-positive patients. The primary endpoint for this trial is progression free-survival.

Numerous challenges still remain in the treatment of ALK-positive lung cancer. However, the work by Solomon and colleagues represents another major step forward. —Justin F. Gainor, MD

been granted breakthrough therapy designation status. Impressively, all three of these agents have shown high response rates (55%–69%) among ALK-positive patients previously treated with crizotinib.8-10 Such activity in crizotinib-resistant patients has in turn prompted questions about the optimal sequencing of ALK inhibitors. Specifically, could the use of next-generation ALK inhibitors in the first-line setting delay the emergence of resistance, resulting in comparable or even superior durations of response than those observed with

Finally, the report by Solomon and colleagues also raised important questions about drug development and whether it will be necessary to conduct randomized trials comparing highly active targeted agents with chemotherapy—especially as we begin to focus on even rarer, genetically defined patient populations. For example, ROS1 rearrangements are found in 1% to 2% of NSCLC patients. Like ALK, ROS1 is also a target of crizotinib. Earlier this year, Shaw and colleagues reported findings from a single-arm study of crizotinib in

ROS1-rearranged lung cancer, demonstrating an objective response rate of 72% and a median progression freesurvival of 19.2 months.11 Given this impressive activity, as well as the low frequency of ROS1 rearrangements in lung cancer, it seems unlikely that randomized studies comparing crizotinib with chemotherapy will be feasible. Nonetheless, this may have important implications for the traditional drug development process and raises questions about the necessary benchmarks for regulatory approval of targeted agents in such rare, molecularly defined patient populations. Moving forward, numerous challenges still remain in the treatment of ALK-positive lung cancer. However, it is also clear that treatment options for these patients have advanced at a remarkable pace. The work by Solomon and colleagues represents another major step forward. n

Disclosure: Dr. Gainor is a consultant for Boehringer Ingelheim, Kyowa Hakko Kirin Pharma, and Jounce Therapeutics.

References 1. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-smallcell lung cancer. Nature 448:561-566, 2007. 2. Kwak EL, Bang YJ, Camidge DR, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010. 3. Camidge DR, Bang YJ, Kwak EL, et al: Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: Updated results from a phase

1 study. Lancet Oncol 13:1011-1019, 2012. 4. Solomon BJ, Mok T, Kim DW, et al: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371:2167-2177, 2014. 5. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013. 6. Katayama R, Shaw AT, Khan TM, et al: Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 4:120ra17, 2012. 7. Doebele RC, Pilling AB, Aisner DL, et al: Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472-1482, 2012. 8. Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non-smallcell lung cancer. N Engl J Med 370:11891197, 2014. 9. Gadgeel SM, Gandhi L, Riely GJ, et al: Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF002JG): Results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 15:1119-1128, 2014. 10. Gettinger S, Bazhenova L, Salgia R, et al: ALK inhibitor AP26113 in patients with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC): Updated efficacy and safety data. Ann Oncol 25(suppl 4):iv426iv470, 2014. 11. Shaw AT, Ou SH, Bang YJ, et al: Crizotinib in ROS1-rearranged nonsmall-cell lung cancer. N Engl J Med 371:1963-1971, 2014.

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In mCRPC therapy…

Is there more to the story?

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Please see additional Important Safety Information on the next page. Please see brief summary of full Prescribing Information on subsequent pages.

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mCRPC=metastatic castration-resistant prostate cancer; AST=aspartate aminotransferase; ALT=alanine aminotransferase.

S:10 in

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

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For men with mCRPC who progressed on ADT

In a clinical trial, patients had a median overall survival on ZYTIGA® (abiraterone acetate) of…*

More than 1,000 days. And every day tells a story. 35.3 5.2 MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone† vs 30.1 MONTHS with placebo plus prednisone (active compound).‡

compared with placebo plus prednisone.

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached. Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

IMPORTANT SAFETY INFORMATION (cont) Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival. ADT=androgen-deprivation therapy.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 6/14 016819-140612

Please see brief summary of full Prescribing Information on subsequent pages.

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003307-130924

Learn more today at

www.zytigahcp.com.

Every day tells a story.

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†At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

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Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA 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]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA

ZYTIGA® (abiraterone acetate) Tablets is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. • Increased ZYTIGA Exposures with Food [see Warnings and Precautions]. 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 clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract 11.5 infection 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0

ZYTIGA® (abiraterone acetate) Tablets

Table 1: Adverse Reactions due to ZYTIGA in Study 1 (continued) ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest 7 discomfort 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. 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. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2

ZYTIGA® (abiraterone acetate) Tablets

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA 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 ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, 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 ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly 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 Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

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Future of Oncology Immunotherapy

Determining Why Not All Patients Respond to PD-1 Inhibitors A Conversation With Robert H. Pierce, MD By Jo Cavallo personalized medicine will increase the cost of cancer care.

Phenomenal Future for Immunotherapy

Robert H. Pierce, MD

ecent research1 conducted by Robert H. Pierce, MD, and his colleagues investigating why PD-1 (programmed cell death protein 1) inhibitors result in remarkably durable clinical remissions in some patients with melanoma, whereas others reap a short-term benefit or no benefit at all is showing that response is likely dependent on the presence of PD-L1 and tumor-infiltrating lymphocytes in the patient’s tumor. Termed “adaptive immune resistance,” this compensatory upregulation of PD-L1—the ligand that “turns off ” antigen-specific CD8-positive T cells by activating the PD-1 receptor—may be the potential biomarker researchers have been looking for to accurately predict response to anti–PD-1 therapy. Dr. Pierce, Chief Scientific Officer at OncoSec Medical, a biopharmaceutical company developing DNA-based intratumoral cancer immunotherapies, is planning on using the information gained from this research to investigate whether combining anti–PD-1 drugs, such as pembrolizumab (Keytruda), with therapies that can drive immunogenicity and increase tumor-infiltrating lymphocytes will lead to enhanced responses not just in melanoma patients, but in patients with other cancer types as well. In January 2015, OncoSec Medical announced that it is launching a pilot study to assess the effectiveness of its investigational intratumoral immunotherapy ImmunoPulse IL-12 (interleukin 12) to increase tumor-infiltrating lymphocytes in patients with triplenegative breast cancer. In a wide-ranging interview with The ASCO Post, Dr. Pierce talked about progress being made in immunotherapy; the use of genomic sequencing in the design of clinical trials; and how

What role will immunotherapy play over the next decade? Will it be an effective treatment that can be utilized in many different cancers? Yes, absolutely. I think that is the picture that is clearly emerging. How immunotherapy moves forward will be interesting to observe, because certainly PD-1 inhibitors are proving to be relatively nontoxic and highly effective in at least a significant subpopulation of patients in many different tumor types. However, one of the biggest hurdles facing immunotherapy today is identifying the patients who respond and then finding means to convert nonresponders into responders. Right now, there is a debate about how to sequence therapy for the greatest effectiveness. For instance, in the future, an oncologist who has a melano-

rare disease. How will this change the way pharmaceutical companies develop and test drugs for individual patients? Next-generation DNA and RNA sequencing technologies are allowing us to carve out smaller and smaller buckets of cancer types. I’m a pathologist by training, and we tend to think of tumor types by virtue of their cell of origin and where the malignant cells arise in the body. What we are seeing with immunotherapies is that the tumor histotype does not seem to matter as much as the immunophenotype. Right now, there are many ways one can imagine that next-generation sequencing can guide drug development. In immunotherapy, the mutational load in a patient’s tumor may prove to be a critical determinant in response to immune-based therapies—as those mutated peptides are what the immune system recognizes in the tumor as “foreign.” I think we will see a day in the not too distant future where we can determine from next-generation sequencing

One of the biggest hurdles facing immunotherapy today is identifying the patients who respond and then finding means to convert nonresponders into responders. —Robert H. Pierce, MD

ma patient with a BRAF mutation and a great burden of disease may want to treat him first with a BRAF inhibitor to debulk the cancer and then with a PD-1 inhibitor. Conversely, there may be other circumstances in which you might want to invert that treatment sequence, so I see a future with a lot of choices for potential combinations that are coming down the pike. There is a phenomenal future for immunotherapy both in terms of combining multiple immunotherapies together and also putting immunotherapies together with targeted agents and chemotherapies. Over time, given its relatively benign safety profile, we will likely see PD-1 therapeutics being given in earlier lines of treatment to those patients whose tumors are characterized by a “responsive phenotype.”

Next-Generation Sequencing and Drug Development Advances in genomic sequencing are turning every cancer into essentially a

data that a patient’s tumor has sufficient mutational load to drive an immune response but not enough expression of antigen-processing and presentation machinery and positive co-stimulatory molecules to convert those “virtual” antigens into a bona fide antitumor T- cell response. In such a patient, perhaps an upfront combination with a proimmunogenic stimulus like intratumoral IL-12 will be considered. Given the power of these evolving technologies, we could speculate all day on the possibilities.

Future Design of Clinical Trials How will pharmaceutical companies design clinical studies in the future? Will they be modeled more on the “basket” trial approach, in which patients with different cancers but the same specific genetic alteration or mutation are enrolled into a trial investigating a molecularly targeted therapy? I think there are times when the basket trial approach is appropriate and times when it is not. In particular,

response assessments are often very different, according to the tumor type, and then you end up having what amounts to a bunch of different clinical trials bundled together; so in the end, this approach may not add efficiency. Also, there may be logistic issues stemming from the fact that patients with different tumor types may be seen by different sets of doctors and even different institutions. Despite those limitations, we often look to see whether there is the possibility for a given therapeutic strategy to take advantage of the unifying biology with a basket approach. However, I haven’t been involved in one yet.

Appropriate Use of Biomarkers Doesn’t the basket-trial approach have the potential to eliminate a lot of waste in the development of new drugs, because the results would signal early on which targeted agents might be most effective for specific mutations? Yes, that is absolutely true, and I think that model will be very valuable in the future, particularly for drugs targeting oncogenic “driver” mutations. Patient selection in immunotherapy may not prove to be as straightforward. Whether one is testing an immunotherapy or a mutant kinase, the power of the trial lies in how good your patientselection biomarker is. A truly selective biomarker, such as in detection of mutant BRAF, can enable investigators to see the efficacy of the drug in a smaller and less expensive study. However, as has often been the case, in the initial development of anti–PD-1 monoclonal antibodies, we knew that we had an effective therapeutic before we had the confidence that we had a good biomarker. And, given that some patients who score “negative” for the various assays still respond to PD-1 blockade, there is some controversy about how to use these biomarkers for patient selection in practice. I think we simply need to be clear that every assay has a false-negative rate and a false-positive rate and that we must differentiate the use of a biomarker as a drug development tool for enriching the responder population in a clinical trial from that of using a biomarker in clinical practice to determine patient access to—or reimbursement for—a potentially efficacious therapy. continued on page 44

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Future of Oncology Robert H. Pierce, MD continued from page 43

With the appropriate use of response-enriching biomarkers in clinical trials, we hope to accelerate drug approval and get these therapies to patients as soon as possible.

Cost of Drug Development How will the success of immunotherapy and the development of patient selection biomarkers impact the cost of cancer care? As we develop effective therapies and those therapies prove to be even more effective in combination and these successes result in even more lines of therapy, it is difficult not to imagine the cost of care going up. So, success is driving some of these costs, but, clearly, this is a good problem to have. The rising cost of care is a fact that, as a society, we have to wrap our heads around. Although as a “techno-optimist” I like to think that some low-cost, super-effective technology is waiting around the corner, this may be a dangerous fantasy if it keeps us from dealing with the current economic realities. Effective personalized medicine involves the search for validation and ultimately commercialization of biomarker test kits to classify patients into subpopulations, and this, too, is adding to the cost of drug development. This added dimension of care is something we often do not talk about, but the potential need for codeveloping a companion diagnostic, depending, of course, on the clinical scenario, can present a major economic challenge for smaller companies endeavoring to develop oncology drugs. The development of adoptive T-cell transfer and chimeric antigen receptor T-cell therapy, which are cost-intensive at the point of care, has been fueling considerable discussion on the rising cost problem. And although these therapies appear to show great promise, many of us have questions about their scalability, commercialization, and, ultimately, how to factor them into the finite cost-of-care universe, which is our reality.

ity of life for patients. In terms of therapeutics, I think the next 10 years will be about exploring biologic combinations—combinations of immunotherapies, combinations of immunotherapy with so-called immunogenic chemotherapy, and combinations of immunotherapy with targeted molecules. The next stage will be about employ-

ing these combinations and harnessing multiple physiologic and cytotoxic mechanisms to attack tumors. Immunotherapy is exciting because of the impressive durability of responses and the characteristic long tail on the overall survival curves. We are all focused on raising the percentage of patients who experience those long-duration

responses and significantly increased survival rates. I recently attended a meeting in which there was fairly sober speculation that combination immunotherapies in melanoma would, in the near future, push that overall survival “tail” north of 50%. Part of this push will be the development of new therapies that enhance

Exploring Biologic Combinations What major advances in cancer care do you see happening over the next decade? Will there be more cures and conversions of cancer into a chronic disease? I think the next decade will be characterized by both new cures for some cancers and the conversion of others into controlled chronic states, which are still associated with improved qual-

REFERENCES: 1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240-2247. 2. Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 2011;17(6):1616-1622. 3. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17(5):1169-1180. 4. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786-792. 5. Pao W, Miller VA,

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Future of Oncology immunogenicity, increase tumor-infiltrating lymphocytes, and convert PD-1 nonresponders into responders. In triple-negative breast cancer, the presence of CD8 tumor-infiltrating lymphocytes not only correlates with response to PD-1/PD-L1 therapeutics, but to response to certain chemotherapeutic regimens as well. In breast

cancer, as well as other solid tumor types, I think we are going to find that maximally effective therapy involves a rational combination of immunogenic chemotherapies with immunotherapy, which is really exciting. One of the emerging areas that I predict will become “hot” is the development of intratumoral cancer im-

munotherapies, in which we “take the fight to the tumor,” deploying immunostimulatory molecules directly into the tumor to combat the local immunosuppressive microenvironment to drive a systemic antitumor response. I think we are beginning to see this approach as a real opportunity in the treatment of solid tumors such as tri-

ple-negative breast cancer. n

Disclosure: Dr. Pierce is Chief Scientific Officer at OncoSec Medical, a biopharmaceutical company.

Reference 1. Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-571, 2014.

Jennifer Adair, PhD, Recognized as ‘Outstanding New Investigator’

In EGFRm+ NSCLC

It’s time to uncover what comes next

ennifer Adair, PhD, of the Fred Hutchinson Cancer Research Center, has been named a 2015 Outstanding New Investigator by the American Society of Gene & Cell Therapy (ASGCT). The award recognizes Dr. Adair’s independent research efforts to understand and improve blood stem cell–based gene therapies. Dr. Adair is an Assistant Member of the Clinical Research Division at Fred Hutchinson, where her laboratory aims to develop gene therapies that can cor-

T790M resistance mutations emerge in at least 60% of patients and limit your therapeutic options1-3 Nearly all patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy will experience disease progression. And in nearly two-thirds of these patients, the cause of progression is the EGFR resistance mutation T790M.1-5 The emergence of the T790M mutation reduces the effectiveness of currently available EGFR inhibitors.6 T790M mutations may be detected in both tissue and plasma.1-3,7,8 However, currently, there are no approved therapies to address this driver of EGFR TKI resistance when it emerges. At Clovis Oncology, we’re exploring new approaches in EGFR-mutated non–small cell lung cancer (NSCLC) to address TKI-acquired resistance.

Clovis Oncology is leading the fight

Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73. doi:10.1371/journal.pmed.0020073. 6. Yun C-H, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008;105(6):2070-2075. 7. Zheng D, Ye X, Sun Y, et al. Noninvasive monitoring of dynamics of acquired EGFR-T790M mutation and discovery of its heterogeneity in patients with advanced NSCLC treated with EGFR-TKI. J Clin Oncol. 2014;32(15)(suppl):11049. 8. Taniguchi K, Uchida J, Nishino K, et al. Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res. 2011;17(24):7808-7815. Copyright © 2014 Clovis Oncology. DARO-102 11/14

Jennifer Adair, PhD

rect faulty DNA sequences responsible for inherited blood disorders, improve treatment for brain cancer, and make cells immune to HIV infection. “[This recognition] is huge for an early-career investigator in the field. The American Society of Gene & Cell Therapy was the first of its kind and is the largest society in the world for cell and gene therapy,” Dr. Adair said. At the Outstanding New Investigator Symposium during the ASGCT Annual Meeting on May 14, 2015, Dr. Adair will speak about new technologies her lab developed to understand these cells’ biology, and how her experience in developing new cancer gene therapies has motivated her to develop a portable gene therapy system that lends itself to use even in developing countries without high-tech laboratories. Dr. Adair earned a PhD in genetics and cell biology in 2005 from Washington State University, where she studied the molecular mechanisms of DNA repair. She joined Fred Hutchinson in 2008. n

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Journal Spotlight Hematology

Clonal Hematopoiesis With Somatic Mutations Increases Risk of Hematologic Cancer, Mortality, and Cardiovascular Disease By Matthew Stenger

n two studies recently reported in The New England Journal of Medicine,1,2 whole-exome sequencing of DNA from peripheral blood cells of individuals unselected for hematologic phenotype showed that clonal hematopoiesis with somatic mutations is increasingly common with increasing age and is associated with increased risk of hematologic cancer and death. One study also observed a significant association with incident coronary heart disease and ischemic stroke.2 The presence of clonal hematopoiesis in apparently healthy persons may be an early event in the development of hematologic cancer.

Genovese et al Study Details The study reported by Giulio Genovese, PhD, of the Broad Institute of the Massachusetts Institute of Technology in Cambridge, and colleagues involved analysis of data from wholeexome sequencing of DNA in peripheral blood cells from 12,380 Swedish persons unselected for cancer or hematologic phenotypes.1 Participants had a mean age of 55 years (range, 19–93 years) at the time of DNA collection; 6,245 were controls, 4,970 had schizophrenia, and 1,165 had bipolar disorder. Somatic mutations were identified on the basis of unusual allelic fractions. Data from Swedish national patient registers were used to follow outcomes for 2 to 7 years after DNA sampling. Detectable clonal expansions most frequently involved somatic mutations in three genes—DNMT3A (190 mutations), ASXL1 (35 mutations), and TET2 (31 mutations)—previously implicated in hematologic cancers. Detectable clonal hematopoiesis with candidate driver genes (also including PPMD1 and JAK2 among the most common) was found in only 0.7% of participants aged < 50 years and in 5.7% of participants aged > 65 years. Overall, clonal hematopoiesis with candidate or unknown driver genes was observed in 0.9% of participants aged < 50 years vs 10.4% of those aged > 65 years.

analysis adjusting for age and sex. Of 31 participants receiving such a diagnosis, 13 (42%) had clonal hematopoiesis evident in their initial DNA sample. In analysis adjusting for age and sex, participants with clonal hematopoiesis had significantly increased risk of death (HR = 1.4, P = .03). The reduced overall survival was explained by deaths from cancer and by an association of clonal hematopoiesis with smoking (odds ratio = 2.2, P < .001). Analysis of bone marrow biopsy specimens from two patients at the time of diagnosis of acute myeloid leukemia revealed that the cancers arose from the initially identified clones. The researchers concluded: “Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as

Giulio Genovese, PhD

people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers.” In an interview with The ASCO Post, Dr. Genovese emphasized, “Despite the fact that the risk of conversion of clonal hematopoiesis to cancer is low—about 1% per year, for a large fraction (~42%) of participants who developed cancer— clonal hematopoiesis preceded clinical diagnosis by several months, sometimes up to 3 years. While there is no effective therapy at the moment for people with clonal hematopoiesis, this observation points to a wide window of time for potential intervention.”

Risk of Cancer and Mortality

Jaiswal et al Study Details

Participants with clonal hematopoiesis were significantly more likely to receive a first diagnosis of hematologic cancer ≥ 6 months after DNA sampling (hazard ratio [HR] = 12.9, P < .001) in

The study by Siddhartha Jaiswal, MD, PhD, of Brigham and Women’s Hospital, Boston, and colleagues involved analysis of whole-exome sequencing data of DNA from peripheral

Clonal Hematopoiesis as Risk Factor ■■ Clonal hematopoiesis was found in 0.9% of participants aged < 50 years and in 10.4% of those aged > 65 years. ■■ Clonal hematopoiesis was associated with increased risk of hematologic cancer and overall mortality. ■■ In addition to increased risk of hematologic cancer and all-cause mortality, Jaiswal et al found that presence of somatic mutation increased risk of cardiovascular disease.

blood cells from 17,182 persons who were unselected for hematologic phenotypes.2 The somatic mutations sought were from among previously identified single-nucleotide variants and small insertions or deletions in 160 genes recurrently mutated in hematologic cancer. The study sample was selected from 22 population-based cohorts in three consortia (T2DGENES, GoT2D, and SIGMA T2D). DNA obtained from individual cohorts was further processed at the Broad Institute of Harvard and the Massachusetts Institute of Technology. Participants had a median age of 58 years (range, 19–108 years), 8,741 were women, and 7,860 had type 2 diabetes. Somatic mutations were very rare in persons aged < 40 years, being found in 0 (0%) of 240 aged 20 to 29 years, 1 (0.1%) of 855 aged 30 to 39 years, 50 (1.7%) of 2,894 aged 40 to 49 years, 138 (2.5%) of 5,441 aged 50 to 59 years, 282 (5.6%, 95% confidence interval [CI] = 5.0%–6.3%) of 5,002 aged 60 to 69 years, 219 (9.5%, 95% CI = 8.4%–10.8%) of 2,300 aged 70 to 79 years, 37 (11.7%, 95% CI = 8.6%–15.7%) of 317 aged 80 to 89 years, and 19 (18.4%, 95% CI = 12.1%–27.0%) of 103 aged ≥ 90 years. As noted by the investigators, these rates greatly exceed the incidence of clinically diagnosed hematologic cancer in the general population. The majority of the variants occurred in the three genes DNMT3A (403 variants), TET2 (72 variants), and ASXL1 (62 variants). Among persons aged ≥ 60 years, men were more likely to have a detectable mutation (odds ratio [OR] = 1.3, P = .005).

Cancer, Mortality, Cardiovascular Disease In analysis adjusting for age, sex, and type 2 diabetes status, the presence of a somatic mutation was associated with an increased risk of hematologic cancer (hazard ratio [HR] = 11.1, P < .001). In a model adjusted for age, sex, and

type 2 diabetes status, presence of a mutation was associated with increased all-cause mortality (HR = 1.4, P = .02); Kaplan-Meier analysis among persons aged ≥ 70 years also showed increased risk of death with the presence of a mutation (P < .001). Somatic mutations were associated with an increased risk of diabetes after adjustment for confounding factors (OR = 1.3, P < .001), with individuals with diabetes being slightly more likely to have such mutations in every age group. In multivariable analysis including age, sex, type 2 diabetes status, systolic blood pressure, and body mass index as covariates, presence of a somatic mutation was associated with an increased risk of incident coronary heart disease (HR = 2.0, P = .02) and ischemic stroke (HR = 2.6, P = .003). Targeted sequencing of blood cell DNA obtained 4 to 8 years after the initial DNA collection for 17 mutations in 13 persons showed that the originally detected mutations were still present in all cases. Jaiswal et al concluded: “Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in allcause mortality, with the latter possibly due to an increased risk of cardiovascular disease.” n Disclosure: The Genovese et al study was funded by the National Human Genome Research Institute and others. The Jaiswal et al study was funded by the National Institutes of Health and others.

References 1. Genovese G, Kähler AK, Handsaker, RE, et al: Clonal hematopoiesis and bloodcancer risk inferred from blood DNA sequence. N Engl J Med 371:2477-2487, 2014. 2. Jaiswal S, Fontanillas P, Flannick J, et al: Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488-2498, 2014.

ASCOPost.com | MARCH 10, 2015

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Perspective

Aged to (Im)Perfection: Age-Related Clonal Hematopoiesis? By Michelle M. Le Beau, PhD

ive decades ago, the analysis of metaphase chromosomes in the hematologic malignancies provided our first broad glimpse into the genetic anatomy of a malignant cell. Today, the advent of high-throughput methods such as next-generation sequencing, capable of surveying the entire genome, provides an unprecedented opportunity to develop an integrated molecular profile of each patient’s tumor, based on

Michelle M. Le Beau, PhD

the chromosomal pattern, gene/miRNA/lncRNA expression, DNA methylation/epigenomic pattern, and gene mutation status, promising a revolutionary change in the way we diagnose, characterize, and treat cancer. Although work in the hematologic malignancies has been at the vanguard of efforts to elucidate the molecular pathogenesis of cancer, there are a number of unanswered questions. For example, we do not yet know the full spectrum of genetic changes, the order in which these mutations occur (ie, which mutations are initiating events and which are typically cooperating events), or the prognostic significance associated with many cooperating mutations. Recent studies, including those by Genovese et al1 and Jaiswal et al2— reviewed in this issue of The ASCO Post—have provided new insights into these questions, tying together seemingly disparate observations, such as the phenomenon of clonal hematopoiesis and the increased incidence of hematologic malignancies in the elderly.

Clonal Hematopoiesis Mature blood cells are generated from hematopoietic stem/progenitor cells, which sustain hematopoiesis for Dr. Le Beau is Arthur and Marian Edelstein Professor of Medicine in the Section of Hematology/Oncology and Director of the Comprehensive Cancer Center at the University of Chicago.

decades by virtue of their self-renewal properties. The fact that hematopoietic stem/progenitor cells could undergo clonal expansion—a term called “clonal hematopoiesis”—was first suggested by the observation of clonal remissions in patients with acute myeloid leukemia (AML), based initially on the detection of a skewed pattern of the X-linked glucose-6-phosphate dehydrogenase enzyme variants in female patients and later with X-linked DNA polymorphisms.3 Several decades later, the detection of the translocation-specific fusion transcripts, such as the RUNX1/ RUNX1T1 fusion from the t(8;21), in bone marrow cells from AML patients with durable remissions suggested that this clonal hematopoiesis resulted from the expansion of cells that harbored an initiating, driver mutation. These observations dovetail nicely with later findings using genomic studies, which revealed that, in some patients, stem cells carrying a subset of the mutations present in the cancer cells are able to survive chemotherapy, acquire novel mutations, and, ultimately, trigger a relapse.4 Parallel observations of the detection of leukemia/lymphoma-associated chromosomal translocations, such as the t(14;18)/IGH-BCL2 fusion, in blood samples of healthy individuals suggested that cancer-associated early mutations (1) may occur in hematopoietic stem/progenitor cells in the absence of overt disease; (2) may be present many years before disease develops; and (3) are required, but insufficient, to result in disease.

Mutation Burden In 2012, several reports suggested that clonal hematopoiesis resulting from an expansion of cells that have an initiating mutation might be a feature of the aging hematopoietic system.4-6 Busque et al identified TET2 mutations in neutrophils of healthy elderly females with clonal hematopoiesis as defined by altered ratios of X inactivation in peripheral blood.4 By using high-throughput sequencing of the genomes of AMLs, as well as the exomes of hematopoietic stem/progenitor cells from healthy individuals, Welch et al concluded that most of the mutations found in

AML genomes actually occurred in hematopoietic stem/progenitor cells before they acquired the leukemiainitiating mutation.5 The investigators hypothesized that some genetic mutations confer advantages to affected hematopoietic stem/progenitor cells, resulting in enhanced self-renewal and clonal expansion. To address the issue of whether such mutations affect additional genes involved in leukemia and lymphoma, they analyzed 2,728 blood samples, sequenced to a relatively high depth of coverage (average of 107.5× coverage) as germline controls for a variety of solid tumors analyzed by The Cancer Genome Atlas (TCGA).6 Surprisingly, this analysis confirmed that the overall frequency of blood-specific mutations increased with age (ranging from 1.2% to 6.8% for subjects in their 40s vs 80s) and revealed that blood cells of more than 2% of all individuals and 5% to 6% of people older than 70 years contain mutations that may represent premalignant events (eg, recurrent mutations in leukemia/lymphoma-associated genes that cause clonal hematopoiesis, most commonly DNMT3A, TET2, JAK2, ASXL1, and TP53). The studies by Genovese et al and Jaiswal et al approached the issue of clonal hematopoiesis in an unbiased fashion by using whole-exome sequencing data from DNA of peripheral blood cells of large cohorts of individuals who were unselected for cancer or hematologic phenotypes.1,2 Genovese et al1 used data from 12,380 individuals from Swedish national patient registries, whereas Jaiswal et al2 analyzed 17,182 individuals from cohorts (cases and controls) in type 2 diabetes association studies or the Jackson Heart Study. Key findings of these studies follow. Clonal hematopoiesis, as evidenced by detectable somatic mutations, is rare in individuals younger than age 40 but increases appreciably with each decade of life, reaching approximately 10% in persons older than 65 years and approximately 18% in persons 90 years of age or older. Moreover, mutations persist over time. Intriguingly, the incidence of hematologic malignancies mirrors this pattern. The majority of clonal mutations occurred

in three genes, DNMT3A, ASXL1, and TET2, recapitulating the types of mutations in these genes, which have been detected as somatic mutations in myeloid neoplasms. The most common change was a base-pair change, namely a cytosineto-thymine transition, resulting from the deamination of a cytosine base, considered to be a somatic mutational signature of aging.5,7 The presence of somatic mutations was associated with an increased risk of hematologic malignancies (hazard ratio [HR] = 11.1, 95% confidence interval [CI] = 3.9–32.62; HR = 12.9, 95% CI = 5.8– 28.71). Notably, a higher proportion of mutant leukocytes (a variant allele frequency ≥ 0.10, which is equivalent to ≥ 20% of cells) conferred a higher risk of developing a hematologic malignancy. In two cases, DNA-sequencing analysis of bone marrow cells at the time of diagnosis of AML confirmed that the leukemia was derived from the earlier mutant clones.2 Somatic mutations were also associated with an increase in all-cause mortality1,2 as well as an increased risk of incident coronary heart disease and ischemic stroke.2 The estimates of mutation frequency derived from the three studies1,2,6 summarized here are very conservative, since the sequencing depth of coverage limited mutation detection to the level of a 2% to 3% variant allele frequency (≥ 4%–6% of cells in a population); ultimately, greater than 1,000× sequencing depth or singlecell sequencing may be required to determine the actual incidence. Moreover, other types of alterations—eg, gene fusions, chromosomal abnormalities, and copy-number changes— were not included in the analyses.

Ramifications and Next Steps These pivotal studies provide new insights into the multistep process of leukemogenesis, as well as risk factors for increased mortality and cardiometabolic disease in the elderly. The findings support emerging data that mutations in genes such as DNMT3A, JAK2, ASXL1, TET2, TP53, and others are initiating events for myelodysplastic syndrome, AML, myeloproliferative neoplasms, and continued on page 52

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ASCOPost.com | MARCH 10, 2015

PAGE 52

Perspective

Michelle M. Le Beau, PhD continued from page 47

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chronic myelogenous leukemia, whereas other changes characteristic of these diseases are likely to occur later as cooperating mutations (eg, IDH1, RUNX1, NRAS, NPM1, or FLT3 mutation), which are important for disease progression, a distinction that is relevant to the current dogma of therapeutic targeting of the primary changes. In this current era of next-generation sequencing, caution is warranted when using blood as a surrogate reference for the germline genome, particularly in elderly individuals. Care must also be taken when interpreting leukemia-associated mutations detected in peripheral blood as an incidental finding: Although they signify an elevated risk, they do not support a diagnosis of hematologic malignancy without other corroborating evidence. The incidence of myeloid neoplasms in the elderly is less than 0.1%, yet approximately 6% have leukemia-associated mutations in blood cells. The fact that most individuals with evidence of clonal hematopoiesis do not progress to overt disease makes it premature to sequence DNA from blood samples to enable early detection of hematologic malignancies. In the future, expanded studies are needed to identify those individuals who are at the highest risk—including ascertaining the risk associated with specific mutated genes or combinations of genes, particularly in cell type-specific contexts—as well as to identify the effect of coexisting germline cancer predisposition mutations and the influence of lifestyle factors. Ultimately, singlecell sequencing may be required to identify high-risk combinations of

The ASCO Post Wants to Hear From You

genes co-occurring in the same cells. Although we currently lack interventions that are suitable for large groups of patients who may have only a low or modest risk of cancer, in the future, the use of sequencing of DNA from peripheral blood to identify high-risk persons or to monitor clonal expansions could facilitate clinical trials to reduce the risk of progression to hematologic malignancies or other cancers. n

Disclosure: Dr. Le Beau reported no potential conflicts of interest.

References 1. Genovese G, Kähler AK, Handsaker RE, et al: Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371:2477-2487, 2014. 2. Jaiswal S, Fontanillas P, Flannick J, et al: Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 371:2488-2498, 2014. 3. Jacobson RJ, Temple MJ, Singer JW, et al: A clonal complete remission in a patient with acute nonlymphocytic leukemia originating in a multipotent stem cell. N Engl J Med 310:1513-1517, 1984. 4. Busque L, Patel JP, Figueroa ME, et al: Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 44:1179-1181, 2012. 5. Welch JS, Ley TJ, Link DC, et al: The origin and evolution of mutations in acute myeloid leukemia. Cell 150:264-278, 2012. 6. Xie M, Lu C, Wang J, et al: Agerelated mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20:14721478, 2014. 7. Alexandrov LB, Nik-Zainal S, Wedge DC, et al: Signatures of mutational processes in human cancer. Nature 500:415-421, 2013.

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

The goal seemed insurmountable: to find a way to unleash the immune system’s power to fight cancer.

And we achieved it at Dana-Farber.

To many physician-researchers and scientists, finding a way to get the body’s immune system to attack cancer cells is a momentous achievement. And Dana-Farber researchers helped make it happen. We found that some cancer cells elude the body’s immune defenses by cloaking themselves in the proteins PD-L1 and PD-L2. This discovery led to the development of several immunotherapies that are already demonstrating promising results and better quality of life for some people with deadly cancers. In fact, the new therapies have improved outcomes for many patients with advanced metastatic melanoma, kidney cancer, Hodgkin lymphoma, bladder cancer, stage IV lung cancer, and more. And the sky is the limit. Videos, whitepapers and more at DiscoverCareBelieve.org/PD-1.

The ASCO Post | MARCH 10, 2015

PAGE 54

Direct From ASCO

Conquer Cancer Foundation Researcher Spotlight

Conquering Cancer With James D. Murphy, MD, MS, and Neil M. Iyengar, MD

ames D. Murphy, MD, MS, Assistant Professor in the Department of Radiation Medicine at the University of California, San Diego, received a 2012 Conquer Cancer Foundation (CCF)

continue to pursue,” he continued. “Currently, we have multiple ongoing health outcomes research projects focusing on palliative care, which all stemmed from the Conquer Cancer Foundation grant.” Dr. Murphy’s Young Investigator Award was generously supported by the ASCO Clinical Practice Committee.

They identified a process called white adipose tissue inflammation, which Dr. Iyengar explained is “inflammation in the fatty tissue in the breast that leads to increased estrogen signaling [there].” This inflamed fatty tissue

I think Conquer Cancer Foundation donors really should feel the same excitement that we do about the science, but also feel proud that they’re directly [affecting] both public health and the individual health of patients.

Researcher Spotlight

James D. Murphy, MD, MS

of ASCO Young Investigator Award for his research focusing on access to the delivery of palliative radiation therapy. Dr. Murphy’s research confirmed his suspicion that there were substantial racial and age-based disparities in access to this treatment. “Ultimately, we hope that understanding these barriers will fuel further research aimed at improving access to care,” said Dr. Murphy. “This grant provided the foundation for avenues of research that I

The link between obesity and breast cancer has long been established, but Neil M. Iyengar, MD, Assistant Attending Physician at Memorial Sloan Kettering Cancer Center and recipient of a 2013 Conquer Cancer Foundation of ASCO Young Investigator Award, was not satisfied that research had yet disclosed the full story. Traditionally, studies about the link between obesity and breast cancer have focused on measurements of size, like body mass index or waist circumference. In the course of their study, Dr. Iyengar and his team identified a different measurement by looking specifically at the adipose tissue in the breast.

whose metabolic health puts them at increased risk of breast cancer. “By defining a more precise population for breast cancer prevention, we’ll be more successful in identifying effective, biologically targeted intervention

—Neil M. Iyengar, MD

was present in 90% of the patients with breast cancer in Dr. Iyengar’s study who were obese and 30% of patients in the study who were not obese. Dr. Iyengar’s hope is that with further study, his preliminary data will help better define the populations

strategies for breast cancer,” he said. Dr. Iyengar’s Young Investigator Award was generously supported by the Breast Cancer Research Foundation. n © 2015. American Society of Clinical Oncology. All rights reserved.

Expanding the Reach of ASCO’s Educational Efforts

atherine H. Van Poznak, MD, Associate Professor of Medical Oncology at the University of Michigan, uses the skills she learned as a 2010–2011 participant in ASCO’s Leadership Development Program (LDP) to further the Society’s educational efforts through her service on the Professional Development

Catherine H. Van Poznak, MD

Committee and Continuing Medical Education Subcommittee, among other activities. She discussed her educational experiences and expectations for the future of education with ASCO Connection. How did you benefit from the Leadership Development Program? The Leadership Development Program covered many different aspects of leadership and provided new and im-

proved insights into coordinating efforts of a team. For example, the skills I learned in the conflict management session have helped me work more effectively within both clinical- and research-focused teams. The advocacy training was extremely valuable as well. Through an ASCO LDP trip to Capitol Hill, I learned about the interface between ASCO and policymaking. That experience gave me the skills I needed to be an ASCO representative during the One Voice Against Cancer’s advocacy day on Capitol Hill in July 2014, where we advocated for cancer research funding. What impact do you want to have through education-related committee service? I would like to broaden and deepen the scope of resources available to ASCO members to assist them in continuing education, Maintenance of Certification, and lifelong learning. ASCO offers top-notch educational symposia, publications, and diverse resources through ASCO University®. My hope is that members will be able to find solutions to all of their educational needs through ASCO and bolster their competency.

This goal extends to every member, from our medical students to our emeritus members. What educational gaps do you see oncology professionals facing? There are gaps in various areas, but certainly the rapid changes in molecular testing have been profound. ASCO is already helping the membership understand the biologic mechanisms behind these pathways through its journals, ASCO University, and scientific meetings. In many cases, our understanding of the biology exceeds our ability to clinically act on this molecular information. Guidance on how to use therapies based on specific pathways and in specific clinical circumstances is an area where ASCO has an opportunity to fill a tremendous gap. What are you looking forward to accomplishing in the near future? I’m very excited about the potential of CancerLinQ™ (ASCO’s rapid learning system). This system will provide the ability to perform self-assessment and offer directed learning opportunities. I’m excited about the work of the Professional Development Committee on women’s

professional development. We’re also assessing how subpopulations of members within ASCO may have unique educational needs and how to address them through our education and quality efforts. How has volunteering added value to your membership experience? Volunteering for ASCO committees is intellectually stimulating and emotionally satisfying. It’s an honor and a privilege to work with such dedicated colleagues to advance patient care. Through my volunteer activities, I’ve interacted with members from all practice settings, and the rich diversity broadens my own horizons. It’s a joy to volunteer, and I hope that all interested members will consider applying to serve on a committee. For more information on the Leadership Development Program, Leadership Skills Seminar, and other educational opportunities available from ASCO, visit asco.org/professional-development. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Expanding the Reach of ASCO’s Educational Efforts.” ASCO Connection, January 2015: 5. All rights reserved.

ASCOPost.com | MARCH 10, 2015

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Direct From ASCO

Highlights From the 2014 ASCO Quality Care Symposium

he 2014 ASCO Quality Care Symposium was held October 17 to 18 in Boston and featured research on combating disparities, improving end-of-life care, and finding opportunities for cost reduction. These highlights have been adapted from ASCO Quality Care Symposium Daily News (quality.asco.org/dn).

which provides low-income subsidies for medications, have greater adherence to tamoxifen or aromatase inhibitors in all racial and ethnic groups, compared to those not enrolled (white women: 71% vs 62%; black women: 67% vs 55%; Hispanic women: 71% vs

55%).2 Importantly, the study found that enrollment in the program also reduces racial and ethnic disparities in adherence. Among women not enrolled, white women had significantly higher adherence rates than black and Hispanic women (62% vs 55%).

Physician and Patient Survey Reveals Gaps in Symptom Management A study of 2,487 patients, 4 to 12 months from a locoregional breast or colon cancer diagnosis, found that continued on page 56

Participation in Tumor Boards Associated With Improved Outcomes A study of nearly 5,000 patients with lung or colorectal cancer and 1,600 oncologists found that patients with extensive-stage small cell lung cancer and stage IV colorectal cancer had significantly lower mortality rates if treated by physicians with frequent tumor board participation (P = .05), compared to those treated by physicians with less often/never tumor board participation.1 Additionally, patients whose physicians participated in tumor boards weekly were more likely to enroll in clinical trials, compared to patients whose physicians participated less often/never (OR = 1.6, 95% confidence interval [CI] = 1.1–2.2).

Medicare Program Reduces Racial Disparities in Adherence to Hormone Therapy After Breast Cancer Surgery A study of more than 23,299 participants suggests that women with breast cancer who are enrolled in the Medicare Part D Extra Help program,

Introduce Your Patients to PRE-ACT

Now

OAK

Enrolling

A Randomized Phase III Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Failed Platinum Therapy (NCT02008227, Study ID GO28915)

MPDL3280A1 Patients with locally advanced or metastatic NSCLC who have failed platinum-containing chemotherapy

(an engineered anti-PDL1 antibody)

N=850

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Docetaxel

Primary Endpoint:

Secondary Endpoints:

• Objective survival

• Safety: incidence of adverse events • Overall response rate • Progression-free survival • Duration of response

Key Inclusion Criteria 2:

Key Exclusion Criteria 2:

• Locally advanced or metastatic NSCLC • • • •

• History of autoimmune disease

(stage IIIB, stage IV, or recurrent) Representative FFPE tumor specimens Disease progression during or following platinum-containing treatment regimen Measurable disease, defined by RECIST v1.1 ECOG performance status of 0-1

• Active hepatitis B or hepatitis C • Prior treatment with docetaxel, CD137 agonists,

anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

For more information

his free, video-based program, called Preparatory Education About Clinical Trials (PRE-ACT), helps patients and their caregivers learn about clinical trials and address barriers to participation. Direct your patients to cancer.net/preact to learn more about this online resource. Also, visit cancer. net/blog to read a guest blog post about PRE-ACT by Neal Meropol, MD, FASCO, creator of PRE-ACT. n

Visit: clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp

Call: Genentech Trial Information Support Line: 1-888-662-6728 (US only)

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 use of any product for unapproved purposes. 2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp.

The ASCO Post | MARCH 10, 2015

PAGE 56

Direct From ASCO

ASCO Supports HHS Shift Toward Alternative Payment Models

he U.S. Department of Health and Human Services (HHS) has announced its intention to shift Medicare away from the current fee-for-service model and toward a system that pays providers based on the quality—rather than the quantity—of care they provide their patients. The announcement marks the first time in Medicare’s history that HHS has set explicit goals regarding alternative payment models and value-based payments. HHS plans to tie 30% of fee-forservice Medicare payments to quality or value measures through alternative payment models, such as Accountable

Care Organizations (ACOs) or bundled-payment arrangements, by the end of 2016, and tie 50% of payments to these models by the end of 2018. Further, the agency’s plans include tying 85% of all traditional Medicare payments to quality or value by 2016, and 90% by 2018, through programs such as the Hospital Value Based Purchasing and the Hospital Readmissions Reduction Programs. ASCO supports the HHS shift toward alternative payment models that encourage patient-centered, highquality, high-value patient care, which aligns with ASCO’s own proposal to

2014 Quality Care Symposium

Private Payer Data Help Paint Clearer Picture of End-of-Life Care

continued from page 55

overall, 77% of the cohort reported talking to clinicians about pain, and 70% said they received advice on pain management.3 Overall, 78% of patients said they discussed fatigue symptoms, but only 61% said they received advice about managing it. Rates of discussion and advice about emotional distress were lower: Overall, 59% of patients reported discussing these symptoms, and 55% say professionals gave them advice. The study also found a gap between the number of patients who were bothered by these symptoms and those who received help. A total of 61%, 74%, and 46% of patients were bothered by pain, fatigue, and emotional distress, respectively, but only 58%, 40%, and 46%, respectively, were definitely getting help with the symptom.

Combining data from private payers with data from cancer centers could provide a novel way of assessing the quality of end-of-life care, according to a study that analyzed patient information gathered from both Dana-Farber Cancer Institute and from Blue Cross Blue Shield of Massachusetts.4 The study found that in the last 30 days of life, 59.6% of the 674 patients studied were hospitalized, and in that same time period, 47.8% of patients visited the emergency department, 8.5% underwent radiation, 30.6% underwent red blood cell transfusion, and 5.9% received a platelet transfusion. The study also found that 82 patients (12.2%) died in the intensive care unit, and 193 patients (28.6%) died in an acute care facility. n

reform payment for oncology care, released in May 2014. Consolidated Payments for Oncology: Payment Reform to Support Patient-Centered Care for Cancer, a detailed proposal for a new approach to physician payment for cancer care services under Medicare, would fundamentally restructure the way oncologists are reimbursed for cancer care in the United States. The proposal aims to do so by focusing payment on the full range of patient services that oncologists provide while incentivizing high-quality, patient-centered care. Developed by oncologists in com-

Alana Biggers, MD, MPH, discusses Abstract 2: “Medicare Part D low-income subsidy and disparities in breast cancer treatment.”

References 1. Kehl KL, Landrum MB, Kahn KL, et al: Tumor boards among physicians caring for lung and colorectal cancer patients. 2014 ASCO Quality Care Symposium. Abstract 179. Presented October 17, 2014. 2. Biggers A, Neuner J, Smith E, et al: Medicare Part D low-income subsidy and

munity-based practices across the United States, the ASCO proposal also aims to improve the quality of cancer care by focusing on the value, rather than the volume, of services provided. ASCO will work closely with HHS as the agency implements its plan. Find out more about ASCO’s physician payment model proposal at www. asco.org/paymentreform, and visit ASCO in Action at www.asco.org/ advocacy/news for future developments on this issue. n © 2015. American Society of Clinical Oncology. All rights reserved.

disparities in breast cancer treatment. 2014 ASCO Quality Care Symposium. Abstract 2. Presented October 17, 2014. 3. Smith T, Castro K, Troeschel A, et al: Developing symptom management quality improvement reports with data from a registry-based patient reported outcomes (PRO) collection method. 2014 ASCO Quality Care Symposium. Abstract 180. Presented October 17, 2014. 4. Stuver SO, Fraile B, Donohue CC, et al: Novel data sharing between a comprehensive cancer center and a private payer to better understand care at the end of life. 2014 ASCO Quality Care Symposium. Abstract 1. Presented October 17, 2014.

Highlights From the 2014 Palliative Care in Oncology Symposium

he inaugural 2014 Palliative Care in Oncology Symposium was held October 24 to 25 in Boston. Over 200 abstracts were presented, covering topics such as the integration of palliative care into treatment and the financial hardships facing people living with cancer. The following abstracts were among those highlighted in the ASCO Press Program.

‘Co-rounding’ of Medical Oncologists and Palliative Care Physicians Improves Outcomes Three daily, formal meetings between medical oncologists and palliative care specialists in a medical oncol-

ogy inpatient unit were associated with significant improvements in both health system-related and patient-related outcomes.1 The study found that the 783 patients in the “co-rounding” intervention group had a significant decrease in mean length of hospital stay (4.17 days vs 4.51 days; P = .02), compared to the 731 patients admitted before the onset of the intervention. The intervention group also showed significant improvement in 7- and 30-day readmission rates (15% and 23% reduction, respectively [P = .03, P = .05]). “To our knowledge, this is the first example where palliative care physicians

and medical oncologists are working side by side every day on an inpatient oncology ward,” said lead study author Richard Riedel, MD, an Associate Professor of Medicine and Medical Director at Duke University Medical Center.

“Smart Technology” System Improves Symptoms of Hospice Patients and Caregivers Early findings from a study of 319 families suggest that the use of a telephone-based system that monitors symptoms and provides health coaching to caregivers leads to decreased symp-

toms among patients and their caregivers in the final weeks of life.2 The symptom care intervention allowed family caregivers to call into the automated system to report on the presence and severity of patient symptoms and the severity of their own distress and symptoms. The automated system then provided customized, real-time coaching, such as how to improve the patient’s breathing. Preliminary analyses indicated that the family caregivers’ combined symptoms improved more in the symptom care group (P = .003, mixed effects model), as did patient symptoms (P = .003). continued on page 57

ASCOPost.com | MARCH 10, 2015

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Direct From ASCO 2014 Palliative Care Symposium continued from page 56

Financial and Work-Related Hardships Among U.S. Cancer Survivors Twenty-seven percent of cancer survivors have at least one financial problem, such as debt or bankruptcy, and 37% have to modify work plans— for example, switching to a less-demanding job—due to a cancer diagnosis, according to a study out of the University of California, Davis.3 The research explored disparities in financial burden among a large, nationally representative group of 1,592 cancer survivors. Women, younger survivors, racial and ethnic minorities, and uninsured survivors were disproportionately burdened.

Insured Patients Alter Lifestyle, Medical Care to Cope With Cost of Cancer Treatment A small nationwide survey of 174 patients found that some insured patients are changing their lifestyle and medical care to cope with cancer treatment

Richard Riedel, MD, discusses Abstract 3: “Early palliative care on an inpatient oncology unit: Impact of a novel co-rounding partnership on patient and health system outcomes.”

costs—with some modifications potentially jeopardizing their medical care.4 The study found that 89% of survey participants used at least one lifestylealtering strategy, such as spending less on basics like food and clothing (57%), and 39% used at least one medical care-altering strategy, such as not filling a prescription (28%). Younger age, higher education, and shorter time on chemotherapy were associated with greater likelihood of adopting lifestyle-coping strategies. n References 1. Riedel RF, Slusser K, Power S, et al: Early palliative care on an inpatient oncology unit: Impact of a novel co-rounding partnership on patient and health system outcomes. 2014 Palliative Care in Oncology Symposium. Abstract 3. Presented October 25, 2014. 2. Mooney K, Berry P, Wong B, et al:

Helping cancer-family caregivers with endof-life home symptom management: Initial evaluation of an automated symptom monitoring and coaching system. 2014 Palliative Care in Oncology Symposium. Abstract 85. Presented October 24, 2014. 3. Whitney RL, Bell J, Reed S, et al: Work and financial disparities among adult cancer survivors in the United States. 2014 Palliative Care in Oncology Symposium. Abstract 238. 4. Nipp RD, Zullig LL, Samsa G, et al: Coping with cancer treatment-related financial burden. 2014 Palliative Care in Oncology Symposium. Abstract 161.

Accelerating Breakthroughs Launching Careers Improving Cancer Care

ConquerCancerFoundation.org

Save the Date

Best of ASCO® Boston

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July 31–August 1, 2015

August 7–8, 2015

Renaissance Boston Waterfront Hotel

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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 | MARCH 10, 2015

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Announcements

ASCO Collaborates in Launch of Crowd-Sourced Molecular Oncology Tumor Board Series

he ASCO University®, the College of American Pathologists (CAP), and the Association for Molecular Pathology (AMP) recently announced their collaboration to create the Molecular

Oncology Tumor Board series, an online and user-driven resource designed to help cancer care providers with the interpretation and understanding of tumor molecular profiling tests and studies.

The new crowd-sourced series allows for maximum user input and interaction and encourages a multidisciplinary discussion of this rapidly growing area of cancer care. Access to

B:16.75”

the Molecular Oncology Tumor Boards will be available for free beginning this month through the ASCO Connection website, ASCOConnection.org. “Understanding the results of tumor

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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Announcements

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molecular profiling studies is challenging, and the field of cancer genomics is rapidly changing, with new information being generated at a dizzying pace,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO. “All oncologists struggle to keep abreast of this information and to learn how to use tumor molecular profiling to deliver

high-quality, personalized cancer care. We hope that this new educational program will foster learning about tumor molecular genomics in an engaging and interactive format fueled by real-world case studies.” Each month the Molecular Oncology Tumor Boards will feature a casebased discussion involving genetic or

genomics in the treatment of cancer. The open forum will allow participants to post questions or comments about the cases, engage in discussion, and compare approaches. Two rotating faculty members, a medical oncologist and pathologist, will lead the case discussion each month, provide input, and, after 2 weeks of

—Richard L. Schilsky, MD, FACP, FASCO

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discussion, will post a summary of the case discussion that addresses actionable aberrations identified and treatment options available based on clinical parameters. The information provided in the case discussions is designed to be educational and is not intended to make treatment recommendations. The Molecular Oncology Tumor Boards are available to anyone who creates an ASCO.org account and logs into ASCOConnection.org. Participants who complete and pass a short post-test can also earn Continuing Medical Education (CME) credit. n S:10”

One event wasbOne Grade event 5 severity. was Grade 5 severity.

We hope that this new educational program will foster learning about tumor molecular genomics in an engaging and interactive format fueled by real-world case studies.

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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

Contact

The ASCO Post

Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

The ASCO Post | MARCH 10, 2015

PAGE 62

JCO Spotlight Breast Cancer

Combination Treatment Every 2 Weeks May Benefit Some Women With High-Risk Early-Stage Breast Cancer By Matthew Stenger

n a phase III trial (SWOG S0221) reported in the Journal of Clinical Oncology, George T. Budd, MD, of Taussig Cancer Center, Cleveland Clinic, and colleagues found no difference in disease-free survival among four different combinations of continuous or every-other-week doxorubicin/ cyclophosphamide (AC) and weekly or every-2-week paclitaxel in patients with node-positive or high-risk nodenegative breast cancer.1 Both the AC comparison and the paclitaxel comparison were halted for futility at interim analyses. In the current analysis, a difference in overall survival was observed among regimens, and subgroup analysis suggested benefit of every-2-week AC and every-2-week paclitaxel among patients with hormone receptor–negative/HER2-negative disease.

clitaxel weekly for 12 weeks (n = 697), or AC weekly for 15 weeks plus paclitaxel weekly for 12 weeks (n = 648). The primary endpoint was disease-free survival.

Futility Boundaries Crossed The futility boundary was crossed for the AC comparison at the first interim analysis in September 2010. Accrual was suspended in November 2010, and the trial was reopened in December 2010, with all patients assigned to four cycles of AC every 2 weeks and randomly assigned to receive the two paclitaxel schedules (total, 578 addi-

■■ Disease-free survival was similar in all treatment groups. ■■ Subgroup analysis suggested that every-2-week AC and every-2-week paclitaxel may be better in hormone receptor–negative/HER2-negative tumors.

weekly paclitaxel, and 1.12 (95% CI = 0.87–1.44) for continuous AC/weekly paclitaxel. Comparison of all four groups showed a significant difference in overall survival (P = .040), with the highest overall survival reported in the every2-week AC and every-2-week paclitaxel

Patients with hormone receptor– negative/HER2-negative high-risk breast cancers may have improved outcome when treated with the onceevery-2-week regimen.

Study Details This 2 × 2 factorial design trial tested two hypotheses: (1) that a novel continuous schedule of AC was superior to six cycles of AC once every 2 weeks; and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks. The first randomization compared intravenous doxorubicin at 60 mg/m2 on day 1, intravenous cyclophosphamide at 600 mg/m2 on day 1, and subcutaneous pegfilgrastim (Neulasta) at 6 mg on day 2 every 2 weeks vs intravenous doxorubicin at 24 mg/m2 once per week, oral cyclophosphamide at 60 mg/ m2 once daily, and subcutaneous filgrastim (Neupogen) at 5 µg/kg rounded to the nearer of 300 or 480 µg once daily (except on the days of intravenous drug administration). The second randomization was subsequent intravenous paclitaxel at 175 mg/m2 on day 1 once every 2 weeks and subcutaneous pegfilgrastim at 6 mg on day 2 every 2 weeks for six cycles vs intravenous paclitaxel 80 mg/m2 once per week for 12 weeks. Between December 2003 and November 2010, 2,716 patients were randomly assigned to receive AC every 2 weeks for six cycles plus paclitaxel every 2 weeks for six cycles (n = 678), AC weekly for 15 weeks plus paclitaxel every 2 weeks for six cycles (n = 693), AC every 2 weeks for six cycles plus pa-

Phase III SWOG Trial in Early-Stage Breast Cancer

—George T. Budd, MD, and colleagues

tional patients). The futility boundary for the paclitaxel comparison was crossed at the third interim analysis in September 2012.

Evidence of Interaction The current analysis included outcomes through October 2013. No significant interaction of the AC and paclitaxel factors was found in the interim analyses. However, after a median follow-up of 6 years, a significant interaction developed between the two randomization factors (P = .024 for disease-free survival, P = .010 for overall survival) among the 2,716 originally randomized patients, which precluded interpretation of the two factors separately.

Survival Results Comparison of all four groups simultaneously showed no difference in disease-free survival (P = .11). Compared with the AC every-2-week/paclitaxel every-2-week group, hazard ratios were 1.32 (95% confidence interval [CI] = 1.04–1.68) for continuous AC/ paclitaxel every 2 weeks, 1.24 (95% CI = 0.98–1.59) for AC every 2 weeks/

group; compared with this group, hazard ratios were 1.44 (95% CI = 1.08– 1.93) for continuous AC/paclitaxel every 2 weeks, 1.46 (95% CI = 1.09–1.95) for AC every 2 weeks/weekly paclitaxel, and 1.24 (95% CI = 0.91–1.68) for continuous AC/weekly paclitaxel.

Subset Analysis Unplanned subset analyses to investigate the possible interaction between the AC and paclitaxel schedules suggested that the observed difference in overall survival was confined to patients with hormone receptor–negative/HER2-negative tumors (P = .067), with no evidence of difference in patients with hormone receptor–positive/HER2-negative tumors (P = .90) or HER2-positive tumors (P = .40).

Toxicity Grade 3 or 4 leukopenia occurred in 20% of patients during treatment with AC every 2 weeks and 15% of patients during treatment with continuous AC; grade 3 or 4 neutropenia occurred in 26% and 23%, respectively; and grade 3 or 4 febrile neutropenia occurred in

6% and 2%, respectively. Grade 3 or 4 leukopenia (7% vs 1%) and neutropenia (12% vs 2%) were more common during treatment with weekly paclitaxel vs every-2-week paclitaxel, but rates of febrile neutropenia were similar (0.1% vs 0.2%). Grade 3 or 4 allergic reactions (1.4% vs 0.5%), musculoskeletal pain (11% vs 3%), and neurologic toxicity (17% vs 10%) were more common during every-2-week paclitaxel. Deaths due to toxicity during paclitaxel given every 2 weeks were due to heart failure after AC every 2 weeks in one patient, pneumonitis in one patient, and unclear/multifactorial factors in two patients. Deaths due to toxicity during treatment with weekly paclitaxel were caused by heart failure after AC every 2 weeks in one patient and pneumonitis in two patients. All planned AC treatment was completed by 88% of patients receiving AC every 2 weeks and by 83% of those receiving continuous AC (P < .001), with 7.9% vs 11% (P = .006) stopping AC early due to adverse events. The investigators concluded: “Patients achieved a similar disease-free survival with any of these regimens. Our study suggests the hypothesis that patients with hormone receptor–negative/HER2-negative high-risk breast cancers may have improved outcome when treated with the once-every2-week regimen, and we recommend that this hypothesis be investigated in other studies.” n

Disclosure: This study was supported by the National Cancer Institute, the Canadian Cancer Society Research Institute, and Amgen. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. Budd GT, Barlow WE, Moore HC, et al: SWOG S0221: A phase III trial comparing chemotherapy schedules in highrisk early-stage breast cancer. J Clin Oncol 33:58-64, 2015.

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Perspective

The Search for Optimal Adjuvant Breast Cancer Chemotherapy: The End of an Era? By Rowan T. Chlebowski, MD, PhD

sing a complex and innovative study design, Budd and colleagues from the Southwest Oncology Group (SWOG) addressed, in a randomized multicenter trial,1 an issue that has been under evaluation for over 40 years—namely, what are the optimal dose and schedule for adjuvant breast cancer chemotherapy? Major study objectives of the SWOG S0221 trial—reviewed in this issue of The ASCO Post—included a comparison of a “dose-dense” schedule of administration with a continuous or “metronomic” schedule of administration with more constant drug exposure. As a second objective, two commonly used paclitaxel schedules of administration were also compared. All regimens included growth factor support.

Background Behind Study Regimens Before considering the outcome of SWOG S0221, it is useful to review the background supporting the selection of the study objectives and the chemotherapy regimens being evaluated. Decades ago, the schedule of chemotherapy question was framed as “low-dose continuous” vs “higher-dose intermittent” therapy. Higher-dose intermittent therapy was defined by the time needed for recovery from myelosuppression after infusional administration (often 3 weeks between administrations). Examples of low-dose continuous regimens under evaluation then included oral daily cyclophosphamide and doxorubicin given on a lowerdose weekly infusion schedule.2 Over time, intermittent therapy adjuvant regimens won favor, including the combination of doxorubicin plus cyclophosphamide (AC) and the addition of fluorouracil (FAC), largely based on convenience and toxicity considerations. Subsequently, the question regarding the optimal adjuvant chemotherapy schedule was reframed as comparing conventional (interDr. Chlebowski is Principal Investigator in the Division of Medical Oncology and Hematology at the Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center in Torrance, California.

mittent therapy again defined by the time needed for recovery from myelosuppression) vs dose-dense administration with growth factor support to

allow for shorter intervals in intermittent therapy with the same dosage. In the Intergroup 9741 trial, a dosedense, every-2-week doxorubicin

plus cyclophosphamide then paclitaxel regimen resulted in disease-free survival and overall survival benefit continued on page 64

The ASCO Post | MARCH 10, 2015

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Perspective

Rowan T. Chlebowski, MD, PhD ings from the SWOG S0221 trial, continued from page 63

over the then-standard every-3-week schedule using the same agents and dosages.3 Over time, findings from subgroup analyses from the 9741 trial suggested most of the superiority was limited to women with hormone receptor–negative cancers.4 Selection of the metronomic or continuous dosing schedule for evaluation in SWOG S0221 was based on preclinical studies and early clinical results. Interestingly, one of the clinical trials cited to support the selection, a phase III comparison of a standard intermittent administration chemotherapy to a continuous daily oral cyclophosphamide schedule incorporating growth factor support as neoadjuvant therapy for inflammatory local breast cancer, was reported to show no significant difference between the schedules.5 So, it is not exactly clear why the continuous regimen went forward in SWOG S0221. The weekly paclitaxel regimen, a regimen not requiring growth factor support, was evaluated in SWOG S0221 based on findings from the E1199 trial. Weekly paclitaxel for 12 weeks after standard doxorubicin and cyclophosphamide was found to improve disease-free survival and overall survival when compared with then-standard every-3-week paclitaxel for four cycles in an adjuvant breast cancer setting.6 In another major trial (NSABP B-38) of relevance to find-

Swain and colleagues7 compared a dose-dense schedule of doxorubicin and cyclophosphamide followed by four cycles of dose-dense paclitaxel with six cycles of docetaxel, doxoru-

indicate that for HER2-negative adjuvant breast cancer therapy, comparable efficacy is seen for dose-dense therapy, combination therapy incorporating weekly paclitaxel, and the TAC regimen. Oncologists in practice commonly favor

As we move toward more specifically identified subgroups of patients for adjuvant trial consideration, the SWOG S0221 will be one of the last of such broadbased trials. —Rowan T. Chlebowski, MD, PhD

bicin, and cyclophosphamide (TAC) in an adjuvant setting. Again, no significant differences in efficacy were identified.

SWOG S0221: Comparable Efficacy Finally, we get to the findings from SWOG S0221. The dose-dense, continuous or metronomic, and weekly paclitaxel schedules all gave comparable disease-free survival results, with subset analysis suggesting potential superiority for a dose-dense regimen in women with hormone receptor– negative and HER2-negative tumors. The results provide no particular reason to favor the continuous schedule. In summary, a series of trials over several decades of clinical investigation

one of these regimens based on their experience regarding differences in toxicity, patient convenience, and cost related to growth factor use. As we move toward more specifically identified subgroups of patients for adjuvant trial consideration, the SWOG S0221 will be one of the last of such broad-based trials. n

Disclosure: Dr. Chlebowski reported receiving consulting fees or honoraria from Novartis, Amgen, and Genomic Health; fees for participation in review activities for Pfizer and Novo Nordisk; payment for lectures from Novartis; and payment for educational activities from Educational Concepts Group.

References 1. Budd GT, Barlow WE, Moore HC, et al: SWOG S0221: A phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J

Clin Oncol 33:58-64, 2015. 2. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979. 3. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003. 4. Berry DA, Cirrincione C, Henderson IC, et al: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658-1667, 2006. 5. Ellis GK, Barlow WE, Gralow JR, et al: Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol 29:1014-1021, 2011. 6. Sparano JA, Wang M, Martino S, et al: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663-1671, 2008. 7. Swain SM, Tang G, Geyer Jr CE, et al: Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, nodepositive breast cancer: The NSABP B-38 trial. J Clin Oncol 31:3197-3204, 2013.

Announcements

MD Anderson Receives $22.3 Million in CPRIT Research Funding

he University of Texas MD Anderson Cancer Center has received more than $22 million in research grants from the Cancer Prevention and Research Institute of Texas (CPRIT). The CPRIT awards will go toward studies in the areas of breast, skin, prostate, pancreas, colon, and lung cancers in adults, and leukemia and brain cancer in children. The grants included: • $16 million for Individual Investigator Research Awards (IIRA) • $3.8 million for Children and Adolescent Cancer • $2.5 million for Prevention and Early Detection In addition, Immatics Biotechnologies was one of four Company Formation Awards funded by CPRIT. At

more than $19 million, the project will further enable translation of immunotherapy knowledge from MD Anderson into new therapeutics for cancer patients. MD Anderson has received $215 million in total awards since CPRIT was founded in 2009.

“This is an astounding accomplishment, and we’re extremely pleased that CPRIT has again recognized the significant scientific contributions being made by our world-class researchers,” said MD Anderson President Ron DePinho, MD. “I could not be more proud of the work that occurs every day

I commend those investigators who were awarded funding by CPRIT, as well as all the scientists and clinicians whose daily goal is no less than to end cancer. —Ron DePinho, MD

at this institution and I commend those investigators who were awarded funding by CPRIT, as well as all the scientists and clinicians whose daily goal is no less than to end cancer.” In November 2014, CPRIT adopted new annual priorities to guide its grant awards, and specified that 10 of the awards would focus on childhood and adolescent cancers, and five would address prevention and early detection of cancer. MD Anderson was awarded two grants in each of these new categories, totaling more than $6.3 million. For a listing of individual MD Anderson studies provided with funding by CPRIT, please visit http://www .mdanderson.org/newsroom/news-releases/2015/prit-award-md-anderson22-3-million-in-grants.html. n

ASCOPost.com | MARCH 10, 2015

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Journal Spotlight Hematology

PD-1 Blockade With Nivolumab Produces High Response Rate in Relapsed/Refractory Hodgkin Lymphoma By Matthew Stenger

nti–PD-1 antibodies have been shown to be effective in solid tumors. There is evidence that the malignant Reed-Sternberg cells in Hodgkin lymphomas use the programmed cell death protein 1 (PD-1) pathway to evade immune detection, with alterations in chromosome 9p24.1 increasing levels of the PD-1 ligands PD-L1 and

ter relapse following autologous stem cell transplantation and 18 (73%) after relapse following brentuximab vedotin (Adcetris) treatment.

Responses An objective response occurred in 20 patients (87%), including 4 (17%) with a complete response and 16 (70%)

The frequent clinical responses to nivolumab therapy in heavily pretreated patients with relapsed or refractory Hodgkin’s lymphoma and genetic alterations of the PD-1 ligand loci highlight the importance of the PD-1 immune evasion pathway and the genetically defined sensitivity to PD-1 blockade in this disease. —Stephen M. Ansell, MD, PhD, and colleagues

PD-L2 through JAK-STAT signaling. In an ongoing phase I study reported in The New England Journal of Medicine, Stephen M. Ansell, MD, PhD, of Mayo Clinic, and colleagues found that treatment with the PD-1 inhibitor nivolumab (Opdivo) produced a high response rate in heavily pretreated patients with Hodgkin lymphoma.1

Study Details In the study, 23 patients with relapsed/refractory Hodgkin lymphoma received nivolumab at 3 mg/kg every 2 weeks until complete response, disease progression, or excessive toxicity. Patients had a median age of 35 years (range, 20–54 years); 12 (52%) were male; 20 (87%) were white; Eastern Cooperative Oncology Group performance status was 0 in 6 (26%) and 1 in 17 (74%); 22 (96%) had nodular sclerosis; number of previous systemic therapies was 2 or 3 in 8 (35%), 4 or 5 in 7 (30%), and ≥ 6 in 8 (35%); 4 (17%) had extranodal involvement; 19 (83%) had previous radiotherapy; and 18 (73%) enrolled in the study af-

with a partial response; the remaining 3 patients (13%) had stable disease. Of the 4 patients with a complete response, 3 had not received previous brentuximab vedotin. Among 15 patients with tumor recurrence after autologous stem cell transplantation and brentuximab vedotin, the response rate was 87%, with 1 patient (7%) having a complete response, 12 (80%) a partial response, and 2 (13%) stable disease. All 3 patients who did not undergo autologous stem cell transplantation before brentuximab vedotin treatment had partial responses. Among 5 patients who did not receive brentuximab vedotin, 4 (80%) had responses, including complete response in 3, and 1 patient had stable dis-

ease. In the 20 patients who responded, 12 (60%) had the first response by 8 weeks (range, 3–39 weeks).

Additional Results Progression-free survival at 24 weeks was 86% (95% confidence interval = 62%–95%). At the time of reporting, 6 patients had chosen to undergo stem cell transplantation at the time of the best overall response, and 11 patients continued to maintain response. Median overall survival had not been reached after median duration of follow-up of 40 weeks (range, 0–75 weeks). Analyses of pretreatment tumor specimens from 10 patients showed PDL1 and PDL2 copy number increases and increased expression of the ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicating active JAK-STAT signaling.

Treatment Exposure and Adverse Events Patients received a median of 16 nivolumab doses (range, 6–37) over a median treatment duration of 36 weeks (range, 13–77), with 15 patients (65%) receiving ≥ 90% of the intended overall dose. Reasons for discontinuation of treatment included stem cell transplantation in 6 patients, disease progression in 4 patients, and drug toxicity in 2 patients. The most common drug-related adverse events of any grade were rash (22%), decreased platelets (17%), fatigue (13%), pyrexia (13%), diarrhea (13%), nausea (13%), and pruritus (13%). No drug-related grade 4 or 5 adverse events were reported. Drugrelated grade 3 adverse events occurred in 5 patients (22%) and included myelodysplastic syndrome, pancreatitis,

Role of Nivolumab in Hodgkin Lymphoma ■■ Nivolumab produced a response in 87% of patients. ■■ Responses were observed in patients with failure of both stem cell transplantation and brentuximab vedotin, those with failure of brentuximab and no prior stem cell transplantation, and those who received no prior brentuximab.

pneumonitis, stomatitis, colitis, gastrointestinal inflammation, thrombocytopenia, increased lipase level, decreased lymphocyte level, and leukopenia. Serious adverse events occurred in 3 patients, consisting of grade 3 pancreatitis, grade 3 myelodysplastic syndrome, and grade 2 lymph node pain. The patient with myelodysplastic syndrome had undergone six previous systemic chemotherapies, radiation therapy, and autologous stem cell transplantation but had not received prior bendamustine (Treanda). Dose delay was required in 9 patients (39%) and was due to nonhematologic adverse events in 5. The adverse events leading to treatment discontinuation were myelodysplastic syndrome and thrombocytopenia in 1 patient and pancreatitis in 1 patient. Infusion was interrupted in 2 patients (9%) due to grade 1 hypersensitivity reaction. The investigators concluded: “Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin’s lymphoma.” They noted: “The frequent clinical responses to nivolumab therapy in heavily pretreated patients with relapsed or refractory Hodgkin’s lymphoma and genetic alterations of the PD-1 ligand loci highlight the importance of the PD-1 immune evasion pathway and the genetically defined sensitivity to PD-1 blockade in this disease.”

Dr. Ansell, Alexander M. Lesokhin, MD, of Memorial Sloan Kettering Cancer Center, Margaret A. Shipp, MD, of Dana-Farber Cancer Institute, and Philippe Armand, MD, PhD, of DanaFarber Cancer Institute, contributed equally to The New England Journal of Medicine article. n

Disclosure: The study was funded by BristolMyers Squibb and others. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311-319, 2015.

The ASCO Post | MARCH 10, 2015

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Perspective

For Hodgkin Lymphoma Patients, It Ain’t Over By Anas Younes, MD

ith less than 10,000 patients diagnosed with Hodgkin lymphoma each year and a cure rate of approximately 75% to 80%, drug development for this disease was never a priority for pharmaceutical companies. So when the antibody-drug conjugate brentuximab vedotin (Adcetris) was approved by the U.S. Food and Drug Administration (FDA) in 2011 for the treatment of relapsed Hodgkin lymphoma, with a response rate of 75%, many observers thought that mission was accomplished. Clinical trials incorporating brentuximab vedotin with different chemotherapy regimens proliferated, with many trials reporting encouraging early results.

number of reactive, inflammatory immune cells, Hodgkin lymphoma was cancer’s poster child for illustrating the failure of immune surveillance. On the other hand, it was also a cancer model for exploring novel immune therapy. After many failures, a successful treatment strategy has emerged.

were swift, occurring within the first 2 to 3 months. However, like many drugs tested in multiply relapsed patients, the vast majority of responses were partial, indicating that in this setting, single-agent nivolumab is unlikely to cure patients with relapsed Hodgkin lymphoma.

After more than 4 decades of neglect, drug development for Hodgkin lymphoma is back on track. —Anas Younes, MD

Simple, Naked Antibody Consequently, it was beyond all expectations that another highly active drug would be identified so quickly, earning a Breakthrough Therapy designation from the FDA. What was more surprising is that this active drug, nivolumab (Opdivo), is a simple, naked antibody that reactivates the patient’s own immune cells. With a few malignant cells residing among an overwhelming Dr. Younes is a medical oncologist and Chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center, New York.

As reported by Ansell and colleagues1 and reviewed in this issue of The ASCO Post, nivolumab, an antibody that blocks the ability of programmed cell death protein 1 (PD1) to interact with its natural ligands (PD-L1 and PD-L2) produced a response rate of 87%, with an acceptable safety profile. The response rate was exceptionally high, even among patients whose disease progressed after therapy with brentuximab vedotin. Furthermore, most responses

Next Steps So what is next? In the short-term, nivolumab (and other PD-1/PD-L1 targeted antibodies) will need to be combined with brentuximab vedotin and chemotherapy in different disease settings—post-transplant, pretransplant, and even with front-line chemotherapy regimens. We also need to learn more about the exact mechanism of action, mechanisms of resistance, and biomarkers for patient selection for this class of drugs, so we can de-

velop rationally designed mechanismbased combination regimens. Furthermore, we need to define the optimal duration of therapy for those who achieve complete remissions. In the long run, careful exploration of novel chemotherapy-free and radiation therapy–free combination regimens will need to be performed in a multistep process. The goal for such novel regimens should be clear: higher activity and better safety than the existing therapy. In this new paradigm, brentuximab vedotin and nivolumab are building blocks, as we continue to identify other novel targeted agents. After more than 4 decades of neglect, drug development for Hodgkin lymphoma is back on track. Until we cure every single patient with Hodgkin lymphoma, and ensure that cured patients will enjoy a normal and healthy life, the fat lady should continue to refuse to sing. n

Disclosure: Dr. Younes has received honoraria from Seattle Genetics, Millennium, and Takeda.

Reference 1. Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311-319, 2015.

Don’t Miss These Important Reports in This Issue of The ASCO Post

Peter Paul Yu, MD, FACP, FASCO, on Big Data and Precision Medicine see page 1

Eunice Kwak, MD, on the MET Pathway in Gastroesophageal Cancer see page 11

Jeffrey S. Ross, MD, on Genomic Profiling and Biliary Duct Cancer see page 12

Alexandria T. Phan, MD, on Lanreotide in Pancreatic Neuroendocrine Tumors see page 15

Richard L. Schilsky, MD, on the World Oncology Forum see page 21

Ian Krop, MD, PhD, on PI3K Inhibition in Hormone Receptor–Positive Breast Cancer see page 22

Visit The ASCO Post online at ASCOPost.com

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The first approved PARP inhibitor LYNPARZA is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. • In clinical studies the most common adverse reactions (Grades 1-4) in ≥20% of patients included anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/ musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort

FOR MORE INFORMATION VISIT www.LYNPARZA.com

IMPORTANT SAFETY INFORMATION There are no contraindications for LYNPARZA. Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been conﬁrmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. Monitor complete blood count testing at baseline and monthly thereafter. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. In clinical studies the most common adverse reactions (Grades 1-4) in ≥20% of patients included anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort. Coadministration of drugs which are potent inhibitors or inducers of CYP3A could increase or decrease exposure to LYNPARZA and should be avoided. Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. LYNPARZA is Pregnancy Category D. LYNPARZA is not recommended for use in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal), moderate renal impairment or severe renal impairment, since safety and efﬁcacy have not been established. Please see adjacent Brief Summary of the full Prescribing Information. LYNPARZA is a trademark of the AstraZeneca group of companies. ©2015 AstraZeneca. All Rights Reserved. 3076602 Last updated 01/15

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Journal Spotlight Issues in Oncology

Clinically Inappropriate Patient Demands of Oncologists Happen More Infrequently Than Expected

new study1 conducted at outpatient oncology centers found that only 1% of 5,050 patient-clinician encounters resulted in a clinically inappropriate request, of which very few were

complied with by physicians. Ezekiel J. Emanuel, MD, PhD, of the University of Pennsylvania, and colleagues analyzed interviews with clinicians immediately after they visited

LYNPARZA™ (olaparib) capsules, for oral use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE Treatment of gBRCA-mutated advanced ovarian cancer Lynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14) in the full Prescribing Information]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. DOSAGE AND ADMINISTRATION Patient Selection Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [see Indications and Usage (1) and Clinical Studies (14) in the full Prescribing Information]. Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics. Recommended Dosing The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity. If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time. Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [see How Supplied/Storage and Handling (16.2) in the full Prescribing Information]. Dose Adjustments for Adverse Reactions To manage adverse reactions, consider dose interruption of treatment or dose reduction. The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg. If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg. Dose Modifications for Use with CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [see Drug Interactions (7.2) in the full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents. Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy ( CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza. Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza. Embryo-Fetal Toxicity Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [see Use in Specific Populations (8.6) in the full Prescribing Information]. ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: • Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) in the full Prescribing Information] • Pneumonitis [see Warnings and Precautions (5.2) in the full Prescribing Information]

with patients to assess whether a patient had made a demand, the type of request made, and the clinical appropriateness of it. The interviews were conducted at outpatient oncology facilities at three

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. Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy. In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [see Clinical Studies (14) in the full Prescribing Information] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in 20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days. Table 1 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Adverse Reaction Blood and Lymphatic disorders Anemia Gastrointestinal disorders Abdominal pain/discomfort Decreased appetite Nausea Vomiting Diarrhea Dyspepsia General disorders Fatigue/asthenia Infections and infestations Nasopharyngitis/URI Musculoskeletal and Connective Tissue disorders Arthralgia/musculoskeletal pain Myalgia

3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % 34

43 22 64 43 31 25

8 1 3 4 1 0

21 22

0 0

Table 2 presents the frequency of abnormal laboratory ﬁndings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily. Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Laboratory Parameter* 3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % Decrease in hemoglobin (anemia) 90 15 Decrease in absolute neutrophil count 25 7 (neutropenia) Decrease in platelets (thrombocytopenia) 30 3 Decrease in lymphocytes (lymphopenia) 56 17 Mean corpuscular volume elevation 57 Increase in creatinine* 30 2 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The following adverse reactions and laboratory abnormalities have been identified in 10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in 1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush. Table 3 presents adverse reactions reported in 20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCAmutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo. Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.

Philadelphia-area hospitals between October 2013 and June 2014. The authors evaluated 5,050 patientclinician encounters involving 3,624 continued on page 70

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PAGE 70

Journal Spotlight Patient Demands continued from page 69

patients and 60 clinicians. Most of the patients were women, and the most common cancer was hematologic. Overall, 440 (8.7%) of the 5,050 encounters included a patient demand or request, such as for imaging studies, treatments, or tests, and physicians

Ezekiel J. Emanuel, MD, PhD

LYNPARZATM (olaparib) capsules Table 3 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Adverse Reactions Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and Lymphatic disorders Anemia 25 4 7 2 Gastrointestinal disorders Abdominal pain/discomfort 47 0 58 2 Decreased appetite 25 0 14 0 Nausea 75 2 37 0 Vomiting 32 4 9 0 Diarrhea 28 4 21 2 Dyspepsia 25 0 14 0 Dysgeusia 21 0 9 0 General disorders Fatigue (including asthenia, lethargy) 68 6 53 2 Infections and infestations Nasopharyngitis/Pharyngitis/URI 43 0 16 0 Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal pain 32 4 21 0 Myalgia 25 2 12 0 Back pain 25 6 21 0 Nervous system disorder Headache 25 0 19 2 Respiratory, Thoracic, Mediastinal disorders Cough 21 0 14 0 Skin and Subcutaneous Tissue Dermatitis/Rash 25 0 14 0 Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter* Lynparza Placebo N=53 N=43 Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Decrease in hemoglobin 85 8 58 2 Decrease in absolute neutrophil count 32 8 23 0 Decrease in platelets 26 6 19 0 Mean corpuscular volume elevation 85 44 Increase in creatinine* 26 0 5 0 * Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

DRUG INTERACTIONS Olaparib is primarily metabolized by CYP3A. Anticancer Agents Clinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. Drugs that may Increase Olaparib Plasma Concentrations In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold. Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.4) in the full Prescribing Information]. Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Drugs that may Decrease Olaparib Plasma Concentrations In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3) in the full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions (5.3) in the full Prescribing Information] Risk summary Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy. Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which

complied with 365 (83%) of them. Of all 5,050 patient-clinician encounters, 316 (6.3%) had a clinically appropriate patient demand or request, whereas only 50 (1%) of the encounters had a clinically inappropriate request. Of the 50 clinically inappropriate demands or requests, clinicians complied with 7 of them, which means that in just 0.14% of

2 resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose). In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence. Nursing Mothers It is not known whether olaparib 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 olaparib, 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 Lynparza has not been established in pediatric patients. Geriatric Use In clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged 65 years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE 3 which were reported more frequently in patients aged 65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference. Females of Reproductive Potential Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza. Hepatic Impairment The effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT 2.5 X ULN ( 5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Renal Impairment Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in the full Prescribing Information]. OVERDOSAGE There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically. 17 PATIENT COUNSELING INFORMATION SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE) • Dosing Instructions: Inform patients on how to take Lynparza [see Dosage and Administration (2.1) in the full Prescribing Information]. Lynparza should be taken twice daily. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Lynparza with grapefruit or Seville oranges. • MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions (5.1) in the full Prescribing Information]. • Pneumonitis: Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions (5.2) in the full Prescribing Information]. • Pregnancy and Females of Reproductive Potential: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least one month after receiving the last dose of Lynparza [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.6) in the full Prescribing Information]. • Nursing Mothers: Advise patients not to breastfeed while taking Lynparza [see Use in Special Populations (8.3) in the full Prescribing Information]. • Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 3079901 12/14 Issued: 12/2014

encounters (7 of 5,050) did clinicians order a test or treatment based on a clinically inappropriate request. “At least in oncology, ‘demanding patients’ seem infrequent and may not account for a significant proportion of costs,” the study concludes.

The Myth of the Demanding Patient In a related editorial,2 Anthony L. Back, MD, of the Seattle Cancer Care Alliance, said, “Dr. Gogineni and colleagues report on their empirical inquiry into patient demands, a nemesis that proves to be more mythical than real. The real point of the study, however, is this: We have to stop blaming patients for being demanding. In reality, it is hardly happening. The myth of the demanding patient is more about our own responses and lackluster communication skills.” Dr. Back continued, “It is possible that what the study documents is a point in the evolution of the patientphysician relationship when both sides recognize the complexity of cancer care belies a simple fix.” n References 1. Gogineni K, Shuman KL, Chinn D, et al: Patient demands and requests for cancer tests and treatments. JAMA Oncol. February 12, 2015 (early release online). 2. Back AL: The myth of the demanding patient. JAMA Oncol. February 12, 2015 (early release online).

The ASCO Post

@ASCOPost

ASCOPost.com | MARCH 10, 2015

PAGE 71

State of the Art Head/Neck Cancer

Treating Head and Neck Cancer in 2015 A Conversation With Robert I. Haddad, MD By Ronald Piana

ach year in the United States, about 55,000 people will be diagnosed with head and neck cancer, and of them, about 12,000 will die of the disease. Although advances have been made in the treatment of head and neck cancer, this disease remains persistently problematic, due, in part, to the complex anatomy of the sites involved. To bring readers up to speed on the latest developments in head and neck cancer, The ASCO Post spoke with a leading researcher in the field, Robert I. Haddad, MD, Associate Professor of Medicine at Harvard Medical School and Disease Center Leader in Head and Neck Oncology at Dana-Farber Cancer Institute, Boston.

Education and Training Please tell the readers a bit about your background prior to joining Dana-Farber Cancer Institute. I was born and reared in Lebanon, and I received my medical education at the French faculty of Medicine in Beirut University of Beirut. In 1995, I moved to the United States and did my internal medical residency at St. Luke’s–Roosevelt Hospital in New York. After that, I did my fellowship training in hematology-oncology at the University of Maryland in Baltimore. I joined the staff of Dana-Farber Cancer Institute in 2001 and have been

here ever since. I am currently the leader of the institute’s head and neck oncology program.

Major Advances Over the course of your career, what are the biggest advances you’ve seen in head and neck cancer? The treatment options in head and neck cancer have not changed significantly over the past decade. Surgery, radiation, and chemotherapy remain the main treatment modalities. I believe the major advances in this disease have been the development of newer technologies, such as how we deliver

perform major resections and simultaneously do reconstruction work, allowing our patients to maintain speech and swallowing functions along with other improvements in quality-of-life issues that were previously compromised by the routine use of more invasive surgery.

Radiotherapy Differences Are there any data suggesting a difference in benefit between IMRT and protonbeam therapy? This is an important area that is being looked at in active research. However, for the vast majority of head and neck cancer patients, IMRT should

Head and neck cancer has suffered from a lack of novel approaches…. We’re very optimistic going forward that we will be able to better define and understand the genomics of the disease, which will help us tailor drugs for specific genetic alterations. This will allow head and neck cancer to step into the future of precision medicine. —Robert I. Haddad, MD

radiation therapy, whether by intensitymodulated radiation therapy (IMRT) or proton-beam therapy. There have also been significant advances in the surgical treatment of head and neck cancer and in reconstructive methods. We now have the ability to

Quick Facts About Head and Neck Cancer ■■ Caucasians currently have the highest incidence rates of head and neck cancers, although death is still highest in African Americans. ■■ HPV appears to be responsible for the rise in cancers of the oropharynx (tonsil and base of tongue) in younger nonsmokers. ■■ Approximately $3.2 billion is spent in the United States each year on treatment of head and neck cancers. ■■ People who work in environments with dust, glues, formaldehyde, mustard gas, certain heavy metals, and radium are at higher risk for developing nasal and paranasal cancers. ■■ Sinus cancer should be considered when someone has constant nosebleeds, numbness of the cheek, facial swelling, or pain.

still be standard of care. Obviously, proton-beam therapy is preferred when you’re treating a tumor close to the ocular orbit or to the brain. But most head and neck cancers do not involve those two areas, and so the routine treatment of a patient with an oral cavity cancer generally entails surgery followed by IMRT. Moreover, IMRT produces a significant improvement in outcomes over traditional radiation therapy because of the ability to spare saliva and prevent dry mouth over the course of recovery.

Disease Presentation Has the presentation of head and neck cancer by stage changed over the past decade? Not appreciably. Most of our head and neck patients present with stage IVA locally advanced nonmetastatic cancer. The staging of head and neck

cancer is very peculiar, and even though these patients have stage IVA, they are still highly curable, and usually with a good prognosis. The treatment of head and neck cancer largely depends on the site we are treating. For patients with an anterior tumor of the oral cavity, standard of care is surgery first, with reconstruction, which is typically followed by IMRT or, in some cases, IMRT and chemotherapy. Most patients with posterior tumors of the voice box, the hypopharynx, the larynx, or the oropharynx are treated with chemotherapy and radiation.

Robotic Surgery Is there a role for robotic surgery in head and neck cancer? Definitely. In fact, the availability of robotic surgery now allows the surgeon to remove the tumor in the oropharynx with minimal incisions and a shorter hospital stay. Moreover, robotic surgery in this field is the subject of numerous clinical trials to establish its value, not only in treating patients, but also in allowing a certain amount of de-intensification of radiation and chemotherapy after surgery.

Role of HPV Please discuss the emerging role of human papillomavirus (HPV) in head and neck cancer. Over the past decade, the identification of HPV as a major driver in head and neck cancer has initiated an important change in the epidemiology of this disease and in patient outcomes. We know that HPV-positive patients have a more favorable outcome than their HPV-negative counterparts. And the HPV-positive patients are currently the subjects of numerous clinical trials. When we talk about HPV-related disease, we are basically referring to cancers of the oropharynx. We’ve learned over the past decade that in the United States and Western Europe, continued on page 72

The ASCO Post | MARCH 10, 2015

PAGE 72

Announcements

American Association for Cancer Research Inducts 2015 Class of Fellows of the AACR Academy

he American Association for Cancer Research (AACR) has announced 11 new fellows of the AACR Academy. The AACR Academy is an entity that recognizes individuals who have made exceptional contributions to cancer research and/or cancer-related biomedical science. Only individuals whose work has had a significant and long-lasting impact on the field are eligible for election as an AACR fellow. “Our 2015 class of fellows includes 11 luminaries in the field of cancer research, in honor of the 11 founders of the AACR in 1907. We are delighted to recognize the incredible scientific accomplishments of these illustrious researchers and celebrate how their dedicated efforts have helped accelerate the pace of progress against many of the hundreds of diseases we collectively call cancer,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. Members of the 2015 class of fellows of the AACR Academy are: • Kenneth C. Anderson, MD, Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute • Carlos L. Arteaga, MD, Director, Center for Cancer Targeted Therapies; Director, Breast Cancer Program; and Associate Director for Clinical Research, Vanderbilt-Ingram Cancer Center • Anton J.M. Berns, PhD, Senior Group Leader, Division of Molecular Genetics, Netherlands Cancer Insti-

tute, and Director, Skoltech Center for Stem Cell Research, Moscow • Bruce A. Chabner, MD, Director of Clinical Research, Massachusetts General Hospital • Ronald A. DePinho, MD, President, The University of Texas MD Anderson Cancer Center • Susan D. Desmond-Hellmann, MD, MPH, Chief Executive Officer, Bill & Melinda Gates Foundation • Robert N. Eisenman, PhD, Member, Division of Basic Sciences, Fred Hutchinson Cancer Research Center • Douglas R. Lowy, MD, Deputy Director, Center for Cancer Research; Chief, Laboratory of Cellular Oncology; and Head, Signaling and Oncogenesis Section, National Cancer Institute • Carol L. Prives, PhD, Da Costa Professor, Columbia University • Steven A. Rosenberg, MD, PhD, Chief of Surgery, National Cancer Institute • Craig B. Thompson, MD, President and Chief Executive Officer, Memorial Sloan Kettering Cancer Center All fellows are nominated and elected through a rigorous peer-review process conducted by existing fellows of the AACR Academy and ratified by the AACR Executive Committee. This process involves an assessment of each candidate on the basis of his or her scientific achievements in cancer research and cancer-related biomedical science. This group of global leaders in cancer research offers invaluable insight into the

Robert I. Haddad, MD

do a better job at making primary care doctors and parents aware of the importance of having young people vaccinated against the HPV virus. Also, because we know that HPV-positive patients have successful outcomes, it provides clinicians a better chance at using less-intensive treatments, which make for better quality-of-life outcomes. There are many studies looking at this HPV phenomenon—for instance, the Eastern Cooperative Oncology Group (ECOG) just published its initial observations that showed it could be possible to significantly de-intensify therapy in patients with HPV-positive head and neck cancer. De-intensification of treatment is a

continued from page 71

most cancers in this site are linked to the HPV-16 virus, which is a sexually transmitted virus. There are, of course, other modes of transmission of HPV. The vaccines against HPV we currently have were initially designed for young girls only, but recently, the indications have expanded to boys and girls prior to becoming sexually active. The optimal age for vaccination is between 11 and 13 years. But you have until age 26 in general to vaccinate people. Despite the ability of the HPV vaccine to prevent cervical cancers, the vaccination rate in the United States is dismally low—about 30%. We need to

Kenneth C. Anderson, MD

Carlos L. Arteaga, MD

Anton J.M. Berns, PhD

Bruce A. Chabner, MD

Ronald A. DePinho, MD

Susan D. DesmondHellmann, MD, MPH

Robert N. Eisenman, PhD

Douglas R. Lowy, MD

Carol L. Prives, PhD

Steven A. Rosenberg, MD, PhD

Craig B. Thompson, MD

future of cancer research and patient care and works with the AACR in its mission to prevent and cure all cancers. The AACR will formally induct its 2015 class of elected fellows of the AACR Academy at the AACR Annual Meeting 2015, to be held April 18–22 in Philadelphia. n

major issue in the head and neck cancer community. By the same token, we are also wrestling with whether we should intensify treatment for patients who are HPV-negative, since we know that these patients do not have such a robust prognosis.

Current Research What current research activities are you involved in? The majority of my time is spent on clinical and translational research, phase II and III trials. A current area of interest with my group has been the study of HPV-related oropharynx cancer. We have exciting initiatives looking at HPV vaccines—not in the preven-

tive setting but as therapies. We are also very active in immunotherapy in head and neck cancer, especially with the promise of anti–PD-1 [programmed cell death protein 1] and anti–PD-L1 [PD-1 ligand] agents. Historically, I think head and neck cancer has suffered from a lack of novel approaches, such as the ones I just mentioned. We’re also very optimistic going forward that we will be able to better define and understand the genomics of the disease, which will help us tailor drugs for specific genetic alterations. This will allow head and neck cancer to step into the future of precision medicine. n Disclosure: Dr. Haddad reported no potential conflicts of interest.

ASCOPost.com | MARCH 10, 2015

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Announcements

MD Anderson Names Patrick Hwu, MD, Head of Cancer Medicine

atrick Hwu, MD, Chair of Melanoma Medical Oncology and Sarcoma Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, has been named Division Head of Cancer Medicine. He will take over from Richard

AAHPM Unveils List of Inspiring Hospice and Palliative Medicine Leaders Under 40

he American Academy of Hospice and Palliative Medicine (AAHPM) has released a list of Inspiring Leaders Under 40 in the field. Eligible candidates were evaluated on involvement in AAHPM, educating others about hospice and palliative medicine, participation in charitable work, mentoring of students or residents, and any special circumstances or professional accomplishments that set them apart. Some young oncologists included on the list are: • Justin Baker, MD, FAAHPM, St Jude Children’s Research Hospital • Kimberly Curseen, MD, Winship Cancer Institute • Esme Finlay, MD, Lovelace Medical Center and University Hospital continued on page 74

Champlin, MD, who has been acting Division Head on an ad interim basis. Dr. Champlin will continue to serve as Chair of Stem Cell Transplantation and Cellular Therapy. “Dr. Hwu is an internationally respected physician-scientist who has

25 years of experience in the fields of tumor immunology, targeted therapies, and translational studies,” said Ethan Dmitrovsky, MD, Provost and Executive Vice President. “He’s a seasoned leader, having success-

NOW APPROVED

TO IMPROVE PROGRESSION-FREE SURVIVAL IN GASTROINTESTINAL

AND PANCREATIC

NETs

Kimberly Curseen, MD

INDICATION Somatuline® Depot (lanreotide) Injection 120 mg is indicated for the treatment of adult patients with unresectable, well- or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival.

Warnings and Precautions: Somatuline may reduce gallbladder motility and lead to gallstone formation. Periodic monitoring may be needed. Patients may experience hypoglycemia or hyperglycemia. Glucose level monitoring is recommended and antidiabetic treatment adjusted accordingly. Somatuline may decrease heart rate. In patients treated for GEP-NETs, the incidence of heart rate <60 bpm was 23% with Somatuline vs 16% with placebo. Incidence of heart rate <50 bpm or bradycardia was 1% in each group.

Somatuline may decrease bioavailability of cyclosporine. Cyclosporine dose may need to be adjusted. Adverse Reactions: In the GEP-NET pivotal trial, the most common adverse reactions (incidence >10% and more common than placebo) in patients treated with Somatuline Depot vs placebo were abdominal pain (34% vs 24%), 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%). You may report suspected adverse reactions to FDA at 1-800-FDA-1088 or to Ipsen Biopharmaceuticals, Inc. at 1-888-980-2889.

Please see Brief Summary of full Prescribing Information on the following page. Esme Finlay, MD

*NETs =NEUROENDOCRINE TUMORS.

IMPORTANT SAFETY INFORMATION Contraindications: Somatuline is contraindicated in patients with hypersensitivity to lanreotide. Justin Baker, MD, FAAHPM

continued on page 74

Patrick Hwu, MD

To learn more, visit SomatulineDepot.com

The ASCO Post | MARCH 10, 2015

PAGE 74

Announcements Patrick Hwu, MD continued from page 73

fully chaired two departments and served as codirector of MD Anderson’s Center for Cancer Immunology Research and its immunotherapy platform. He has also held endowed positions, including the Sheikh Mohamed Bin Zayed Al Nahyan DistinSOMATULINE DEPOT® (lanreotide) Injection Brief Summary of Prescribing Information 1 INDICATION SOMATULINE DEPOT Injection 120 mg is indicated for the treatment of patients with unresectable, wellor moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. 4 CONTRAINDICATIONS SOMATULINE DEPOT is contraindicated in patients with history of a hypersensitivity to lanreotide. Allergic reactions (including angioedema and anaphylaxis) have been reported following administration of lanreotide. 5 WARNINGS AND PRECAUTIONS 5.1 Cholelithiasis and Gallbladder Sludge Lanreotide may reduce gallbladder motility and lead to gallstone formation; therefore, patients may need to be monitored periodically [see Adverse Reactions (6.1)]. 5.2 Hyperglycemia and Hypoglycemia Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Hence, patients treated with SOMATULINE DEPOT may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly [see Adverse Reactions (6.1)]. 5.3 Thyroid Function Abnormalities Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare (<1%). Thyroid function tests are recommended where clinically indicated. 5.4 Cardiovascular Abnormalities In patients without underlying cardiac disease, SOMATULINE DEPOT may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to SOMATULINE DEPOT treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with SOMATULINE DEPOT in patients with bradycardia. In patients with baseline heart rates of ≥ 60 beats per minute (bpm) treated with SOMATULINE DEPOT in the GEP-NETs clinical trial, the incidence of heart rate < 60 bpm was 23% as compared to 16 % of placebo-treated patients; 12% of patients had documented heart rates < 60 bpm on more than one visit. The incidence of documented episodes of heart rate < 50 bpm as well as the incidence of bradycardia reported as an adverse event was 1% in each treatment group. Initiate appropriate medical management in patients who develop symptomatic bradycardia. 5.5 Drug Interactions The pharmacological gastrointestinal effects of SOMATULINE DEPOT may reduce the intestinal absorption of concomitant drugs. Lanreotide may decrease the relative bioavailability of cyclosporine. Concomitant-administration of SOMATULINE DEPOT and cyclosporine may necessitate the adjustment of cyclosporine dose to maintain therapeutic levels [see Drug Interactions (7.2)]. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience The safety of SOMATULINE DEPOT 120mg for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) was evaluated in Study 3, a double-blind, placebo-controlled trial. Patients in Study 3 were randomized to receive SOMATULINE DEPOT (N=101) or placebo (N=103) administered by deep subcutaneous injection once every 4 weeks. Patients treated with SOMATULINE DEPOT had a median age of 64 years (range 30-83 years), 53% were men and 96% were Caucasian. Eighty-one percent of patients (83/101) in the SOMATULINE DEPOT arm and eighty-two percent of patients (82/103) in the placebo arm did not have disease progression within 6 months of enrollment

guished University Chair in Cancer Research. We’re delighted that he will be leading this vital division and are thankful for Dr. Champlin’s skillful leadership.” Dr. Hwu earned his medical degree from the Medical College of Pennsylvania in Philadelphia and served as a House Officer in Interand had not received prior therapy for GEP-NETs. The rates of discontinuation due to treatment-emergent adverse reactions were 5% (5/101 patients) in the SOMATULINE DEPOT arm and 3% (3/103 patients) in the placebo arm. Table 1: Adverse Reactions Occurring in >5% in SOMATULINE DEPOT-Treated Patients and Occurring More Commonly Than Placebo-Treated Patients (>5% higher incidence) in the GEP-NETs Clinical Trial

Adverse Reaction

SOMATULINE DEPOT 120 mg (N=101) Any Severe† (%) (%)

Placebo (N=103) Any Severe† (%) (%)

Any Adverse 88 26 90 31 Reactions Abdominal 34* 6* 24* 4 pain1 Musculoskeletal 19* 2* 13 2 pain2 Vomiting 19* 2* 9* 2* Headache 16 0 11 1 Injection site 15 0 7 0 reaction3 Hyperglycemia4 14* 0 5 0 Hypertension5 14* 1* 5 0 Cholelithiasis 14* 1* 7 0 Dizziness 9 0 2* 0 Depression6 7 0 1 0 Dyspnea 6 0 1 0 1 Includes preferred terms of abdominal pain, abdominal pain upper/lower, abdominal discomfort 2 Includes preferred terms of myalgia, musculoskeletal discomfort, musculoskeletal pain, back pain 3 Includes preferred terms of infusion site extravasation, injection site discomfort, injection site granuloma, injections site hematoma, injection site hemorrhage, injection site induration, injection site mass, injections site nodule, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling. 4 Includes preferred terms of diabetes mellitus, glucose tolerance impaired, hyperglycemia, type 2 diabetes mellitus 5 Includes preferred terms of hypertension, hypertensive crisis 6 Includes preferred terms of depression, depressed mood * Includes one or more serious adverse events (SAEs) defined as any event that results in death, is life threatening, results in hospitalization or prolongation of hospitalization, results in persistent or significant disability, results in congenital anomaly/birth defect, or may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed. † Defined as hazardous to well-being, significant impairment of function or incapacitation 7 DRUG INTERACTIONS 7.1 Insulin and Oral Hypoglycemic Drugs Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when lanreotide treatment is initiated or when the dose is altered, and antidiabetic treatment should be adjusted accordingly. 7.2 Cyclosporine Concomitant administration of cyclosporine with lanreotide may decrease the relative bioavailability of cyclosporine and, therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic levels. 7.3 Other Concomitant Drug Therapy The pharmacological gastrointestinal effects of SOMATULINE DEPOT may reduce the intestinal

nal Medicine at The Johns Hopkins Hospital. He completed a fellowship in oncology at the National Cancer Institute, where he continued to work for 10 years as a principal investigator leading tumor immunology studies. He joined MD Anderson in 2003 as the first Chair of Melanoma Medical Oncology. n absorption of concomitant drugs. Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the availability of bromocriptine. Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dose adjustments of concomitant medication may be necessary. Vitamin K absorption was not affected when concomitantly administered with lanreotide. 7.4 Drug Metabolism Interactions The limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution. Drugs metabolized by the liver may be metabolized more slowly during lanreotide treatment and dose reductions of the concomitantly administered medications should be considered. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Lanreotide has been shown to have an embryocidal effect in rats and rabbits. There are no adequate and well-controlled studies in pregnant women. SOMATULINE DEPOT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies in pregnant rats given 30 mg/kg by subcutaneous injection every 2 weeks (five times the human dose, based on body surface area comparisons) resulted in decreased embryo/fetal survival. Studies in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day (two times the human therapeutic exposures at the maximum recommended dose of 120 mg, based on comparisons of relative body surface area) shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities. 8.3 Nursing Mothers It is not known whether lanreotide is excreted in human milk. Many drugs are excreted in human milk. As a result of serious adverse reactions from SOMATULINE DEPOT in animals and, potentially, in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, after taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use The GEP-NETs clinical trial did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from 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. No dose adjustment required. 8.6 Renal Impairment No effect was observed in total clearance of lanreotide in patients with mild to moderate renal impairment receiving SOMATULINE DEPOT 120 mg. Patients with severe renal impairment were not studied. 8.7 Hepatic Impairment SOMATULINE DEPOT has not been studied in patients with hepatic impairment. Manufactured by: Ipsen Pharma Biotech; Signes, France. Distributed by: Ipsen Biopharmaceuticals, Inc. Basking Ridge, NJ 07920 ©2014 Ipsen Biopharmaceuticals, Inc

RX ONLY NET00107

AAHPM Leaders Under 40 continued from page 73

• Arif Kamal, MD, Duke University Medical Center • Thomas LeBlanc, MD, MA, Duke University Medical Center • Kathleen Neuendorf, MD, FAAHPM, Cleveland Clinic • Eric Roeland, MD, FAAHPM, UC San Diego Health System • Cardinale Smith, MD, MSCR, Mount Sinai Hospital, New York The full list can be viewed here: h t t p : / / w w w. a a h p m . o r g / a p p s / blog/?p=2555. n

Arif Kamal, MD

Thomas LeBlanc, MD, MA

Kathleen Neuendorf, MD, FAAHPM

Eric Roeland, MD, FAAHPM

Cardinale Smith, MD, MSCR

ASCOPost.com | MARCH 10, 2015

PAGE 75

Expert’s Corner Hematology

The Current State of Hematologic Malignancies A Conversation With Carl Freter, MD, PhD By Ronald Piana at San Diego, with my sights set on becoming a molecular biologist.

A Host of Mentors

Carl Freter, MD, PhD

ue in part to the refinement of bone marrow transplantation and its many innovations, some leukemias that once were death sentences now have cure rates of up to 90%. As research in transplantation and other promising areas accelerates, we are on the verge of breaking new clinical boundaries in blood cancers. To shed light on the current state of hematologic malignancies, The ASCO Post recently spoke with Carl E. Freter, MD, PhD, Director of the Division of Hematology and Oncology for Saint Louis University School of Medicine (SLU) and the Center for Blood and Marrow Outpatient Transplant at SLU.

From Music to Molecular Biology Tell the readers a bit about your background before joining SLU. I wasn’t one of these people who dreamed of a career in medicine from an early age. I was a serious musician, eventually becoming a classically trained flutist. I left college and was teaching music and playing in the San Diego Symphony. When I tried out for my first serious position at the Los Angeles Philharmonic, I thought I was a shoe in, but I wasn’t even close. After that reality check, I was largely directionless for a while until my parents insisted that I finish college. I took some requisite science courses and a lab course in animal physiology, which I found very interesting. The professor asked me to work in his own lab; I accepted and worked with him over the summer. We published some papers together, and I became interested in pursuing molecular biology, which in the early 1970s was an emerging field. I finished college, having changed my degree from music and romance languages to cell biology, and went to graduate school at the University of California

What reshaped your career path into becoming a physician? That decision was also a journey. I had an opportunity to work in a lab program at Washington University. After speaking with the head of the lab, I was introduced to the famous biochemist Louis Glaser, who was also the Director of the MD/ PhD program. He invited me into his program, which offered a fabulous scholarship, but I turned him down because it required that I attend medical school, and I had no desire to become a doctor. When I told my parents, my father said to call Dr. Glaser immediately and accept the offer. I did, and as I completed my MD and PhD, I discovered I really loved medicine and was also committed

timately building a community cancer center in Yakima, Washington. After about 6 years, I got homesick for being in an academic setting and was recruited by Mike Perry to the University of Missouri, where I was Director of the Hematology Division for another 6 years. After that, I was eventually led to my position here at SLU.

An Assortment of Duties Please describe your current work at the Center for Blood and Marrow Outpatient Transplant? I am Director of the Hematology Division at the Center, including bone and marrow transplant, and Director of the Cancer Center. I essentially do the three legs of the academic mission: care for patients in the clinic, both with hematologic malignancies and breast cancer; teach fellows and residents; and

Our advancing technology and electronic learning systems will exponentially evolve, giving us tools we can only dream of. But I’m a bit old-fashioned and a huge believer in the personal touch of oncology, creating a bond between physician and patient. —Carl E. Freter, MD, PhD

to doing laboratory work. I did my internship and residency at Stanford University, where I developed my interest in hematologic malignancies and became enchanted by the idea that you could use biochemistry to treat a widely metastatic disease like Hodgkin lymphoma. One of my mentors at Stanford was former ASCO President Dr. Saul Rosenberg, who said that a fellowship at the National Cancer Institute would broaden my horizons. So I applied and was accepted to the National Cancer Institute, where I had the incredible fortune to work with notables such as Vincent DeVita, Dan Longo, Bob Young, and Marc Lippman, to name a few. I was specializing solely in blood cancers, but then Marc Lippman’s mentorship influenced my decision to do breast cancer research as well. I left the National Cancer Institute with Dr. Lippman and others to rebuild Georgetown University’s cancer program, which eventually received its National Cancer Institute designation as a comprehensive cancer center. And then I actually went into private practice, ul-

perform clinical research as head of our clinical trials program. Then there are the administrative duties, which can be quite challenging, but I took some courses at Harvard, which have helped me in such a way that I now actually enjoy the administrative challenges. I also have my own laboratory, which is focused on a novel approach to identifying new anticancer drugs by making alterations in lipid metabolism in cancer cells, altering the lipid composition of cell membranes to which cancer cells are particularly sensitive. This approach limits cancer cell growth, kills cancer cells, and also acts to reverse chemotherapy drug resistance.

Newer Therapies Currently, few therapeutic strategies exist for patients with hematologic malignancies who relapse after allogeneic hematopoietic stem cell transplant. Are we making progress in this tough clinical scenario? Yes we are. There are some newer developing therapies coming down the pike that will be helpful to these patients who are now in an unfavorable relapse position. They include immune thera-

pies that specifically target relapsed, resistant cells, like CAR (chimeric antigen receptor) cells, for instance. Patients with acute myeloid leukemia and high-grade lymphomas are in populations that will increasingly likely benefit from being on immunotherapy clinical trials. In fact, for my patients in whom another bone marrow transplant might not be advised, I steer them to clinical trials that are looking at novel immune and monoclonal antibody therapies.

From Dismal to Hopeful Please share a perspective of where we were and where we are today in the treatment of hematologic malignancies. At the beginning of my career, we had a few standard chemotherapy regimens using drugs that were very toxic and relatively ineffective, except for bright spots such as Hodgkin and nonHodgkin lymphomas and sometimes adult acute leukemias. However, over the past few decades, the dismal outlook has changed to one of more hope, in which we have actually transformed many of these once deadly cancers into curable diseases, such as acute promyelocytic leukemia. Also, the array of effective therapies we have today for chronic lymphocytic leukemia is stunning, whereas in my early years, we only had one drug, chlorambucil (Leukeran), for chronic lymphocytic leukemia. The current overall picture is robust and positive. We’re in a renascence in which large clinical trials have looked at specific patient populations and have developed effective therapies for them. Moreover, we’ve seen an extraordinary process of patient population subdivision, primarily on a genetic basis, which shares properties that show us how sensitive they will be to certain chemotherapies.

Genetics With a Personal Touch Building on our growing knowledge of genetics, what’s the next step? Big data collection and having everybody’s genome sequenced. It will be a new paradigm for the future, the promise of truly individualized medicine. To do that, however, we’ll need to find better ways to analyze these massive data sets and apply them in a way that’s reproducible for clinicians and their patients. The sequencing of the human genome was one of the most important scientific endeavors of this century. It has opened continued on page 76

The ASCO Post | MARCH 10, 2015

PAGE 76

FDA Update

FDA Approves Panobinostat Combination for the Treatment of Multiple Myeloma

he U.S. Food and Drug Administration (FDA) has approved panobinostat (Farydak) in combination with bortezomib (Velcade) and dexamethasone for the treatment of patients with multiple myeloma. Panobinostat is the first histone deacetylase (HDAC) inhibitor approved to treat multiple myeloma. It is intended for patients who have received at least two prior standard therapies, including bortezomib and an immunomodulatory agent. “[Panobinostat] has a new mechanism of action that distinguishes it from prior drugs approved to treat multiple myeloma, making it a potentially attrac-

tive candidate agent for the treatment of multiple myeloma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “[Panobinostat’s] approval is particularly important because

it has been shown to slow the progression of multiple myeloma.” In November 2014, the FDA’s Oncologic Drugs Advisory Committee advised the agency that, based on the data reviewed, the drug’s benefits did not outweigh its risks for patients with relapsed multiple myeloma. After the meeting, Novartis Pharmaceuticals submitted additional information supporting panobinostat’s use for a different indication: patients with multiple myeloma who have received at least two prior standard therapies, including bortezomib and an immunomodulatory agent.

Clinical Trial Data The safety and efficacy of panobinostat in combination with bortezomib and dexamethasone were demonstrated in 193 clinical trial participants with multiple myeloma who received at least two prior treatments that included bortezomib and an immunomodulatory agent. Participants were randomly assigned to receive a combination of panobinostat, bortezomib, and dexamethasone or bortezomib and dexamethasone alone.

Study results showed participants receiving the panobinostat combination had a median progression-free survival of about 10.6 months, compared to 5.8 months in participants treated with bortezomib and dexamethasone alone. Additionally, 59% of panobinostat-treated participants saw their cancer shrink or disappear after treatment vs 41% in those receiving bortezomib and dexamethasone.

Side Effects Panobinostat carries a Boxed Warning alerting patients and health-care professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias, and electrocardiographic changes have occurred in patients receiving panobinostat. Because of these risks, the new drug is being approved with a Risk Evaluation and Mitigation Strategy (REMS) consisting of a communication plan to inform health-care professionals of these risks and how to minimize them. The most common side effects of panobinostat were diarrhea, tiredness,

nausea, swelling in the arms or legs, decreased appetite, fever, vomiting, and weakness. The most common laboratory abnormalities were hypophosphatemia, hypokalemia, hyponatremia, increased creatinine, thrombocytopenia, leukopenia, and anemia. Healthcare professionals should also inform patients of the risk of bleeding in the gastrointestinal tract and the lungs and hepatotoxicity. The FDA previously granted panobinostat Priority Review and Orphan Product designation. This approval was taken 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. An improvement in survival or disease-related symptoms has not yet been established for panobinostat. The company is now required to conduct confirmatory trials to verify and describe the clinical benefit of panobinostat. n

FDA Approves Lenalidomide in Combination With Dexamethasone for Newly Diagnosed Multiple Myeloma

he U.S. Food and Drug Administration (FDA) has expanded the existing indication for lenalidomide (Revlimid) in combination with dexamethasone to include patients newly diagnosed with multiple myeloma. Lenalidomide plus dexamethasone was previously approved in June 2006 for use in multiple myeloma patients who have received at least one prior therapy. “The approval of [lenalidomide] as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease,” said Kenneth Anderson, MD, Director, Jerome Lipper Multiple Myeloma Center, Dana-Farber/Brigham and Women’s Cancer Center. “We now have clinical evidence demonstrating

Carl Freter, MD, PhD continued from page 75

many doors previously locked shut, and, among other things, the knowledge it has given us will ultimately make the way we currently do clinical trials obsolete. It’s really a big deal.

Adverse Events

The approval was based on safety and efficacy results from phase III studies, including the FIRST trial, which evaluated continuous lenalidomide in combination with dexamethasone until disease progression vs melphalan, prednisone, and thalidomide (Thalomid) for 18 months as the primary analysis, and a fixed duration of 18 cycles of continuous lenalidomide plus dexamethasone as a secondary analysis, in 1,623 newly diagnosed patients who were not candidates for stem cell transplant. The

primary endpoint of this randomized, open-label, three-arm trial was median progression-free survival. Progression-free survival was significantly longer for patients receiving continuous lenalidomide plus dexamethasone (25.5 months) than for those treated with melphalan, prednisone, and thalidomide (21.2 months; hazard ratio [HR] = 0.72, P = .0001). Median overall survival in the two groups was 58.9 months and 48.5 months, respectively (HR = 0.75, 95% confidence interval = 0.62–0.90) based on a March 3, 2014, interim overall survival analysis. Patients in the lenalidomide-plus-dexamethasone arm had a 25% reduction in the risk of death compared with patients who received melphalan, prednisone, and thalidomide.

Are there any downsides in this new eve of genomic knowledge and rapidly deployed information? Our advancing technology and electronic learning systems will exponentially evolve, giving us tools we can only dream of. But I’m a bit old-

fashioned and a huge believer in the personal touch of oncology, creating a bond between physician and patient. I like to look past the marvelous technology and engage the patient as one person to another, taking notice of all the complex issues that go along with a

diagnosis of cancer. That is the fundamental work of a doctor, and it’s very important that we never lose sight of that. But the future of oncology has never been more promising. n

that starting and keeping newly diagnosed multiple myeloma patients on [lenalidomide] significantly improves progression-free survival.”

Phase III Study Results

Safety results showed that adverse reactions reported in ≥ 20% of patients included diarrhea, anemia, neutropenia, fatigue, back pain, insomnia, asthenia, rash, decreased appetite, cough, pyrexia, muscle spasms, and abdominal pain. The most frequently reported grade 3 or 4 events in the lenalidomide-plus-dexamethasone arm included neutropenia (27.8%), anemia (18.2%), pneumonia (11.3%), thrombocytopenia (8.3%), asthenia (7.7%), fatigue (7.3%), rash (7.3%), back pain (7%), hypokalemia (6.6%), cataract (5.8%), dyspnea (5.6%), deepvein thrombosis (5.6%), and hyper glycemia (5.3%). n

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

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ASCOPost.com | MARCH 10, 2015

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Palliative Care in Oncology Improving the Quality of Palliative Care in Oncology A Conversation With Arif Kamal, MD, FACP By Jo Cavallo

Arif Kamal, MD, FACP

wo years ago, ASCO collaborated with the American Academy of Hospice and Palliative Medicine to develop the Virtual Learning Collaborative, a virtual quality improvement program intended to address the complex care needs of patients with advanced cancer and the care quality for all patients with malignancies. The project is modeled after the Quality Improvement Collaborative model developed by the Institute for Healthcare Improvement (IHI). The program includes a series of structured meetings for particiapnts, including small work groups dedicated to particular aspects of palliative care. The website enables communication with others involved in the pilot and hosts a resource library with information about palliative care best practices, and tools to support implementation of quality improvement science. Pratice teams from 26 medical oncology practices across the country were invited to pilot test the system. The teams were charged of designing, executing, and evaluating a quality improvement project to optimize one aspect of palliative care for patients with malignancies at their organization. Each practice was able to select the area of palliative care that needs the most attention as defined by local stakeholders. For example, teams have selected projects to address standardizing practices for advance care planning, symptom assessment, and improving referral to palliative care. At the end of the pilot testing period in June 2015, participants will complete evaluation activities, including interviews for a selected subset of participants. Throughout the project, teams were encouraged to submit data to ASCO’s Quality Oncology Practice Initiative (QOPI). (For more information on ASCO’s

Virtual Learning Collaborative, go to www.asco.org/vlc.) Arif Kamal, MD, FACP, Assistant Professor of Medicine in the Division of Medical Oncology at Duke University Medical Center and Director of Quality and Outcomes for the Duke Cancer Institute, is a co-investigator on the Virtual Learning Collaborative, as well as a member of ASCO’s Quality of Care Committee and ASCO’s Supportive Care Guidelines Advisory Group. In addition to his work on the Virtual Learning Collaborative, Dr. Kamal is also investigating the rise in burnout among palliative care physicians, a problem that is projected to lead to a loss of over 50% of palliative care clinicians over the next decade, according to the results of a survey1 of 1,241 clinicians conducted by Dr. Kamal and his colleagues. The study found that physician burnout in palliative care is higher—over 62%— than the burnout rate reported in medical oncology—45%. Burnout is most prevalent among younger physicians, those

is now that this imperative is in place, every oncology group across the country is struggling with how to implement high-quality palliative care into its routine oncology care. The onus for developing the Virtual Learning Collaborative was to identify the needs of oncology practices across the country who want to improve their palliative care delivery and to help them understand the components of highquality palliative care delivery from the perspective of palliative care experts across the country while simultaneously facilitating their knowledge in quality improvement methodology and implementation. The Virtual Learning Collaborative creates a cooperative environment in which physicians can learn from each other, share their challenges, and find solutions. In our pilot program in 25 community oncology practices nationwide, our main objective is to provide oncologists with the resources, mentoring, and access to national experts in palliative medicine so they can implement

High burnout among physicians is not a new story. The new story is that if we do not reverse this trend, we will not be able to deliver high-quality palliative care because clinicians are walking away from the discipline. —Arif Kamal, MD, FACP

working more than 50 hours per week, and those with fewer colleagues within their practice. The ASCO Post talked with Dr. Kamal about the implementation of the Virtual Learning Collaborative pilot program and the growing problem of burnout among palliative care physicians and interventions to help prevent it.

Creating a Cooperative Environment Why did ASCO and the American Academy of Hospice and Palliative Medicine decide to develop the Virtual Learning Collaborative? The routine integration of palliative care into usual oncology care is an imperative that has been growing over time and was an effort largely led by ASCO. Palliative medicine has now transitioned from providing supplementary “nice to have” care to “must-have” care for patients. And the challenge with that

a quality-improvement program in their practices. To foster collaboration, participants are organized into small working groups of three teams led by a facilitator who supports shared learning among the teams. Ultimately, what we are trying to do is make sure that ASCO has a portfolio of quality improvement infrastructure in place that addresses the needs and preferences of all oncology practices. We are in the process of updating the program and analyzing the results from our feasibility study. We will then use the data to evaluate the impact on palliative care performance measures and determine how to further refine this model to support quality improvement in palliative care and make a decision about launching the program in more oncology practices.

High Burnout Rate Please talk about your survey of hos-

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.

pice and palliative care clinicians and your findings about their burnout rate. Why did you decide to do the survey? The impetus for this study was an ongoing debate many of us in palliative medicine were having about whether the burnout rate is higher or lower among palliative care physicians than it is among our nonpalliative care colleagues. Data show that about 45% of all physicians in the country report high levels of burnout, but studies investigating burnout did not specifically look at palliative medicine physicians. We thought because palliative care physicians have a professional focus on self-care and quality of life, our burnout prevalence would be less than it is in other medical professions. However, we also knew that palliative care physicians have issues around isolation. Even though palliative care is practiced in two-thirds of all hospitals around the country, most palliative care teams are no bigger than one or two clinicians; this means there isn’t anyone to share the difficulty of talking to another person dying of cancer. There are not many avenues to debrief emotionally, and it can be mentally exhausting. Also, often as palliative care physicians, we do not leave the hospital until after 7:00 PM because we have to meet with patients or family members who work full-time and can’t come in at 5:00 PM; so we get home late and then have to do it again the next day, which can be continued on page 84

The ASCO Post | MARCH 10, 2015

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Palliative Care in Oncology Arif Kamal, MD, FACP continued from page 83

physically exhausting. To determine which area of medicine had the highest burnout rate, my colleagues and I approached the American Academy of Hospice and Palliative Medicine to conduct a survey that served two purposes. One was to understand the predictors of burnout among palliative care physicians; and the second was to understand the demographics of palliative care physicians, such as their age, and how much and where they work. In the survey, we asked about their work/life balance, burnout and career satisfaction, and how long they plan on remaining in the field. We were also interested in learning which characteristics of clinicians

and their work can be changed and which ones cannot. What we found is that 62% of all physicians reported high burnout. Younger age, working in smaller organizations, having fewer colleagues near by, as well as working longer hours and on weekends were all predictors of physician burnout. How will the high rates of burnout among palliative care physicians affect patient care? High burnout among physicians is not a new story. The new story is that if we do not reverse this trend of high burnout, we will not be able to deliver responsive, high-quality palliative care because clinicians are walking away from the discipline. In our survey, 25% of palliative

care physicians said they would leave the field in 5 years, and 50% said they would leave the field in 10 years.

Efforts to Reduce Burnout Are there steps being taken to mitigate the issues causing burnout among palliative care physicians? There are proposals being written into grants to develop interventions to prevent burnout in palliative care physicians. There are also practices already in place to reduce burnout that other disciplines are using, such as mindfulness meditation, but it is unclear whether they will be effective in offsetting burnout in palliative medicine physicians, because a one-sizefits-all approach might not work. Here at Duke University Medical Center, faculty are invited to a closed-

door session each quarter to openly share the issues they face taking care of patients and the emotional reactions, which has been helpful. Other cancer centers have similar in-house programs as well. What is also helpful is just recognizing that what we do is difficult and that it is hard to separate our own experiences and emotions from the routine delivery of care. n

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

Reference 1. Kamal A, Bull J, Wolf S, et al: Prevalence and predictors of burnout among specialty palliative care clinicians in the United States: Results of a national survey. 2014 Palliative Care in Oncology Symposium. Abstract 87. Presented October 25, 2014.

Announcements

Kay Research and Care Center Opens at St. Jude Children’s Research Hospital

t. Jude Children’s Research Hospital in Memphis has officially opened the Kay Research and Care Center. The new $198 million center houses the Eric Trump Foundation Surgery and ICU Center, and the Marlo Thomas Center for Global Education and Collaboration. The St. Jude Red Frog Events Proton Therapy Center, also within the Center, will open this fall. “This is a momentous occasion for St. Jude Children’s Research Hospital, as we open the new Kay Research and Care Center and celebrate the integration of treatment, research, technology, collaboration, and education on the St. Jude campus,” said Richard Shadyac, Jr, President and CEO of ALSAC/St. Jude Children’s Research Hospital. (ALSAC refers to the American Lebanese Syrian

Associated Charities, the fund-raising arm of St. Jude Children’s Research Hospital in Memphis, Tennessee.) The center is named for Kay Jewelers, a longtime supporter of St. Jude, which recently made a commitment to raise $50 million over 10 years in support of the hospital’s lifesaving work. Kay Jewelers has supported St. Jude since 1999, raising more than $40 million to support the children and families of St. Jude. “Our partnership with St. Jude is a source of great pride, and we are honored to support this incredible institution with the amazing work it does,” said Ed Hrabak, Kay Jewelers President. The building’s state-of-the-art Eric Trump Foundation Surgery and ICU Center was made possible by a gener-

Fig. 1: Officials from ALSAC and St. Jude join supporters in celebration of the opening of the Kay Research and Care Center. From left, the group includes Terry Burman of the St. Jude Board, Ryan Kunkel of Red Frog Events, U.S. Congressman Steve Cohen, St. Jude President and CEO James Downing, MD, Tryna Kochanek of Kay Jewelers, Rich Unes of the St. Jude Board, David Bouffard of Kay Jewelers, Eric and Lara Trump of The Eric Trump Foundation and Richard Shadyac, President and CEO of ALSAC/St. Jude.

The Kay Research and Care Center… will be integral to our future as a global innovator in the fight against childhood cancer and other deadly diseases. —James R. Downing, MD

ous $20 million commitment from The Eric Trump Foundation. The center doubles the hospital’s surgery space, accommodating the latest technologies with the flexibility to adapt to future advances. The operating suites are equipped with recording devices and observation rooms, to help doctors around the world learn from techniques perfected at St. Jude. “I’m immensely proud of our incredible pledge to the children of St. Jude. We look forward to supporting St. Jude for many years to come,” said Eric Trump, Eric Trump Foundation Founder. The Marlo Thomas Center for Global Education and Collaboration occupies the entire main floor of the Kay Research and Care Center. The center is designed to be a hub of learning and discovery, using technology to connect doctors and scientists around the world. An entire floor of the Kay Research and Care Center is devoted to the com-

putational biology department, which will play a key role in the hospital’s research over the coming decades. The growth of the department is crucial for the hospital’s work to analyze the immense amount of data provided by the St. Jude-Washington University Pediatric Cancer Genome Project, as well as other St. Jude research efforts to help unlock the secrets of childhood cancer. The St. Jude Red Frog Events Proton Therapy Center, which was created thanks to a $25 million commitment from Red Frog Events, is the world’s first proton therapy center dedicated solely to the treatment of children. “St. Jude is a remarkable place of discovery and interaction, and a place of compassion and healing,” said James R. Downing, MD, St. Jude President and Chief Executive Officer. “The Kay Research and Care Center captures all of these elements under one roof, and will be integral to our future as a global innovator in the fight against childhood cancer and other deadly diseases.” n

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In the Clinic Breast Cancer

Palbociclib as Initial Endocrine-Based Therapy in Postmenopausal Women With Metastatic Breast 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 February 3, 2015, palbociclib (Ibrance) was granted accelerated approval for use in combination with letrozole in treatment of postmenopausal women with estrogen receptor–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for metastatic disease.1,2 Continued approval for this indication may be contingent upon verification of benefit in a confirmatory trial.

Supporting Trial Approval was based on the finding of prolonged progression-free survival with the addition of palbociclib to letrozole in an open-label phase II trial.2,3 In the trial, 165 patients with no prior systemic treatment for metastatic disease were randomized to receive oral palbociclib 125 mg/d for 21 days followed by 7 days off treatment plus letrozole 2.5 mg/d continuously throughout the 28-day cycle (n = 84) or letrozole alone (n = 81). Overall, 43% of patients had received chemotherapy, 33% had received antihormonal therapy as neoadjuvant or adjuvant treatment, and 49% had no prior systemic neoadjuvant or adjuvant treatment; 98% of patients had metastatic disease, 48% had visceral disease, 75% had bone disease, and 19% had bone-only disease. Median investigator-assessed progression-free survival was 20.2 months (95% confidence interval [CI] = 13.8– 27.5 months) in the palbociclib plus letrozole group vs 10.2 months (95% CI = 5.7–12.6 months) in the letrozole group (hazard ratio [HR] = 0.488, 95% CI = 0.319–0.748). A positive effect of palbociclib-letrozole vs letrozole was supported by a retrospective independent radiographic review (HR = 0.621, 95% CI = 0.378–1.019). Among pa-

OF NOTE Palbociclib carries warnings/precautions for hematologic adverse events, infections, and embryo-fetal toxicity.

tients with measurable disease, investigator-assessed objective response rate was 55.4% vs 39.4%.

How It Works Palbociclib is an inhibitor of cyclindependent kinase (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways that induce cellular proliferation. In studies in vitro, palbociclib reduced cellular proliferation of estrogen receptor–positive breast cancer cell lines by blocking progression from the G1 into the S phase of the cell cycle. Treatment of breast cancer cell lines with the combination of palbociclib and an antiestrogen led to decreased retinoblastoma protein (Rb) phosphorylation, reduced expression and signaling of transcription factor E2F, and increased growth arrest compared with treatment with each drug alone. In patient-derived estrogen

OF NOTE Palbociclib is an inhibitor of cyclindependent kinase (CDK) 4 and 6, which are downstream of signaling pathways that induce cellular proliferation. It reduces cellular proliferation of estrogen receptor–positive breast cancer cell lines by blocking progression from the G1 into the S phase of the cell cycle.

For grade ≥ 3 nonhematologic toxicity, palbociclib should be withheld until recovery to grade 1 (or grade 2 if no safety risk to patient) and restarted at the next lower dose. Concomitant use of strong CYP3A inhibitors (eg, clarithromycin, indinavir, ketoconazole), should be avoided with palbociclib. If one must be used, the palbociclib dose should be reduced

Combination Treatment With Palbociclib for Metastatic Breast Cancer ■■ Palbociclib (Ibrance) was granted accelerated approval for use in combination with letrozole in treatment of postmenopausal women with estrogen receptor–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for metastatic disease. ■■ The recommended dose of palbociclib is 125 mg/d for 21 consecutive days followed by 7 days off treatment in each 28-day cycle in combination with letrozole 2.5 mg/d given continuously.

receptor–positive breast cancer xenograft models, the combination of palbociclib and letrozole increased inhibition of Rb phosphorylation, downstream signaling, and tumor growth vs each drug alone.

How It Is Given The recommended dose of palbociclib is 125 mg/d for 21 consecutive days followed by 7 days off treatment in each 28day cycle in combination with letrozole 2.5 mg/d given continuously. Dose modifications are permitted for management of adverse events, with a first reduction to 100 mg/d and a second to 75 mg/d. For hematologic adverse events, no dose adjustment is necessary for grade 3 events. Repeating complete blood cell count at 1 week can be considered, and the next cycle should be withheld until recovery to grade ≤ 2. For grade 3 neutropenia with fever/infection and for grade 4 events, palbociclib should be withheld until recovery to grade ≤ 2 and restarted at the next lower dose.

to 75 mg/d. If the strong inhibitor is discontinued, the palbociclib dose should be increased to the prior dose after three to five half-lives of the inhibitor. Due to the risk of hematologic toxicity with palbociclib, complete blood cell count should be monitored prior to the start of treatment, at the beginning of each cycle, on day 14 of the first two cycles, and as clinically indicated. Patients should be monitored for infection, with dosing withheld as appropriate.

Safety Profile In the phase II trial, the median duration of treatment was 13.8 months for palbociclib and 7.8 months for letrozole in the letrozole-alone group. The most common nonhematologic adverse events of any grade with palbociclib-letrozole were fatigue (41% vs 23% in the letrozole-alone group), upper respiratory infection (31% vs 18%), stomatitis (25% vs 7%), and nausea (25% vs 13%); the most common grade 3 or 4 event was diarrhea (4% grade

3 vs 0%). Any grade 3 or 4 hematologic adverse event rates in the combination group were 75% and 54% for neutropenia (vs 5% and 1% in the letrozole-alone group), 43% and 19% for leukopenia (vs 3% and 0%), 35% and 6% for anemia (vs 7% and 1%), and 17% and 2% for thrombocytopenia (vs 1% and 0%). The most frequently reported serious adverse events in the palbociclibletrozole group were pulmonary embolism (4%) and diarrhea (2%). Adverse events led to dose reduction in 36% of patients receiving the combination and treatment discontinuation in 8% (neutropenia in 6%, asthenia in 1%, fatigue in 1%) vs 3%. Infection was observed in 55% vs 34% of patients. Febrile neutropenia has been observed in patients in the palbociclib clinical program, but no cases were observed in the current trial. Palbociclib carries warnings/precautions for hematologic adverse events, infections, and embryo-fetal toxicity. n References 1. U.S. Food and Drug Administration: Drug approvals: Palbociclib. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm432886 .htm. Accessed February 19, 2015. 2. Ibrance (palbociclib capsule) prescribing information, Pfizer, Inc, February 2015. Available at http://labeling.pfizer.com/ ShowLabeling.aspx?id=2191. Accessed February 19, 2015. 3. Finn RS, Crown JP, Lang I, et al: The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/ TRIO-18): A randomised phase 2 study. Lancet Oncol 16:25-35, 2015.

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).

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Announcements

International Marketing Expert Claire Huang Appointed to Conquer Cancer Foundation Leadership

he Conquer Cancer Foundation of ASCO has announced the appointment of Claire Huang to its Board of Directors. Ms. Huang, an established leader in the fields of marketing, communications, and brand management, will serve a 3-year term.

sion of consumer product companies, beginning at Procter & Gamble. Ms. Huang holds leadership positions on several national and international boards, including the Board of Directors

of Foster Farms poultry company and the US Leadership Council of Cordaid. She serves on the Advisory Board of the South Bronx Educational Foundation, and founded The Fisherman’s Founda-

tion, a nonprofit organization that helps individuals of modest means become self-sufficient. She received an economics degree from De La Salle University in Manila, Philippines. n

FOR THEIR TREATMENT JOURNEY TO CONTINUE,

Claire Huang

“It is a privilege to welcome Claire Huang to the Conquer Cancer Foundation’s leadership,” said W. Charles Penley, MD, FASCO, Chair of the Foundation’s Board of Directors. “She brings to the board a tremendous amount of business knowledge and experience. Perhaps more importantly, she is passionate, energetic, and shares our vision—a world free from the fear of cancer.” Most recently, Ms. Huang served as the first Chief Marketing Officer for JP Morgan Chase, where she worked with marketing teams across all Chase retail and JP Morgan wholesale business to build brands with a client/customer focus. Her marketing background is extensive, and she has held executivelevel positions at Bank of America Merrill Lynch, Fidelity Investments, and American Express. Earlier in her career, she developed her credentials as a turnaround and growth expert in a succes-

The ASCO Post Wants to Hear From You

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.

Write to The ASCO Post at editor@ASCOPost.com

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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ASCOPost.com | MARCH 10, 2015

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Announcements

Douglas R. Lowy, MD, Receives Harrington Prize for Innovation in Medicine

he second annual Harrington Prize for Innovation in Medicine has been awarded to oncologist/ researcher Douglas R. Lowy, MD, Chief of the Laboratory of Cellular Oncology and Deputy Director of the National Cancer Institute.

The Harrington Prize for Innovation in Medicine, established in 2014 by the Harrington Discovery Institute at University Hospitals in Cleveland and The American Society for Clinical Investigation (ASCI), honors a physician-scientist who has moved science forward with achieve-

ments notable for innovation, creativity, and potential for clinical application.

Research Leading to HPV Vaccine Dr. Lowy is being recognized for his key discoveries that led to development

of the human papillomavirus (HPV) vaccine. The vaccine developed by Dr. Lowy (in collaboration with Merck and GlaxoSmithKline) was approved by the U.S. Food and Drug Administration (FDA) in 2006, and was the first licensed vaccine continued on page 88

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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Important Safety Information (continued)

The ASCO Post | MARCH 10, 2015

PAGE 88

Announcements Douglas R. Lowy, MD continued from page 87

to prevent cancer by guarding against the sexually transmitted infection that causes the disease. It is estimated that the HPV vaccine can afford close to 100% protection, and thus, Dr. Lowy’s research has the potential to prevent virtually all of the many cancers caused by HPV.

Douglas R. Lowy, MD

“I can’t think of anyone more deserving than Dr. Lowy to receive The Harrington Prize for Innovation in Medicine,” said Francis S. Collins, MD, PhD, Director of the National Institutes of Health (NIH). “Through his leadership in the development of the HPV vaccine, he has made profound contributions to the prevention of cer-

vical cancer. He continues to seek ways to reduce the burden of this disease in developing countries.”

Background and Research Dr. Lowy received his MD from New York University School of Medicine. Between 1970 and 1973, he was a research associate in the Laboratory of Viral Dis-

$0CO-PAY CO-PAYPROGRAM PROGRAM $0 ®® • Availableforforeligible eligiblepatients patientsthrough throughREACH REACH anda aselect selectnetwork networkofofSPPs* SPPs* • Available and • Onlypatients patientsnot notcurrently currentlyenrolled enrolledininthe theREACH REACHCo-pay Co-payAssistance AssistanceProgram Programare areeligible eligible • Only –Currentparticipants participantsmay mayenroll enrollupon upontheir theirannual annualrenewal renewaldate date –Current

• ContactREACH REACHatat1-866-639-2827 1-866-639-2827ororvisit visitwww.STIVARGA-US.com/hcp/ www.STIVARGA-US.com/hcp/forformore moreinformation information • Contact *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. Void 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. Void 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% vsvs 7%). The incidence of of Grade 3 HFSR (17% vsvs 0%), Grade 3 rash (6% <1%), serious adverse reactions erythema Grade 3 rash (6% vsvs <1%), serious adverse reactions of of erythema multiforme (0.2% 0%), and Stevens-Johnson syndrome (0.2% multiforme (0.2% vsvs 0%), and Stevens-Johnson syndrome (0.2% 0%) was higher STIVARGA-treated patients. Toxic epidermal vsvs 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.

Hypertension: STIVARGA caused increased incidence Hypertension: STIVARGA caused anan increased incidence of of hypertension (30% with STIVARGA with placebo mCRC). hypertension (30% with STIVARGA vsvs 8%8% with placebo in in mCRC). 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 blood pressure adequately controlled. Monitor blood pressure blood pressure is is adequately controlled. Monitor blood pressure weekly first 6 weeks treatment and then every cycle, weekly forfor thethe first 6 weeks of of treatment and then every cycle, or or more frequently, clinically indicated. Temporarily permanently more frequently, asas clinically indicated. Temporarily or or permanently withhold STIVARGA severe uncontrolled hypertension. withhold STIVARGA forfor severe or or uncontrolled hypertension. 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 vsvs 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 any across allall clinical trials. Perform anan evaluation forfor RPLS in in any 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 USA 100100 Bayer Boulevard, PO PO BoxBox 915,915, Whippany, NJNJ 07981-0915 USA © 2014 Bayer HealthCare Pharmaceuticals Whippany, © 2014 Bayer HealthCare Pharmaceuticals Inc.,Inc., Whippany, NJNJ ® ® ® ® ® ® ® ® , 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

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 can cause fetal harm when Embryo-Fetal Toxicity: STIVARGA can 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 pregnant while taking this drug, patient should apprised pregnant while taking this drug, thethe patient should bebe apprised potential hazard fetus. of of thethe potential hazard to to thethe fetus. Nursing Mothers: Because many drugs excreted human Nursing Mothers: Because many drugs areare excreted in in human milk and because potential serious adverse reactions milk and because of of thethe potential forfor serious adverse reactions nursing infants from STIVARGA, a decision should made in in nursing infants from STIVARGA, a decision should bebe made whether discontinue nursing discontinue drug, taking whether to to discontinue nursing or or discontinue thethe drug, taking into account importance drug mother. into account thethe importance of of thethe drug to to thethe mother. Most Frequently Observed Adverse Drug Reactions Most Frequently Observed Adverse Drug Reactions inin 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 vsvs placebo-treated patients mCRC, respectively, were: asthenia/fatigue (64% patients in in mCRC, respectively, were: asthenia/fatigue (64% vsvs 46%), decreased appetite and food intake (47% 28%), HFSR/ 46%), decreased appetite and food intake (47% vsvs 28%), HFSR/ PPE (45% 7%), diarrhea (43% 17%), mucositis (33% 5%), PPE (45% vsvs 7%), diarrhea (43% vsvs 17%), mucositis (33% vsvs 5%), weight loss (32% 10%), infection (31% 17%), hypertension weight loss (32% vsvs 10%), infection (31% vsvs 17%), hypertension (30% 8%), and dysphonia (30% 6%). (30% vsvs 8%), and dysphonia (30% vsvs 6%). References: 1. STIVARGA Prescribing Information. Whippany, Bayer HealthCare References: 1. STIVARGA Prescribing Information. Whippany, NJ:NJ: Bayer HealthCare Pharmaceuticals 2014. 2. Data Bayer HealthCare Pharmaceuticals Pharmaceuticals Inc;Inc; 2014. 2. Data on on ﬁle,ﬁle, Bayer HealthCare Pharmaceuticals Inc.Inc.

B:1B

T T:15

S S:14

B:16.5” 16.5”

T:15.5” 5.5”

S:14.75” 4.75”

ASCOPost.com | MARCH 10, 2015

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Announcements

eases, National Institute of Allergy and Infectious Diseases, NIH. He trained in internal medicine at Stanford University, dermatology at Yale University, and started his laboratory at the NCI in 1975. In addition to his own research, Dr. Lowy is a leader in promoting public health issues related to HPV-associated diseases, especially cervical cancer in de-

veloping nations. He is an effective advocate for sustainable comprehensive cervical cancer control in the developing world. He is an elected member to the prestigious National Academy of Sciences and is recipient of numerous awards and honors including the National Medal of Technology and Innovation from President Obama in 2014. Dr.

® ® (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 Severeand andsometimes sometimesfatal fatalhepatotoxicity hepatotoxicityhashasbeen beenobserved observedin in • •Severe clinical trials [see Warnings and Precautions (5.1)]. clinical trials [see Warnings and Precautions (5.1)]. Monitor hepatic function prior and during treatment [see Warnings • •Monitor hepatic function prior to to and during treatment [see Warnings and Precautions (5.1)]. and Precautions (5.1)]. Interrupt and then reduce discontinue Stivarga hepatotoxicity • •Interrupt and then reduce or or discontinue Stivarga forfor hepatotoxicity manifestedbybyelevated elevatedliver liverfunction functiontests testsor orhepatocellular hepatocellular asasmanifested necrosis, depending upon severity and persistence [see Dosage and necrosis, depending upon severity and persistence [see Dosage and Administration (2.2)]. Administration (2.2)].

Lowy has or currently serves as a member of many scientific editorial boards, advisory boards, and grant committees. In addition to receiving a $20,000 honorarium, Dr. Lowy will deliver the Harrington Prize Lecture at the 2015 ASCI and Association of American Physicians Joint Meeting on April 24, 2015, and publish a review in the April

issue of Journal of Clinical Investigation. It is estimated that one out of every six cancers worldwide is caused by infection, with HPV leading to more cancers than any other virus. Infection by HPV causes virtually all cervical cancers, the third deadliest cancer in women worldwide, as well as a high percentage of vaginal, oropharyngeal, and other cancers. n

Monitor blood pressure weekly first 6 weeks treatment and then Monitor blood pressure weekly forfor thethe first 6 weeks of of treatment and 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 and Administration (2.2)]. Dosage and Administration (2.2)]. Cardiac Ischemia and Infarction 5.55.5 Cardiac Ischemia and Infarction Stivargaincreased increasedthetheincidence incidenceof ofmyocardial myocardialischemia ischemiaandandinfarction infarctionin in Stivarga 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 further cardiac ischemia. potential benefits outweigh thethe risks of of further cardiac ischemia.

B:11.1875” B:11.1875” T:10.75” T:10.75” S:9.875” S:9.875”

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 5.65.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) ReversiblePosterior PosteriorLeukoencephalopathy LeukoencephalopathySyndrome Syndrome(RPLS), (RPLS),a syndrome a syndrome Reversible subcortical vasogenic edema diagnosed characteristic finding MRI, of of subcortical vasogenic edema diagnosed byby characteristic finding onon MRI, occurredin inoneoneof of1200 1200Stivarga-treated Stivarga-treatedpatients patientsacross acrossall allclinical clinicaltrials. trials. occurred Performananevaluation evaluationforforRPLS RPLSin inanyanypatient patientpresenting presentingwith withseizures, seizures, Perform 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 patients who develop RPLS. Stivarga in in patients who develop RPLS. indicated treatment patients with metastatic colorectal Discontinue Stivargais is 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, anan anti-VEGF therapy, and, if if Gastrointestinal Gastrointestinalperforation perforationor orfistula fistulaoccurred occurredin in0.6% 0.6%of of1200 1200patients patients KRAS wild type, anti-EGFR therapy. KRAS wild type, anan anti-EGFR therapy. treated with Stivarga across clinical trials; this included four fatal events. treated with Stivarga across all all clinical trials; this included four fatal events. Gastrointestinal Stromal Tumors Study 2.1% (4/188) Stivarga-treated patients who were treated during 1.21.2 Gastrointestinal Stromal Tumors In In Study 2, 2, 2.1% (4/188) of of Stivarga-treated patients who were treated during Stivargais isindicated indicatedforforthethetreatment treatmentof ofpatients patientswith withlocally locallyadvanced, advanced, thetheblinded blindedor oropen-label open-labelportion portionof ofthethestudy studydeveloped developedgastrointestinal gastrointestinal Stivarga unresectable metastatic gastrointestinal stromal tumor (GIST) who have fistula fistulaor orperforation; perforation;of ofthese, these,two twocases casesof ofgastrointestinal gastrointestinalperforation perforation unresectable or or metastatic gastrointestinal stromal tumor (GIST) who have 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 0.3% 1200 inhibitors Severe drug induced liver injury with fatal outcome occurred in in 0.3% of of 1200 regorafenib should stopped least 2 weeks prior scheduled surgery. should bebe 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 bebe 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 bebe discontinued in in fatal hepatic failure occurred 1.6% patients regorafenib arm 1, 1, fatal hepatic failure occurred in in 1.6% of of patients in in thethe regorafenib arm andand judgment patients with wound dehiscence. with wound dehiscence. 0.4% patients placebo arm; patients with hepatic failure in in 0.4% of of patients in in thethe placebo arm; all all thethe patients with hepatic failure hadhad patients metastatic disease in the liver. Study fatal hepatic failure occurred in 0.8% 5.95.9 Embryo-Fetal metastatic disease in the liver. In In Study 2, 2, fatal hepatic failure occurred in 0.8% Embryo-Fetal Toxicity Toxicity patients regorafenib arm [see Adverse Reactions (6.1)]. of of patients in in thethe regorafenib arm [see Adverse Reactions (6.1)]. Stivargacancancause causefetal fetalharm harmwhen whenadministered administeredto toa pregnant a pregnantwoman. woman. Stivarga 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 patients experiencing elevated liver function tests drug liver function tests weekly in 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 less than 3 times ULN baseline. until improvement to to less than 3 times thethe ULN or or baseline. drug, patient should apprised potential hazard a fetus [see thisthis drug, thethe patient should bebe apprised of of thethe potential hazard to to a fetus [see Temporarilyhold holdandandthen thenreduce reduceor orpermanently permanentlydiscontinue discontinueStivarga Stivarga Use Use Specific Populations (8.1)]. Temporarily in 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 byby 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 anan 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 4 of 632 (0.6%) Stivarga-treated patients in Studies 1 and 2 and • Cardiac occurred in 4inof 632 (0.6%) of 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 INR levels more frequently patients receiving warfarin • Gastrointestinal hemorrhage. Monitor INR levels more frequently in 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 reactionrates ratesobserved observedin inthetheclinical clinicaltrials trialsof ofa drug a drugcannot cannotbebedirectly directly reaction Dermatological Toxicity 5.35.3 Dermatological Toxicity compared rates clinical trials another drug may reflect to to rates in in thethe 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 rate observed practice. observed in in practice. subcutaneous tissues (72% versus 24% Study 1 and 78% versus 24% rate andand subcutaneous tissues (72% versus 24% in in Study 1 and 78% versus 24% mostfrequently frequentlyobserved observedadverse adversedrug drugreactions reactions(≥20%) (≥20%)in inpatients patients Study including hand-foot skin reaction (HFSR) also known palmar- TheThemost 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 Study 1 and 67% versus 12% Study than placebo- specified), versus 7%7% in in Study 1 and 67% versus 12% in in Study 2),2), than in in thethe 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 The 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 The 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 trial (Study which randomized (2:1), double-blind, placebo-controlled trial (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% 1200 Stivarga-treated patients 500 patients (median age 61 years; 61% men) with previously-treated Toxic epidermal necrolysis occurred in 0.17% of 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. 160 daily first 3 weeks each 4 week treatment cycle and of of 160 mgmg daily forfor thethe first 3 weeks of of each 4 week treatment cycle and WithholdStivarga, Stivarga,reduce reducethethedose, dose,or orpermanently permanentlydiscontinue discontinueStivarga Stivarga 253 Withhold 253 patients (median years; 60% men) received placebo. The median patients (median ageage 6161 years; 60% men) received placebo. The median depending severity persistence dermatologic toxicity [see Dosage duration depending onon thethe severity andand persistence of of dermatologic toxicity [see Dosage duration therapy was (range 0.3, 47.0) weeks patients receiving of of therapy was 7.37.3 (range 0.3, 47.0) weeks forfor patients receiving Administration (2.2)]. Institute supportive measures symptomatic relief. Stivarga. andand Administration (2.2)]. Institute supportive measures forfor symptomatic relief. Stivarga. Due adverse reactions, 61% patients receiving Stivarga Due to to adverse reactions, 61% of of thethe patients receiving Stivarga required a dose interruption and 38% patients had their dose reduced. required a dose interruption and 38% of of thethe patients had their dose reduced. Hypertension 5.45.4 Hypertension Drug-relatedadverse adversereactions reactionsthat thatresulted resultedin intreatment treatmentdiscontinuation discontinuation Stivarga caused increased incidence hypertension (30% versus Stivarga caused anan 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) and rash were who received placebo. Hand-foot skin reaction (HFSR) and rash were Hypertensivecrisis crisisoccurred occurredin in0.25% 0.25%of of1200 1200Stivarga-treated Stivarga-treatedpatients patients patients Hypertensive most common reasons permanent discontinuation Stivarga. most common reasons forfor permanent discontinuation of of Stivarga. across clinical trials. The onset hypertension occurred during first thethe across all all clinical trials. The 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 Table1 1compares comparesthetheincidence incidenceof ofadverse adversereactions reactions(≥10%) (≥10%)in inpatients patients Study 1 and Study Study 1 and Study 2).2). receiving Stivarga and reported more commonly than patients receiving receiving Stivarga and reported more commonly than in in patients receiving initiateStivarga Stivargaunless unlessblood bloodpressure pressureis isadequately adequatelycontrolled. controlled. placebo placebo (Study DoDonotnotinitiate (Study 1).1).

The ASCO Post | MARCH 10, 2015

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Announcements

Texas Center for Proton Therapy Names Andrew K. Lee, MD, Medical Director

ndrew K. Lee, MD, has been named Medical Director of the Texas Center for Proton Therapy. Dr. Lee launched proton therapy treatment at The University of Texas MD Anderson Cancer Center almost 9 years ago, treating the facility’s first proton therapy patient in 2006. In his

new role, Dr. Lee will lead North Texas’ first facility offering next-generation proton therapy treatment technology. The new proton therapy center is a collaboration of Texas Oncology, The US Oncology Network, McKesson Specialty Health, and Baylor Health

Enterprises and is expected to treat its first patients in late 2015.

Step Forward in Cancer Care “Dr. Lee is one of the finest, most experienced, and committed cancer physicians in oncology today. Combining

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).

his outstanding clinical skills and expertise with the most advanced proton therapy technology available is a major step forward in cancer care in Texas,” said R. Steven Paulson, MD, Chairman and President of Texas Oncology. “In bringing the most up-to-date

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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Announcements

16.5”

15.5”

4.75”

Andrew K. Lee, MD

proton technology to North Texas, the leadership of Texas Oncology and its collaborators continue to demonstrate their commitment to enhancing the care of cancer patients, in this region and beyond. I am excited to join the team and contribute to the outstanding vision of this organization,” said Dr. Lee. “Proton therapy not only saves lives, but it reduces

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.

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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.

the Program for Advanced Technology, and serving as the Medical Director of the MD Anderson Proton Therapy Center. Dr. Lee was one of the first physicians to treat patients with pencil-beam scanning, which enables greater accuracy in tumor treatments. He also pioneered the use of fiducial markers and imageguidance at MD Anderson, to improve tumor localization and optimize the accuracy of proton therapy. Dr. Lee also served as the first Program Director of the MD Anderson Cancer Center Proton Fellowship. He was recently recognized at MD Anderson as the first radiation oncologist to receive the coveted University Cancer Foundation Faculty Achievement Award in Patient Care. Dr. Lee is board certified in radiation oncology, specializing in prostate and other genitourinary cancers. He earned his medical degree at the University of Minnesota Medical School and completed his residency in radiation oncology at Harvard Medical School–Joint Center for Radiation Therapy. He also earned a Master of Public Health degree with an emphasis on clinical effectiveness from the Harvard School of Public Health. He has coauthored more than 100 peer-reviewed articles, abstracts, and book chapters on his research. “Our goal at the Texas Center for Proton Therapy is to create more cancer survivors with renowned medical expertise, advanced technology, and the compassionate, personalized care for which Texas Oncology is known,” said Gary Barlow, Director of the Texas Center for Proton Therapy. “Having a recognized leader and brilliant physician such as Dr. Lee now heading our medical team will benefit each and every patient who enters our facility.” S:9.875”

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.

side effects, which significantly improves the quality of life for cancer survivors.” Dr. Lee joins the Texas Center for Proton Therapy following almost 14 years at The University of Texas MD Anderson Cancer Center, where he pioneered many firsts in the field of proton therapy, including treating the first patient, serving as the first and founding Director of

About the Texas Center for Proton Therapy The 63,000 square foot facility will feature an advanced fixed beam treatment room and two isocentric gantry treatment rooms, each containing a 30-foot tall, 110-ton machine that rotates 360 degrees, to enable the most accurate positioning of the proton beams on patient tumors. Physicists currently are meticulously calibrating the proton beam equipment, anchored by a 220-ton cyclotron, to submillimeter accuracy, in preparation for treating its first patients later this year. The new center has been designed to create a positive, supportive treatment experience. Patients undergoing proton therapy will have access to on-site laboratory services and the newest imaging technology. n

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Through the Lens of Oncology History

Bringing the History of Cancer to Film

Filmmakers Ken Burns and Barak Goodman turn the best-selling book The Emperor of All Maladies: A Biography of Cancer into a compelling three-part documentary on PBS. By Jo Cavallo

Ken Burns Presents

Cancer: The Emperor of All Maladies A Film by Barak Goodman will be broadcast on PBS on March 30, March 31, and April 1. Check local listings for broadcast times.

ike the book it’s based on, the television documentary Ken Burns Presents Cancer: The Emperor of All Maladies, A Film by Barak Goodman chronicles the history of cancer and the devastation it has brought to the lives of countless people, from its first documented appearance over 5,000 years ago to its wide-reaching impact today. Adapted from the Pulitzer Prize–winning book The Emperor of All Maladies: A Biography of Cancer (Scribner, 2010) by Siddhartha Mukherjee, MD, PhD, the film is part historical thriller, part

detective mystery, and most of all, a compelling human drama told through the remarkable stories of cancer researchers, patients, and their families.

and in the growing awareness of the causes of the disease, which ushered in a new age in scientific knowledge. The

Pioneering Research Produced and directed by Barak Goodman in collaboration with Executive Producer and Series Creative Consultant Ken Burns, the film is divided into three 2-hour segments. The first episode of the documentary centers on the pioneering research of Sidney Farber, MD, whose groundbreaking 1948 study of the folic acid antagonist aminopterin as a treatment for children with acute leukemia1 launched the modern era of chemotherapy. Using archival footage of the advocacy efforts of Dr. Farber and philanthropist Mary Lasker to raise funding for cancer research and reduce cancer deaths, the film documents their success in convincing Congress to increase the budget of the National Cancer Institute (NCI) and securing passage of the National Cancer Act of 1971, which declared a “War on Cancer.” The first part also explores the fits and starts of progress being made in the mid-20th century in the use of combination chemotherapies to treat cancer

Ultimately, this is a very hopeful film and one that will make people feel better about cancer … and about what would happen today if they or their loved ones were diagnosed with the disease. —Barak Goodman

episode features interviews with the most innovative researchers of the time, including Emil J. Freireich, MD, discussing his work with Emil Frei, MD, in the 1950s and 1960s. Their investigations showed that using multiple chemotherapy agents could produce lasting remissions in children with acute lymphoblastic leukemia, among others. In the second episode, the film moves into advances made over the next 2 decades in the understanding of the genetic basis of cancer and the discovery in the early 1980s by J. Michael

Telling the Story of Cancer A Conversation With Ken Burns By Jo Cavallo

cclaimed documentarian Ken Burns (The Civil War, Baseball, Jazz, The Central Park Five, and The Roosevelts: An Intimate History) has been making films for more than 35 years. His most recently completed project, scheduled to air on PBS this spring, is Ken Burns Presents Cancer: The Emperor of All Maladies, A Film by Barak Goodman, a three-part documentary directed by Barak Goodman and based on

the best-selling book The Emperor of Maladies: A Biography of Cancer, by Siddhartha Mukherjee, MD, PhD. The ASCO Post talked with Mr. Burns, Executive Producer, Cowriter, and Senior Creative Consultant on the new documentary, about the making of the film, how the process differed from his experiences on earlier films, and what he learned from the project.

Bishop, MD, and Harold Varmus, MD, now Director of the NCI, of the first human oncogene.

Waking the Dead Cancer: The Emperor of All Maladies is dedicated to your mother, Lyla, who died of breast cancer when you were 11. How has her death influenced your past work and your desire to create this documentary on cancer? Just the absence of somebody in your life makes you interested in history. I had a father-in-law who told me that what I did for a living was continued on page 97

‘This Is Our Time’ The final episode showcases the optimism prevalent in cancer research today, as the understanding of what causes cancer on a molecular level continues to grow. That understanding has led to the advent of targeted therapies, which are resulting in durable remissions for some patients with cancer and even turning some cancers into chronic diseases. “Every field in medicine has had a moment in history that has been transforming—the moment where the knowledge that was required to change the field became available,” José Baselga, MD, PhD, Physician-in-Chief and Chief Medical Officer at Memorial Sloan Kettering Cancer Center, New York, tells viewers in the introduction to the film. “And my prediction is that the next 20 years [will be] the age of discovery for cancer and the age for new therapies. This is our time.”

Challenges of Adapting the Book to Film According to the film’s director Barak Goodman, more than 100 people were interviewed and nearly 700 hours of film produced over the course of 2 years, which then had to be whittled down to just 6 hours for the final production. While most of the documentary was filmed at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Through the Lens of Oncology History Medicine in Baltimore and Charleston Area Medical Center in West Virginia, ASCO’s 2013 Annual Meeting in Chicago served as one of the film’s locations, where many of the experts appearing in the film were interviewed. Mr. Goodman, whose documentaries include Scottsboro: An American Tragedy and Clinton, said making Cancer: The Emperor of All Maladies presented unique difficulties. “Artistically and aesthetically, making this film was enormously challenging. I don’t think there has ever been a film project that has attempted to weave a historical narrative with a verité contemporary film and a science film together in this way,” said Mr. Goodman. “I think this film is utterly unique in that way. It was also extremely emotionally challenging because we got very, very close to the patients we filmed, some of whom didn’t survive their cancer.” Among those connected with the film who did not survive their disease was the actor Edward Herrmann, who narrates the film. He died of glioblastoma a few weeks after completing his work on the documentary.

Making the Story Accessible Telling a story about a subject as complex—and frightening—as cancer, and making it understandable and accessible to a large general audience, also posed challenges for Mr. Goodman. “The only way viewers could fully understand the science in episode 3, which details the exciting developments happening in cancer research today, was by having a primer on

Sidney Farber, MD (above), in 1947, used antifolates to induce remissions in children with leukemia. Later, Dr. Farber teamed up with philanthropist Mary Lasker to raise funding for cancer research and secure passage of the National Cancer Act of 1971, which declared a “War on Cancer.”

Emil Frei, MD

Emil J. Freireich, MD

Harold Varmus, MD

J. Michael Bishop, MD

what cancer is—and in the first two episodes, that is what they get. The science is embedded in the historical narrative, so without even knowing it, viewers are learning the basics of what cancer is before they get to the more detailed science in the last episode,” explained Mr. Goodman. While the stories chronicling the

setbacks and advances in cancer research over the past 8 decades give the film its scientific soul, it is the contemporary stories of patients undergoing therapy that give it heart. “I hope that people aren’t scared away by the subject,” said Mr. Goodman. “I think the audience will be fascinated by this film and will want

to watch it and see how the stories of the patients turn out. Ultimately, this is a very hopeful film and one that will make people feel better about cancer … and about what would happen today if they or their loved ones were diagnosed with the disease. We are entering a new day, and things are looking up. People shouldn’t be terrified to

watch the program and see how treatments are improving in cancer.” n Reference 1. Farber S, Diamond LK: Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med 238:787-793, 1948.

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Through the Lens of Oncology History Story of Cancer continued from page 92

wake the dead and that I could make Abraham Lincoln, Jackie Robinson, and Louis Armstrong come back to life. “Who do you think,” he asked, “you are trying to wake up?” And that is a good way to understand why I do what I do. There was no way I could not make The Emperor of All Maladies. First of all, Sid [Mukherjee] has written an extraordinary book—a work of literature—and we’re obligated now as citizens not to ignore the subject of cancer any longer, but to become participants in its story. One way of thinking about it is, if cancer is, in fact, the emperor of all maladies, that makes us its subjects. And the question is are we going to be willing slaves to this disease or are we going to put up a fight? I think the film is an attempt to describe what the fight has been so far, where we are now in cancer research, and where we might be going, so one would hope that it would light some minds on fire. At the most basic level, the film is an amazing detective story, a series of biographies and discoveries of false dawns, and new legitimate hopes for more effective treatments. We stand right now at the threshold of an amazing age in cancer research that we cannot deny. We just have to be willing to look at the progress that has been made and the prospects for the future clearly. One out of two men and one out of three women will get cancer; you can’t put your head in the sand and be an ostrich, pretending the disease is not there right in front of us. Cancer affects all of us, and we think we’ve told a riveting story that will engage everyone.

A Historical Thriller How would you describe the film? I think most of all it is a historical thriller. The number 1 question is what is cancer? The film takes viewers through the history of millennia of mistakes. The early cancer researchers didn’t know what caused the disease, but they thought if they cut it out or zapped it or poisoned it, the cancer

would go away, and the film shows the limited successes and multitude of failures they had. Then you see how the researchers began to refine their discoveries and ask some important questions, including is cancer a virus? And sometimes the answer came back “yes.” Is cancer caused by environmental factors? Yes, certainly, the most obvious example being smoking. Is cancer caused by genetics? Yes to that question, too. The film also has a long section on prevention strategies and how researchers are investigating the use of a person’s immune system to fight

Photo by Cable Risdon.

lenges that were different in so far as we were integrating more complex science into a film than we usually do. I’ve done a film on the engineering complexities of building the Brooklyn Bridge (Brooklyn Bridge, 1981), and there are other films where we have gotten deep in the scientific weeds, but this film is one in which the actual detective story is a scientific one, so that’s different. At the end of the day, though, you’ve got a narrative, you’ve got a master, and what I found is that my reactions to it were no different than any other film I’ve made. My main concern was how do we make the elements of

I think we have all forgotten that the real heroism in life takes place in the unknown moments, away from the glare of the cameras. Heroism is in the courage displayed by people as they struggle with this particular disease. —Ken Burns

cancer. We show how all of the conventional therapies of surgery, chemotherapy, and radiation are still around but are being used in conjunction with more refined, less toxic therapies. Cancer has been around for as long as we’ve been around, and in the film we introduce the audience to a series of human beings who have tackled the problem. Since most of the progress in cancer research has happened over the past 3 or 4 decades, many of those researchers are still alive; we’ve got them in our film. And we get to interview them now with the virtue of some hindsight. The film shows how we are now at a time in the history of cancer that can’t be ignored. We are obligated to get involved, ask some hard questions, and follow the leads. It is one hell of a story.

New Challenges Were there some challenges and concerns making this film that were different from your previous documentaries? Yes, there were some obvious chal-

the film better, how do we tell this story better, does the audience really need to know that much science, can we simplify a specific term for them in our writing, is that talking head sound bite really the best one to use for this moment, is that music working, does that animation serve us? Of course, we also have the cinema verité scenes, the patient case studies in which we were granted extraordinary privilege—principally at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore and Charleston Area Medical Center in West Virginia—to accompany people on some of the most arduous journeys of their lives or their loved ones’ lives.

Irony and Urgency Two people instrumental in getting this film made—producer Laura Ziskin, who died of metastatic breast cancer before production on the film began, and actor Edward Herrmann, the narrator of the film, who died of glioblastoma shortly

after completing work on the film—never got to see the finished product. How did their deaths affect the final production? Ed died within weeks of completing the film, so the irony of his and Laura’s death is not lost on us. Ed was also the voice on my last major series, The Roosevelts: An Intimate History. It is part of the difficult but inevitable triage of life that we would lose Laura and we would lose Ed in the course of producing this film. And that adds a kind of urgency, it seems to me, for everyone to work together and figure out what we can do about this disease. Funding for basic research, essential research, general research has been cut so significantly in the past decadeand-a-half, which doesn’t bode well if we are going to take the opportunities that are presented to us right now and make some real, true advances in curing cancer. We need help. So I think an informed public becomes an active and vocal constituency for the support of that research.

Real Heroism What did you learn about the people portrayed in this film—in particular, the patients, their caregivers, and the health professionals who treat them? In our superficial media culture we use the word “hero” all wrong. We expect heroism to be about perfection. Heroism, the Greeks taught us, is never about perfection. It’s about the negotiation between a person’s strengths and weaknesses. I think we have all forgotten that the real heroism in life takes place in the unknown moments, away from the glare of the cameras. Heroism is in the courage displayed by people as they struggle with this particular disease. So for me, just the privilege of engaging this story, the privilege of getting to know not just the so-called ordinary folks—the patients and their family members—who are in our scenes, but also the extraordinary surgeons and scientists who have helped those people overcome cancer or are on the cusp of figuring out strategies and therapies that will make cancer chronic and treatable instead of fatal for many people, was beyond inspiring to me. n

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The ASCO Post | MARCH 10, 2015

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Through the Lens of Oncology History The Journey From Book to Film

A Conversation With Siddhartha Mukherjee, MD, PhD By Jo Cavallo Oncology at Columbia University Medical Center in New York, about the translation of his book to film, his hope that it will start an ongoing national dialogue on the progress being made in cancer therapy, and the need for increased research funding.

Similar but Different

oon after publication of The Emperor of All Maladies: A Biography of Cancer (Scribner) in 2010, the book’s author Siddhartha Mukherjee, MD, PhD, received a call from Laura Ziskin, a film producer and cofounder of Stand Up To Cancer, who was interested in obtaining the film rights to Dr. Mukherjee’s Pulitzer Prize–winning book. Ms. Ziskin, a breast cancer survivor, later teamed with Sharon Percy Rockefeller, the President and CEO of WETA, a PBS station in Washington, DC, and a colorectal cancer survivor, to produce the film. Ms. Rockefeller then put Dr. Mukherjee together with acclaimed documentarian Ken Burns to adapt the book to film. “Laura had been looking to produce a film about cancer that gave an honest appraisal of where we are on the ‘War on Cancer’ and a history of how we got here and said the book provides the perfect template for that,” said Dr. Mukherjee. “After discussing the film adaption with Ken Burns, I thought teaming up with Stand Up To Cancer and Ken’s production company provided the perfect match to bring the book to film, and that’s how the documentary got started.” (Ms. Ziskin died of metastatic breast cancer in 2011, before production on the film began.) The ASCO Post talked with Dr. Mukherjee, Assistant Professor of Medicine in the Division of Medical

The Emperor of All Maladies: A Biography of Cancer was so enormously popular, garnering every major award, including the Pulitzer Prize for General Nonfiction. How well do you think it translates to film? I think the book translates incredibly well into film. We thought about the film very, very deeply, and it was clear that telling the story of cancer in the film was going to be more complicated in some ways than in the book. For example, we picked up new characters from real life, including researchers and patients, and we followed the patients throughout their disease. Obviously, the stories are not the same as in the book, but they are very similar. Also, the way they intersect and are interspersed with history is very similar, so you get the feel of the book but in a different form. The other incredible thing is that the film is exciting to watch. You can convey excitement in a different way in a film than in a book. Viewers will see how the pace picks up around the discovery of the oncogene in the early 1980s, and suddenly you realize what a monumentally important discovery that was, how it was so counterintuitive, and how everyone came into that discovery thinking a completely different thing. There are so many little devices in the film that bring the book to life. There is a lovely piece—I don’t even know how they got this archival footage—with four different cancer wards and four different ways of thinking of cancer. The match between the narration and the archival footage is so incredible and seamless.

Executive Summary Despite great advances in cancer therapy, nearly 600,000 people die of the disease each year, and the word “cancer”

is still very frightening to people. Why do you think the film will be appealing to a large, general audience? The way the film is made makes learning about cancer exciting. It reminds us that there has been enormous progress in cancer treatment and how much has changed over the past century. We haven’t had this kind of executive summary on cancer with so many of the world’s greatest authorities on film in the history of cancer. In 1971, Congress declared a “War on Cancer,” and 40-odd years later, we have a chance to go back and ask where we are today, in the most authoritative way.

Making an Impact What are you hoping happens as a result of this documentary? Do you think it might change people’s perceptions of cancer, get them to recognize the importance of participating in clinical trials, or increase federal funding for research?

cause we learned from our past mistakes and were able to make strides in cancer advances. So presenting that information is the best form of advocacy. The film doesn’t tell you to fund basic science at the National Institutes of Health; you reach that conclusion by yourself. You see why understanding the biology of leukemia at the National Cancer Institute in the 1950s and 1960s was critical to curing patients with leukemia for the first time. If that doesn’t motivate viewers to become advocates of basic and clinical scientific research, I don’t know what will.

Transformative Process You have said that you wrote the book because one of your patients asked you, “What is this disease I’m fighting?” And you were compelled to learn about the history of cancer, the current state of cancer research, and what happens next. What stage is cancer research in today?

We are in the middle of a transformative process in which we know more about the cancer cell than we ever have before, and we are trying to convert all that knowledge into more effective therapies.… Now the question is, can the knowledge we have gained be made into medicines, effective prevention strategies, and cures? —Siddhartha Mukherjee, MD, PhD

I would say all of those things. I think they deserve to be changed and will be changed. Telling people honestly where we are in cancer research without pushing the message on them is the greatest form of advocacy and creates a kind of platform to fully answer the question, how did we get here? We got here because of basic science, because of physicians, because of the enormous dedication of patients, because of the immense wisdom of funding cancer research both at the basic science and clinical science level, because patients participated in trials, and be-

We are in the middle of a transformative process in which we know more about the cancer cell than we ever have before, and we are trying to convert all that knowledge into more effective therapies. The cancer cell, the physiology of cancer, the physiology of cancer patients, and understanding the role of the immune system are all pieces that we are going to fit into the cancer puzzle, and that knowledge didn’t exist 10 or even 5 years ago. Now the question is, can the knowledge we have gained be made into medicines, effective prevention strategies, and cures? n

ASCOPost.com | MARCH 10, 2015

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Patient’s Corner

Cancer Was My Wake-Up Call to a Healthier Life

A diagnosis of stage IV ovarian cancer has taught me the importance of taking care of both my mental and physical health. By Teresa Pedersen, as told to Jo Cavallo

come from strong physical stock and inherited a sort of “tough it out mentality” when it comes to coping with the usual aches and pains that creep up as you age. So by the time I realized that my legs had become so swollen and my breathing so labored it was difficult for me to walk, I could barely make my way into the emergency room of my local hospital to find out what was wrong. It turns out I was in much worse shape than I could have imagined. An ultrasound of my abdomen showed that I had a large mass on my ovary, and a computed tomography (CT) scan found that I had blood clots in both legs, which had broken off and traveled to my lungs.

Unfortunately, the treatment didn’t end there. The surgery was followed by six rounds of a combination regimen of cisplatin and paclitaxel to kill off any remaining cancer cells, and for a while, it appeared the therapy had worked. A series of CT scans could find no trace of the cancer and for the first time in months, I started to relax.

Making Lifestyle Changes Ever since my diagnosis, my overarching goal has been to maintain a sense of normalcy. I wear a wig so people can’t see that I’m a cancer survivor—I don’t want their pity. But I have also made some dramatic lifestyle changes in my life. I left a high-stress job for one that

No one ever said to me, ‘Teresa, you only have 6 months to live,’ even though statistically that was probably my fate, and that has made all the difference in my recovery. —Teresa Pedersen

Intensive Care I was immediately taken to the intensive care unit for more diagnostic tests and treatment to dissolve the blood clots. Within 2 days, I was scheduled for surgery to biopsy the tumor, which turned out to be stage III ovarian cancer; a total hysterectomy and a bilateral salpingo-oophorectomy followed to remove the remnants of the cancer. I remained in the hospital for 21 days and had to have physical therapy to learn how to walk again.

However, 6 months later, the cancer (now stage IV) recurred in my liver, and I had six additional treatments of very aggressive chemotherapy, which included carboplatin and more paclitaxel to shrink the tumor, followed by surgery to remove what was left of the malignancy. Finally, I had 30 infusions of topotecan, the last one in September 2013, and so far, my CT scans show no signs of tumor recurrence.

doesn’t consume my every waking moment, and I’m taking better care of myself physically. I gave up my earlymorning ritual of eating candy bars and drinking Coke for breakfast and have cut my refined sugar intake by more than 90%. I’m also following the American Cancer Society guidelines for physical activity and exercise at least 150 minutes per week.

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

It’s pathetic to say, but at 51, I’m healthier now than I’ve ever been in my adult life.

Maintaining Hope I am also trying to maintain a positive attitude. I stopped going to ovarian cancer support group meetings, because I found them to be too sad. There was a real sense of hopelessness among many of the survivors there, and I have to remain positive to get through each day and put distance between cancer and me. I’ve been fortunate to have a wonderful oncologist, who never speculates on what my ultimate outcome might be. Right from the very beginning, he gave me hope and said that he was going to do everything he could to treat my cancer. No one ever said to me, “Teresa, you only have 6 months to live,” even though statistically that was probably my fate, and that has made all the difference in my recovery. I don’t know what the future will bring, but I am determined to embrace life and live every day as it comes. I’ve learned that a life without hope is no life at all. n Teresa Pedersen lives in Nampa, Idaho.

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

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

S:9.25”

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

S:13”

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 March Advanced Prostate Cancer Consensus Conference March 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

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

NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-14 • Hollywood, Florida For more information: www.nccn.org/AC2015 ESMO Symposium on Signalling Pathways in Cancer 2015 March 13-14 • Barcelona, Spain For more information: www.esmo.org/Conferences/ Signalling-Pathways-2015Personalised-Medicine 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 American Society of Preventive Oncology (ASPO) Annual Meeting March 15-17 • Birmingham, Alabama For more information: http://aspo.org/annual-meeting ACCC 41st Annual National Meeting March 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ calendar.asp 14th St. Gallen International Breast Cancer Conference March 18-21 • Vienna, Austria For more information: www.oncoconferences.ch

New Trends in Anticancer Drug Development March 23-25 • Madrid, Spain For more information: www.cnio.es/es/index.asp Personalised Cancer Medicine and Big Data Analysis – 7th International Conference of Contemporary Oncology March 25-27 • Poznań, Poland For more information: www.termedia.pl/Konferencje?Invitat ion&e=372&p=2787

Melanoma and Cutaneous Malignancies Meeting April 10-11 • New York, New York For more information: www.healio.com/meeting/ hemonctodaymelanoma/ home?promocode689-8045

Multidisciplinary Spine Oncology Symposium April 17-18 • New York, New York For more information: www.mskcc.org/events/cme/ multidisciplinary-spine-oncologysymposium/form

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

VAHO Spring 2015 Membership Conference April 17-18 • Hot Springs, Virginia For more information: www.accc-cancer.org/ossn_network/ VA/VAHO-meetings.asp

2015 Business of Oncology Summit and 2015 Annual Meeting & Spring Session April 10-12 • Orlando, Florida For more information: www.flasco.org International Society of Geriatric Oncology (SIOG) USA Forum April 11 • Tampa, Florida For more information: www.siog.org

Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.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

EORTC-EANO-ESMO 2015 March 27-28 • Istanbul, Turkey For more information: www.ecco-org.eu/Events/EORTC_ EANO_ESMO-2015

OSMO Spring 2015 Oncology Conference April 11 • Portland, Oregon For more information: www.osmo.org/events/view/26

Northern New England Clinical Oncology Society March 27-28 • Portsmouth, New Hampshire For more information: http://nnecos.org/spring

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/

46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

April

ASCO Multidisciplinary Cancer Management Course (MCMC) April 15 • Vina Del Mar, Chile For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses

American Brachytherapy Society Annual Meeting April 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index.cfm

ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ELCC2015-Lung-Cancer

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 continued on page 104

Save the Date

13th International Conference on Malignant Lymphoma (ICML) June 17–20, 2015 Lugano, Switzerland The 13-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

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2015 Oncology Meetings continued from page 103

Fourth Annual Cancer Pain Conference April 24-26 • Scottsdale, Arizona For more information: www.cancerpainconference.org

2015 ASCO State Affiliates’ Reception May 31 • Chicago, Illinois For more information: www.asco.org/about-asco/stateaffiliate-leadership-conference

May

June

International Society of Geriatric Oncology (SIOG): Cancer Care of the Older Adult Across the Cancer Continuum May 1 • New York, New York For more information: www.siog.org

International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/

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 WCIO 2015 May 6-9 • New York, New York For more information: http://www.wcioevents.org

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 Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org

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 American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.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

MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July 7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp

International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/

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/

14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com

ASCO Multidisciplinary Cancer Management Course (MCMC) August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses

The 13th Annual Scientific Meeting of JSMO July 16-18 • Sapporo, Japan For more information: www.congre.co.jp/jsmo2015/en/index .html

Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/

NRG Oncology Meeting July 16-19 • Denver, Colorado For more information: www.gog.org/meetinginformation .html

European Society for Medical Oncology Academy 2015 August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

APOS 12th Annual Conference and IPOS 17th World Congress of PsychoOncology July 28-August 1 • Washington, DC For more information: http://www.apos-society.org 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

CAP-ACP 2015 Annual Meeting June 20-23 • Montreal, Canada For more information: www.cap-acp.org/annual_meeting .php

ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

August

September International Palliative Care Workshop September 3-5 • Fez, Morocco For more information: www.asco.org/international-programs/ international-palliative-care-workshops 25th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists September 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org

October Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

30th Annual Harvard “Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis and Immunology” October 5-8 • Boston, Massachusetts For more information: http://steele .mgh.harvard.edu/tumorcourse

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Announcements

ASCO Commends Margaret Hamburg, MD, for Leadership as FDA Commissioner

SCO expresses deep gratitude to Margaret Hamburg, MD, for her 6 years of vision and progress as Commissioner of the U.S. Food and Drug Administration (FDA). Dr. Hamburg, one of the longest-serving FDA commissioners, leaves a legacy of important

Margaret Hamburg, MD

advances in regulatory science and medicine. The tools available to oncologists to care for our patients, including both drugs and diagnostics, have expanded tremendously in the past 6 years as a result of Dr. Hamburg’s efforts. “Under Dr. Hamburg’s leadership, we have made great strides in cancer treatment and in how we implement precision medicine,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO. “Dr. Hamburg has been at the forefront of ensuring that the FDA is keeping pace with these rapid scientific changes and using available mechanisms to speed patient access to safe and effective therapies.” Among her many accomplishments has been an increase in the speed and efficiency of medical product reviews, the expansion of FDA-expedited approval mechanisms, and the development of the

Under Dr. Hamburg’s leadership, we have made great strides in cancer treatment and in how we implement precision medicine. —Richard L. Schilsky, MD, FACP, FASCO

Breakthrough Therapies designation for therapies to help patients with serious or life-threatening diseases. In 2014, nearly half of the novel new drugs approved received expedited approval, including drugs for cancer. Under her watch, the agency also established a regulatory pathway for biosimilar biological products, as well as approval of companion diagnostic tests that are used with targeted therapies

to determine whether a patient will respond to a specific therapy. Dr. Hamburg has provided important leadership in the regulation of tobacco products, most notably extending regulatory authority to

electronic cigarettes (e-cigarettes) and other electronic nicotine delivery systems (ENDS). She has also been instrumental in creating a culture of transparency and open-door involvement at the FDA.

“Dr. Hamburg laid the groundwork to ensure that these meaningful initiatives will continue past her tenure,” Dr. Schilsky said. “ASCO is grateful for her service to our country and to all Americans.” n

E FP red F a t rin ) Cle P a 0(k m m 51 Ma FDA w No

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MammaPrint + BluePrint: Beter together. Convenient online ordering available at www.agendia.com. Agendia, Inc. 22 Morgan, Irvine, CA 92618 (888) 321-2732 www.agendia.com © 2015 1 Cristofanilli M, et al. Cancer Res. 2012;72(24 Suppl):Abstract nr P3-05-01. 2 Whitworth P, et al. Ann Surg Oncol. 2014 Aug 7. [Epub ahead of print];doi: 10.1245/s10434-014-3908-y.

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Announcements

Thomas J. Rutherford, MD, PhD, Named Network Physician Director of Cancer Services at Western Connecticut Health Network

estern Connecticut Health Network (WCHN) has named gynecologic oncologist Thomas J. Rutherford, MD, PhD, an expert in the area of ovarian cancer, as the Network Physician Director of Cancer Services. As Director, Dr. Rutherford will create a new model of cancer delivery in the dynamic environment of the programs at the Praxair Cancer Center at Danbury Hospital, Diebold Family Cancer Center at New Milford Hospital, and the Whittingham Cancer Center at Norwalk Hospital. “WCHN delivers the same quality and standard of care, if not better, than anywhere in the country, at a better value, with easy accessibility within our local communities by a friendly care team,” Dr. Rutherford said. “I am looking forward to integrating the many excellent cancer programs and services, and the outstanding expertise of our cancer care team at WCHN, to continue to grow our efforts to provide the highest quality and standard of cancer care to our patients.” Dr. Rutherford will lead the expansion of the WCHN cancer services. His

philosophy is total cancer care: prevention; high risk screening; research; genomics; a personal and individualized treatment plan; supportive and survivorship care; as well as the end of life care to support the medical and personal needs of every patient and their family. He be-

join the WCHN family and lead our expert cancer team,” said WCHN President and CEO, John M. Murphy, MD. “He has an outstanding reputation for his clinical and research experience, and a compassionate approach to caring for patients. His vision and leadership will enhance the

I am looking forward to integrating the many excellent cancer programs and services, and the outstanding expertise of our cancer care team at WCHN, to continue to grow our efforts to provide the highest quality and standard of cancer care to our patients. —Thomas J. Rutherford, MD, PhD

lieves that disease-site specific programs, comprised of interdisciplinary teams led by surgeons, medical oncologists, and radiation oncologists, will develop a unified state-of-the-art treatment plan for all patients at each WCHN Cancer Center. “We are thrilled to have Dr. Rutherford

great care provided by an excellent team in place today, and guide us as we transform cancer care for our community.” Dr. Rutherford is a board-certified gynecological oncologist and an authority on gynecologic cancers. Prior to WCHN, he served as Professor of Gyne-

cologic Oncology and Director of Gynecologic Oncology Fellowship at Yale University School of Medicine. During that time, Dr. Rutherford played a key role in the development of the gynecologic oncology department, including growing a research division that encompassed basic and translational research at both the institutional and cooperative group levels. A recognized researcher, Dr. Rutherford has focused on prevention, early detection, and treatment of ovarian cancer and other gynecologic malignancies. He has authored more than 100 scientific journal articles, worked to isolate the stem cell associated with ovarian cancer, and developed the standard of care for the treatment of ovarian cancer. Dr. Rutherford will continue to influence the evolution of WCHN’s cancer research program with emphasis on basic science research that will lead to translational clinical programs, clinical trial development, and novel therapies. Dr. Rutherford obtained his bachelor’s degree from Roanoke College and his doctoral and medical degrees from the Medical College of Ohio at Toledo. n

John A. Hartford Foundation Names Terry Fulmer, PhD, RN, as New President

he John A. Hartford Foundation announced that Terry Fulmer, PhD, RN, FAAN, University Distinguished Professor and Dean of the Bouvé College of Health Sciences at Northeastern University, will become its new President.

Terry Fulmer, PhD, RN, FAAN

Dr. Fulmer, who is also Professor of Public Policy and Urban Affairs in the College of Social Sciences and Humanities at Northeastern, succeeds Corinne H. Rieder, EdD, who has led the Foundation since 1997. Dr. Fulmer will officially join the Foundation in May 2015. “We are extremely pleased to have Terry Fulmer at the Foundation’s helm,” said Norman H. Volk, Chairman of the John A. Hartford Foundation. “She is an incisive thinker and passionate ad-

vocate for older adults. She has been a champion of geriatrics throughout her career. She will be a charismatic leader, not only for the Foundation, but for new ideas that drive real improvements in how our nation delivers health care to older people and their families.” “I am honored and thrilled to take on this role,” said Dr. Fulmer. “Throughout my career, the John A. Hartford Foundation has been a central and dynamic force for better geriatrics care and education. I look forward to guiding Hartford’s efforts to change practice and policy and continuing to amplify our voice on behalf of older adults.”

Leading Expert in Geriatrics Dr. Fulmer, who received her PhD at Boston College, is a leading expert in geriatrics and is best known for her research on elder abuse and neglect, which has been funded by the National Institute on Aging and the National Institute for Nursing Research. She is an elected member of the Institute of Medicine, and currently serves as the Chair of the National Advisory Committee for the Robert Wood Johnson Foundation Executive Nurse Fellows Program. She has

served as the first nurse on the board of the American Geriatrics Society and as the first nurse to serve as president of the Gerontological Society of America. Previous to her role as Dean of the Bouvé College of Health Sciences, Dr. Fulmer served as the Erline Perkins McGriff Professor of Nursing and founding Dean of the New York University (NYU) College of Nursing. For 15 years, she also served as Codirector of the Hartford Institute for Geriatric Nursing at NYU, which the Foundation began supporting in 1996. She has also held faculty appointments at Boston College, Columbia University, Yale University, and the Harvard Division on Aging. Dr. Fulmer will build on the contributions of Dr. Rieder, the first woman to lead the Foundation and to serve as its President. During Dr. Rieder’s tenure, the Foundation expanded its efforts to build academic capacity in geriatrics in schools of medicine, nursing, and social work, creating a lasting impact in all these disciplines. Additionally, she led efforts to build major funding partnerships with the National Institute on Aging to continue the Foundation’s long-running Paul B. Beeson Career De-

velopment Awards in Aging Research program, the Medical Student Training in Aging Research (MSTAR) program, and the Grants for Early Medical/Surgical Specialists’ Transition to Aging Research (GEMSSTAR) program. Most recently, she has overseen the Foundation’s strategic shift towards direct influence on practice change and the more immediate determinants of the quality of health care for older adults.

About the Foundation The John A. Hartford Foundation is a private philanthropy working to improve the health of older Americans. After 3 decades of championing research and education in geriatric medicine, nursing, and social work, the Foundation pursues opportunities to put geriatrics expertise to work in all healthcare settings. The Foundation was established by John A. Hartford. Mr. Hartford and his brother, George L. Hartford, both former Chief Executives of the Great Atlantic & Pacific Tea Company, left the bulk of their estates to the Foundation upon their deaths in the 1950s. To learn more, visit www.jhartfound.org. n

ASCOPost.com | MARCH 10, 2015

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Announcements

Theodore Lawrence, MD, PhD, Named Director of University of Michigan Comprehensive Cancer Center

heodore S. Lawrence, MD, PhD, has been named Director of the University of Michigan Comprehensive Cancer Center. Dr. Lawrence succeeds Max S. Wicha, MD, who founded the Cancer Center 27 years ago.

Theodore S. Lawrence, MD, PhD

“This is a tremendous program, with talented and dedicated faculty and staff, a terrific research infrastructure, and superb core facilities,” said Dr. Lawrence, who will assume the title of Max S. Wicha Distinguished Professor of Oncology. He is also Chair of Radiation Oncology at the University of Michigan Medical School. Dr. Lawrence cites the Cancer Center’s strength in precision medicine, drug discovery, and health policy research, as well as opportunities to deepen clinical

and translational research efforts. The center’s “comprehensive” status is designated by the National Cancer Institute and reflects participation in cancer basic, clinical, and population sciences research, with strong interactions among those areas. A center must also provide public information, education, and outreach programs. University of Michigan is one of two comprehensive cancer centers in Michigan, and one of 41 across the country. “Michigan has been the epicenter of many global advances in cancer research and care. As patients, families, and the scientific community look to us for the next breakthroughs, we are fortunate to have the expertise of an established leader of Dr. Lawrence’s caliber to guide the Cancer Center into a very promising future,” said James O. Woolliscroft, MD, Dean of the University of Michigan Medical School and Lyle C. Roll Professor of Medicine. In addition to continuing to advance the Cancer Center’s research excellence, Dr. Lawrence plans to grow the center’s statewide presence as part of an effort to bring cancer care closer to home. “The vast majority of cancer care can be done in the community with

strong partnerships. We want to create more of those partnerships to allow more patients in our state to receive the right care in the right place,” Dr. Lawrence said. Dr. Lawrence’s laboratory interests are focused on chemotherapeutic and molecularly targeted radiosensitizers. His clinical research combines these laboratory studies with conformal radiation, guided by metabolic and functional imaging, to treat patients with

Society of Chairs of Radiation Oncology, and both the Board of Scientific Councilors and the Board of Scientific Advisors of the National Cancer Institute. He is a member of the Institute of Medicine of the National Academy of Sciences. He has received the ASTRO Gold Medal, an ASCO Statesman Award, and the 2014 Outstanding Investigator Award from the Radiological Society of North America. Dr. Lawrence joined the faculty of

As patients, families, and the scientific community look to us for the next breakthroughs, we are fortunate to have the expertise of an established leader of Dr. Lawrence’s caliber to guide the Cancer Center into a very promising future. —James O. Woolliscroft, MD

pancreatic and other gastrointestinal cancers. Dr. Lawrence expects to continue patient care and research activities as Cancer Center Director. In addition, Dr. Lawrence has served in leadership positions in many of the most prestigious oncology societies, including ASCO, the American Society of Radiation Oncology (ASTRO), the Radiation Oncology Institute, the

the University of Michigan in 1987, following a fellowship in medical oncology and a residency in radiation oncology at the National Cancer Institute. He received his research degree in cell biology from the Rockefeller University in New York, followed by his medical degree from Cornell University, and an internal medicine residency at Stanford University. n

Lee Schwartzberg, MD, Appointed Vice Chairman of Caris Centers of Excellence Network

aris Life Sciences, a biosciences company focused on precision medicine, announced the designation of West Cancer Center in Memphis as a Center of Excellence site in the Caris Centers of Excellence for Precision Medicine Network. Additionally, Lee S. Schwartzberg, MD, Medical Director of West Cancer Center, has been appointed Vice Chairman of the Network, helping to guide the development of standards for tumor profiling, design tumor profiling research protocols, and foster a collaborative environment for Network members. “Molecular profiling is quickly becoming a critical component of cancer care, as increasing numbers of clinicians rely on advanced tumor profiling technologies to better inform their approach to cancer diagnosis and treatment. This is particularly true of rare and aggressive cancers, which are notoriously difficult to treat,” said Dr. Schwartzberg, who

is also Division Chief of Hematology/ Oncology and Professor of Medicine at the University of Tennessee Health Science Center. “We are excited to join the Network and to form a consensus framework for how molecular profil-

practices for integrating and utilizing molecular profiling in oncology practice, while also striving to increase widespread adoption and patient access to personalized medicine in clinical settings. “We are very pleased to partner

We are excited to join the Network and to form a consensus framework for how molecular profiling can be best applied to enable more precisely targeted therapeutic decision-making for each patient. —Lee S. Schwartzberg, MD

ing can be best applied to enable more precisely targeted therapeutic decisionmaking for each patient.” As a Network member, West Cancer Center will actively participate in the development of standards of care and best

with Dr. Schwartzberg and West Cancer Center to develop standards for incorporating tumor profiling into clinical care for patients with cancer,” said John Marshall, MD, Chairman of the Network, Professor of Medicine and

Oncology at Georgetown University School of Medicine, and Chief of Hematology/Oncology at Georgetown Lombardi Comprehensive Cancer Center. “The Caris Centers of Excellence for Precision Medicine Network aims to improve treatment outcomes and reduce the financial burden of cancer care. We look forward to working with other high-impact institutions, like West Cancer Center, and continuing the expansion of this network.” As Vice Chairman of the Network, Dr. Schwartzberg will co-lead the development of standards and best practices for incorporating profiling into clinical care while also creating a large cooperative group of both academic and community-based oncology practices. The Network will pursue outcomes-focused research projects, create optimal tissuehandling protocols for profiling, and establish profiling educational forums for physicians and patients. n

The ASCO Post | MARCH 10, 2015

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In Memoriam

Lee W. Wattenberg, MD, the ‘Father of Chemoprevention’ Dies at 92 By Ronald Piana

ne of the early giants in the field of cancer prevention, Lee W. Wattenberg, MD, died on December 9, 2014, at the age of 92.

In 1966, Dr. Wattenberg published what would be regarded as a landmark paper in the American Association for Cancer Research (AACR) journal Cancer Research. During his research, he reviewed 36 years of animal studies, looking at the effects of various compounds on carcinogenesis, which set forth the framework for understanding how these compounds worked. It was in this seminal paper that Dr. Wattenberg introduced the term “chemoprophylaxis.” This work recognized the promise of the field of cancer prevention, playing a prominent role in its evolution.

His Many Accomplishments Lee W. Wattenberg, MD

A native New Yorker, Dr. Wattenberg received his BS from City College of New York in 1941 and then went on to attain his medical degree from the University of Minnesota School of Medicine. He later became a distinguished faculty member for more than 60 years. Dr. Wattenberg attributed his lifelong passion for cancer prevention to his work as a junior biologist with the Medical Research Group of the Manhattan Project, whose efforts were dedicated to studying the effects of radiation as it related to the development of the atomic bomb.

Dr. Wattenberg served in the army during the Korean War; he was stationed at Walter Reed Hospital, performing research to aid the war effort. During

ing the field of cancer prevention. He would later investigate two categories of chemopreventive agents: synthetic compounds that might prevent carcinogen-induced lung cancer, and dietary constituents, such as the cruciferous plants cabbage and broccoli. He also studied the processes that cause irreversibility in carcinogenesis and sought to determine whether and how these processes could be targeted for intervention. Adding to his list of research accomplishments, Dr. Wattenberg also pioneered the use of aerosols to deliver drugs in lung cancer. Dr. Wattenberg was president of the AACR from 1992–1993 and was elected as a Fellow of the AACR Academy in 2013. His many contributions to the AACR included terms as Associate Editor for Cancer Research and Cancer

Lee has inspired the work of a whole generation of cancer prevention researchers, which, in addition to his own personal contributions, will leave a lasting legacy of saving lives from cancer. —Margaret Foti, PhD, MD

his long and illustrious career, Dr. Wattenberg contributed prolifically to the scientific literature, constantly advanc-

Epidemiology, Biomarkers & Prevention. He chaired the first cancer prevention symposium at the 1979 AACR An-

 In Memoriam

Lee W. Wattenberg, MD December 21, 1921 – December 9, 2014 

nual Meeting, served as the chair of the Annual Meeting Program Committee in 1982, and was a featured speaker at the AACR conferences on Frontiers in Cancer Prevention Research. Dr. Wattenberg also served on the AACR board of directors from 1985–1988 and from 1991–1994. During his presidency, he launched the Associate Member Council in 1992 to represent the interests of early-career scientists.

‘A Lasting Legacy’ In a tribute to Dr. Wattenberg, Margaret Foti, PhD, MD, Chief Executive Officer of the AACR, noted, “About two-thirds of all cancers are preventable. Because of Lee Wattenberg’s dedication to and belief in the promise of cancer prevention, the field has taken its rightful place as one of the most important areas of cancer research,” she noted. “Lee has inspired the work of a whole generation of cancer prevention researchers, which, in addition to his own personal contributions, will leave a lasting legacy of saving lives from cancer.” Colleagues across the nation fondly remembered Dr. Wattenberg as a self-effacing teacher and scientist who rightly deserved recognition as the “Father of Chemoprevention.” He is survived by his wife of 70 years, Esther; four children; eight grandchildren; and a great-granddaughter. n

ASCOPost.com | MARCH 10, 2015

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In the News Infectious Disease

Measles Presents Greater Risks in Children Being Treated for Cancer By Charlotte Bath

easles outbreaks in the United States during 2014 and early 2015 have yielded an unprecedented number of cases nationwide, raising concerns about the threat measles poses to cancer patients (especially children) who may be at risk for severe complications and even death due to measles infection. “In normal children, measles is an acute viral respiratory illness characterized by a prodrome of high fever with cough, coryza, and conjunctivitis, known as ‘the three C’s,’ followed by the evolution of a pathognomonic enanthema (Koplik spots) in the oropharynx and a diffuse red maculopapular rash. Measles pneumonitis is the most feared complication, and it is associated with a high rate of mortality. As many as 1 in 20 children with measles may develop lung infection.” Alison G. Freifeld, MD, who specializes in infectious diseases in cancer patients, said in an interview with The ASCO Post. Dr. Freifeld is Professor in the Department of Internal Medicine at the University of Nebraska Medical Center, Omaha. “Measles encephalitis is also rare, occurring in 1 out of 1,000 cases, which can lead to seizures and mental deterioration. More common complications include otitis media, bronchopneumonia, laryngotracheobronchitis, and diarrhea,” Dr. Freifeld said.

At the University of Nebraska, we adhere to current guidelines advocating MMR vaccination at 24 months after autologous or allogeneic stem cell transplant in patients without chronic graft-vs-host disease or ongoing immune suppression. Earlier MMR vaccination may be advised in a measles outbreak setting, but data are limited in stem cell transplant recipients. —Alison G. Freifeld, MD

Children With ALL at Risk “In 2000, measles was declared eliminated in the United States. Since then, measles cases have ranged from as few as 37 in 2004 to 644 in the 2014 outbreak. The majority of cases have been among people who are not vaccinated against measles. Concerns now abound regarding the vulnerability of children with cancer who may contract the infection,” Dr. Freifeld said. “Prior to 2000, children with acute lymphocytic leukemia (ALL), in particular, were reported to develop severe and often fatal measles pneumonia.1

Children with ALL seem to be at particular risk for severe measles, due to the more frequent loss of protective antibodies postchemotherapy compared with childen who have other cancers.2 Profound chemotherapy-induced Bcell depletion may be linked to the measles risk,” she continued. “The most effective way to protect children with ALL is to ensure timely vaccination of their family members and community contacts with measles, mumps, rubella (MMR) vaccine. No case of vaccine strain virus transmission to cancer patients has ever been reported,” she noted.

Stem Cell Transplant Recipients and Measles Vaccine In a majority of stem cell transplant recipients, antigen-specific antibody titers, including those for measles, decline progressively over time posttransplant. Accordingly, a fixed schedule of vaccination is prescribed for all autologous and allogeneic stem cell transplant recipients. MMR and other live virus vaccination is not recommended until patients are considered immunologically competent: at least 2 years post–allogeneic transplant, off immunosuppression, and free of chronic graft-vs-host disease.3 During a measles outbreak in Brazil, 34 stem cell transplant patients not on immunosuppression were safely immunized between 1 and 2 years posttransplant, raising the question of whether this vaccine should be given earlier than 2 years in general. “Early vaccination with MMR would be of interest to explore in a multicenter protocol,” said Dr. Freifeld. “Determining if MMR is safe and immunogenic in some populations of post–stem cell transplant patients— for example autologous recipients— could be beneficial,” she commented. “Currently at the University of Nebraska transplant program, we assess measles titers for post–stem cell transcontinued on page 110

Expect Questions About Measles From Parents of Children With Cancer

ith the large outbreak of measles that has spread to more than a dozen states, questions from parents of children with cancer should be expected and encouraged. Parents should “talk to their physician about what the level of risk may be for their child who is undergoing cancer treatment (or has been previously treated) so that they have an understanding of how cocooned their child may or may not need to be,” Alison G. Freifeld, MD, told The ASCO Post. “I don’t want people to overreact, but on the other hand, we are dealing with dealing with immunosuppressed children who may be very susceptible to measles and its complications,” she said. Dr. Freifeld is a specialist in infectious diseases in cancer patients and Professor, Internal Medicine at the University of Nebraska Medical Center in Omaha. In allogeneic stem cell transplant recipients, measles (and other antigen-

specific) antibody titers wane with time after transplant, and patients may become susceptible to measles. The degree of risk is probably fairly low, but cases of severe disease are reported.1 Immunization against many vaccine-preventable diseases is standard after both autologous and allogeneic hematopoietic stem cell transplant. Dr. Freifeld noted.

Period of Vulnerability “The guidelines state that patients who have had allogeneic stem cell transplant can be vaccinated 2 years after the transplant as long as they are not still on immunosuppression for graftvs-host disease,” she continued. “At that point, live vaccines like measles, mumps, rubella are considered safe and most immunogenic. Until then, these patients are considered vulnerable to acquiring measles.” It is hard to guard against exposure to the measles virus. “It is such

a contagious virus, and patients who develop measles are considered infectious between 4 days before the development of rash until 4 days after the rash actually appears. So it is difficult to predict who is going to be carrying the virus and shedding it. Even if a measles patient is in a room and then leaves, the virus can still linger on surfaces for a couple of hours,” Dr. Freifeld said. If exposure to measles is suspected, patients with cancer who have not been vaccinated or revaccinated following a hematopoietic stem cell transplant should “strongly be considered for receiving postexposure prophylaxis with intravenous immunoglobulin given within 6 days of exposure,” Dr. Freifeld advised. Measles can also be more difficult to diagnose in children with cancer because “sometimes immunocom-

promised patients don’t develop the rash at all,” she added. With or without the rash, if measles is a possible diagnosis, then a throat, nasal or nasopharyngeal swab should be sent for detection of measles RNA by real-time polymerase chain reaction (RT-PCR). Dr. Freifeld advised physicians and parents to “be very aware of any outbreaks in their area. Pay attention to your local news.” And, she stressed, “be sure to vaccinate well children, because the vaccine is 97% effective.” n

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

Reference 1. Rubin LG, Levin MJ, Ljungman P, et al: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 58:309318, 2014.

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In the News Measles in Cancer Patients continued from page 109

plant patients seen for 1- and 2-year follow-up visits but are not performing active surveillance. We adhere to the current [American Society for Blood and Marrow Transplantation/Infectious Diseases Society of America] guidelines to reserve MMR for patients out 2 years

or more from stem cell transplant. However, if measles activity becomes more widespread in our region, we may need to consider early vaccination in some of our seronegative transplant patients who are out more than 1 year. Two MMR injections at least 2 months apart would be recommended to promote adequate responses,” stated Dr. Freifeld.

‘Hallmark’ Measles Rash May Not Develop Although a diffuse bright red maculopapular rash is characteristic of measles virus disease, as many as 30% of immunocompromised patients do not develop a rash.1 Identifying these patients is challenging and depends on clinical and epidemiologic clues. Chil-

dren being treated for ALL and other immunocompromised cancer patients who have unexplained pneumonitis or encephalitis should be tested for measles virus, if active cases have been confirmed in the region. “That makes it a real challenge,” Dr. Freifeld acknowledged, “because the rash, of course, is the hallmark of mea-

If Measles Was Declared ‘Eliminated’ in 2000, Why the Outbreak?

“I

n 2000, measles was declared eliminated from the United States,” according to the Centers for Disease Control and Prevention (CDC). That statement appeared in the same document reporting a large multistate outbreak of measles linked to an amusement park in California and that “has spread to more than a dozen other states.” The CDC explains: Elimination is defined as the absence of endemic measles virus transmission in a defined geographic area, such as a region or country, for 12 months or longer in the presence of a wellperforming surveillance system. However measles cases and outbreaks still occur every year in the United States because measles is still commonly transmitted in many parts of the world, including countries in Europe, Asia, the Pacific, and Africa. An estimated 20 million people become infected with measles worldwide each year, of whom 146,000 die. Since 2000, when measles was declared eliminated from the U.S., the annual number of cases has ranged from a low of 37 in 2004 to a high of 644 in 2014. The majority of cases have been among people who are not vaccinated against measles. Measles cases in the United States occur as a result of importations by people who were infected while in other countries and from transmission that may occur from those importations. Measles is more likely to spread and cause outbreaks in U.S. communities where groups of people are unvaccinated. n

The

cellence STARTS x e f o uit s r u p

WIT H

QO PI

ARE YOU READY TO BEGIN? Delivering high quality care is your #1 goal. The best way to accurately assess the quality of care you deliver is by participating in QOPI (Quality Oncology Practice Initiative). Developed by ASCO, QOPI is your resource for established quality measures based on published guidelines and expert consensus. QOPI provides a standardized process to routinely assess care, a secure web-based data submission and reporting system, and access to special improvement projects. PA R T I C I PAT E I N Q O P I TO : • Understand the care you provide relative to care guidelines and national benchmarks • Gather reliable information to guide improvement activities

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• Meet external quality reporting requirements • Move towards QOPI Certification Participate in QOPI and demonstrate your commitment to quality care. Get started at qopi.asco.org. qopi@asco.org 571-483-1660

Quality Cancer Care: Pursuing Excellence

ASCOPost.com | MARCH 10, 2015

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In the News

sles, and it is what we depend upon to make the diagnosis clinically. Evaluating whether family members or schoolmates have had a measles-like rash or illness may also be helpful. The patient should have serum IgM and IgG antibodies sent to assess immune status, and real-time polymerase chain reaction [RT-PCR] can identify the measles virus RNA in blood or bronchoscopy fluid for rapid diagnosis,” she said. “Laboratory confirmation is essential for all sporadic measles cases and all outbreaks. Detection of measlesspecific IgM antibody and measles RNA by RT-PCR are the most common methods for confirming measles infection,” according to the Centers for Disease Control and Prevention (CDC). Health-care providers should obtain

“both a serum sample and a throat swab (or nasopharyngeal swab) from patients suspected to have measles at first contact with them. Urine samples may also contain virus, and when feasible to do so, collecting both respiratory and urine samples can increase the likelihood of detecting measles virus.”4 There is no drug therapy for measles, Dr. Freifeld noted, only supportive care.

Postexposure Immunoglobulin According to the CDC, immunoglobulin should be administered to people who have been exposed to measles and are at risk for severe illness and complications from measles. This includes people with severely compromised immune systems, who do not yet have onset of measles symptoms.

“It would absolutely be a good idea to give immunoglobulin” to patients with cancer who have been exposed to measles but do not have symptoms, Dr. Freifeld said. She cited a study from the Cochrane Database that found that the risk of measles was up to 83% lower for nonimmune people receiving intramuscular or intravenous immunoglobulin within 7 days of exposure to measles.5 The investigation included 1 randomized trial, 2 quasirandomized trials, and 10 cohort studies involving a total of 3,925 participants. n

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

References 1. Kaplan LJ, Daum RS, Smaron M, et al: Severe measles in immunocompromised

patients. JAMA 267:1237-1241, 1992. 2. Bochennek K, Allwinn R, Langer R, et al: Differential loss of humoral immunity against measles, mumps, rubella and varicella-zoster virus in children treated for cancer. Vaccine 32:3357-3361, 2014. 3. Rubin LG, Levin MJ, Ljungman P, et al: 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 58:309-318, 2014. 4. Centers for Disease Control and Prevention: Measles (rubeola): For healthcare professionals (updated February 9, 2015). Available at www.cdc.gov/measles/hcp/. Accessed February 11, 2015. 5. Young MK, Nimmo GR, Cripps AW, et al: Post-exposure passive immunisation for preventing measles. Cochrane Database Syst Rev 4:CD010056, 2014.

Dianne Knight, MD, Awarded Fellow Status from the American Academy of Hospice and Palliative Medicine

ianne Knight, MD, Physician in the Supportive Care Medicine Department at Moffitt Cancer Center, has been honored with the designation of Fellow of the American Academy of Hospice and Palliative Medicine. The Academy is the professional organization for physicians and other health care professionals committed to improving the care of patients with serious or lifethreatening conditions.

Dianne Knight, MD

Advancement to fellowship status within the Academy honors dedication and scholarship in the field of hospice and palliative medicine. Dr. Knight received the designation at the Annual Assembly of the American Academy of Hospice and Palliative Medicine in Philadelphia. At Moffitt, Dr. Knight manages distressing symptoms in patients with cancer, with the goal of rapid alleviation of

patient discomfort. She is part of an interdisciplinary team that focuses on patient and family understanding of treatment options, emotional and spiritual support, and care planning. Dr. Knight received her MD from the University of Miami School of Medicine. She completed a pediatric residency at Orlando Regional Medical Center, and is board certified in Pediatrics and Hospice and Palliative Medicine. n

The Marquette Harbor Lighthouse, on Lake Superior’s South Shore, Michigan Photo by Steve Gualdoni, PA-C, UP Health System – Marquette Hematology Oncology, Marquette, MI. Send your high-resolution digital photo with caption to editor@ASCOPost.com.

The ASCO Post | MARCH 10, 2015

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In the Literature

Emerging Clinical Data on Cancer Management OVARIAN CANCER High-Quality Diet Before Ovarian Cancer Diagnosis May Lengthen Survival An overall high-quality diet at least 12 months before a diagnosis of ovarian cancer “was associated with a statistically significant 27% lower risk of death after ovarian cancer,” an analysis of dietary data from the Women’s Health Initiative showed. The protective effect was strongest among women with a waist circumference of less than or equal to 88 cm and no history of diabetes. “Physical activity level did not modify the association between diet quality and survival,” Cynthia A. Thomson, PhD, RD, of the University of Arizona in Tucson, and colleagues reported in the Journal of the National Cancer Institute. “We identified 636 centrally adjudicated cases of ovarian cancer within the Women’s Health Initiative Observational Study or Clinical Trials of 161,808 postmenopausal women followed from 1995 to 2012,” the authors explained. Dietary quality was selfreported and calculated according to the Healthy Eating Index (HEI-2005). Women were diagnosed with ovarian cancer at a mean age of 62.9 years. “The most important finding was the marked 27% lower risk of mortality after ovarian cancer diagnosis in women who reported higher overall dietary quality (tertile 3) compared with the lowest score (tertile 1),” the investigators noted. The hazard ratio (HR) for the highest vs lowest tertile was 0.73 (95% CI = 0.55–0.97, Ptrend = .03). “The association between the Healthy Eating Index and ovarian cancer–specific mortality was similar but attenuated (HR for the highest vs lowest tertile = 0.75; 95% CI = 0.55–1.01; Ptrend = .06),” the researchers added. No association was found between morality after ovarian cancer and any of the individual dietary components, such as total fruits, vegetables, grains, meats, oils, sugars, or alcoholic beverages, “suggesting that it is the overall dietary pattern that is relevant,” the investigators noted. After adjusting for age and stage of disease, all-cause mortality was higher in black women than in nonHispanic white women. Women with a waist circumference of at least 88 cm and those with a previous diagno-

sis of diabetes had significantly higher risks of death. “A large (N = 1,070) randomized, controlled trial is currently underway to test the hypothesis that dietary changes toward a higher Healthy

Eating Index, along with physical activity, adopted after treatment for stages II to IV ovarian cancer will improve progression-free survival (NCT00719303),” the authors reported. Whether changing diet to in-

2015

crease the diet-quality score after an ovarian cancer diagnosis would offer improvements in mortality has yet to be determined.” Thomson CA, et al: J Natl Cancer Inst 106(11):dju314, 2014.

Annual Conference

ADVANCING THE STANDARD OF CANCER CARE TM

March 12 – 14, 2015 • The Diplomat • Hollywood, Florida

NCCN celebrates 20 years!

EARN UP TO

15 CME/CE CREDITS!

Commemorative Events: Thursday, March 12, 2015 • Keynote Address: 20 Years of Improving the Quality, Effectiveness, and Efficiency of Cancer Care CME/CE credits are not available for this session.

Robert W. Carlson, MD, CEO, NCCN

• 20 Years of Improving Cancer Care Together— An NCCN Roundtable Discussion CME/CE credits are not available for this session.

Moderator: Clifford Goodman, PhD, The Lewin Group

• Welcome Reception (Exhibition Hall) Join NCCN for a reception in celebration of our 20th Anniversary.

New for 2015! Customize your learning with Track Sessions throughout the conference.

Track Session Topics: Breast Cancer Lung Cancer Hematologic Malignancies

Friday, March 13, 2015 • Roundtable: Value-Based Decision-Making at the Bedside Moderator: Clifford Goodman, PhD, The Lewin Group

Skin Cancer Gastrointestinal Cancer

Saturday, March 14, 2015

Genitourinary Cancer

• Roundtable: What are the Characteristics of an Optimal Clinical Practice Guideline?

Supportive Care

Moderator: F. Marc Stewart, MD, Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance

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In the Literature

COLON CANCER Racial Disparities in Survival Related More to Health Differences at Diagnosis Than to Subsequent Treatment The persistent disparity in colon cancer survival by race seemed to be related more to differences in health at diagnosis than to differences in subsequent treatment, according to an analysis of data from the Survey, Epidemiology, and End Results (SEER)–Medicare database. “Our study suggests that the most effective route to reducing the racial survival disparity is to find ways to reduce the disparity in presentation, so fewer black patients present with advanced disease,” Jeffrey H. Silber, MD, PhD, of the Center for Outcomes Research, The Children’s Hospital of Philadelphia, and colleagues wrote in the Annals of Internal Medicine. The investigators obtained SEER– Medicare data for 1991 to 2005 for 16 SEER sites throughout the United States (including all sites except the Alaska Native Tumor Registry). A total of 7,677 black patients aged 65 years or older diagnosed with colon cancer were matched with three successive sets of 7,677 white patients with colon cancer, first on the basis of demographic characteristics, next on presentation, and then on treatment. “The three matches sequentially removed aspects of the disparity while leaving other aspects in place, so we could develop an understanding of how the disparity occurs,” the investigators noted. The demographic characteristics match controlled for age, gender, diagnosis year, and SEER site and showed an absolute difference in 5-year survival between black and white patients of 9.9% (95% CI, 8.3%–11.4%; P < .001), which remained unchanged between 1991 and 2005. This represented a difference in median survival of 19 months. The presentation match controlled for demographic characteristics plus comorbid conditions and tumor characteristics, including stage and grade, decreased the 5-year survival difference to 4.9% (CI, 3.6%–6.1%; P < .001), or a difference in median survival of 8 months. The treatment match included presentation variables plus details of surgery, radiation, and chemotherapy and decreased the 5-year survival difference to 4.3% (CI, 2.9%–5.5%; P <􏰂.001), or a difference in median survival of 7 months. “The disparity in survival attributed to treatment differences made up only an absolute 0.6% of the

overall 9.9% survival disparity,” the investigators noted. “The residual disparity in the treatment match is similar to the 5-year survival disparity between black and white patients in the U.S. population as a whole,” the authors observed. “Although similar, we do not suggest that this is acceptable.” Silber JH, et al: Ann Intern Med 161:845-854, 2014.

CUTANEOUS ADVERSE EVENTS Cutaneous Adverse Effects Associated With Tyrosine Kinase Inhibitors May Impact Quality of Life and Adherence to Treatment Tyrosine kinase inhibitors “are associated with numerous adverse effects, many of which are cutaneous and can affect patients’ quality of life and impede their adherence to long- term treatment,” National Cancer Institute (NCI) investigators concluded after studying the adverse effects of the tyrosine kinase inhibitor cabozantinib (Cometriq) and comparing them with the effects of other tyrosine kinase inhibitors, such as sunitinib (Sutent) and sorafenib (Nexavar). “Clinical phase I and II trials of cabozantinib have been conducted in various malignant neoplasms including medullary thyroid, gastric, renal cell, pancreatic, and prostate cancers. A randomized, placebo-controlled, phase II study has been completed in patients with castrate-refractory prostate cancer, and phase III trials are ongoing in renal cell carcinoma, prostate cancer, and hepatocellular carcinoma. A phase III trial involving 330 patients with medullary thyroid cancer demonstrated improvement in median progression-free survival to 11.2 months vs 4 months with placebo,” the investigators reported. Cabozantinib is also under investigation for treatment of urothelial carcinoma, and the authors described the development of skin reactions to cabozantinib among 41 consecutive adults with metastatic, progressive urothelial carcinoma enrolled in an NCI open-label, nonrandomized, phase II clinical trial. One or more cutaneous toxic effects occurred in 30 of the 41 patients (73%). The most common adverse effect was hand-foot skin reaction, which occurred in 22 patients (54%). Hand-foot skin reaction “is a frequently observed sequela of conventional chemotherapeutic agents and typically improves on treatment cessation,” the authors noted,

but “tyrosine kinase inhibitors are typically prescribed for long-term treatment, and, as a result, hand-foot skin reaction has become a major management issue in the use of these therapies.” Hand-foot skin reaction is the most common cutaneous toxic effect seen with sorafenib and sunitinib, the authors pointed out, and “the median onset of hand-foot skin reaction in our cohort (4 weeks) is comparable to the onset of hand-foot skin reaction associated with sorafenib (2–4 weeks) and sunitinib (4–12 weeks).” Although hand-foot skin reaction has been associated with a favorable outcome in patients receiving sorafenib, studies are needed to determine whether handfoot skin reaction is a biomarker of clinical outcome in patients receiving cabozantinib. “Current therapeutic recommendations for hand-foot skin reaction are primarily based on case reports and series owing to a lack of clinical trial data. Dose modification or drug discontinuation usually leads to rapid improvement of painful lesions but at the potential expense of cancer response,” the researchers stated. Patients should be advised to avoid mechanical trauma to the skin, such as from intense exercise; friction from tightly fitted shoes, gloves, or clothing; and extreme hot or cold temperatures. Generalized pigment dilution and/ or hair depigmentation occurred in 18 patients (44%) in the cabozantinib study, and the authors noted “hair and skin depigmentation is also observed in association with sunitinib and imatinib.” Depigmentation is usually reversible within a few weeks of discontinuation of therapy.

“Xerosis was also noted in our series in 8 patients (20%) and is a well-recognized phenomenon in association with sorafenib (10%–20%) and sunitinib (16%). In our cohort, xerosis primarily affected the distal extremities, and all patients with xerosis also developed hand-foot skin reaction,” the researchers wrote. “Frequent application of emollients with urea, 5% to 10%, usually results in improvement of xerosis.” Scrotal erythema/ulceration occurred in 6 patients (15%) in the cabozantinib study and has been noted in case reports of patients treated with sunitinib and sorafenib. “Scrotal erythema/ulceration in our cohort was managed with treatment interruption and supportive approaches. Physicians should be aware that this adverse effect may be underrecognized and should be alert that patients may be hesitant to mention genital or perianal symptoms,” the authors advised. “Subungual splinter hemorrhages were observed in five patients (12%) in our cohort and are frequently seen with tyrosine kinase inhibitors that block vascular endothelial growth factor receptor function, particularly sunitinib and sorafenib,” the investigators noted. The splinter hemorrhages did not require treatment. The researchers concluded that it is crucial for dermatologists to be familiar with skin reactions associated with tyrosine kinase inhibitors and for dermatologists and oncologists to work together to manage these symptoms. n Zuo RC, et al: JAMA Dermatol 151:170-177, 2015. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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Issues in Oncology Peter Paul Yu, MD, FACP, FASCO continued from page 1

and to increase research on the genetic mechanisms that lead to cancer and other diseases.

Broader Innovations Needed The President’s proposal is hugely welcome, and ASCO hopes that it will find bipartisan support in Congress. Federal research financing has driven extraordinary medical progress, and these new investments could yield important new knowledge. Along with new research, however, broader innovations are needed. In fact, the full potential of precision medicine will be realized only if we rethink how we collect, analyze, and learn from all of the cancer care that patients receive, whether at major clinical trial sites or in small oncology practices across the country. It will require creating digital health systems that support population health; the identification of special populations of cancer patients based on clinical and molecular characteristics and aggregation of data across such populations. We all recognize that too few of our patients participate in clinical trials— just about 3%, in fact. That pool of patients is not just small. It’s also not rep-

resentative of many of the patients we see in our practices every day—patients who are often older or less healthy than the people who are eligible for trials. Meanwhile, most cancer doctors already find it difficult, if not impossible, to constantly review and interpret new research findings and rapidly incorporate this knowledge into day-to-day care. Over time, the President’s new initiative will produce even more information for physicians to track, understand, and apply. Put simply, cancer doctors need more: We need more information to inform the care of our patients, and we need more support to make sense of it all.

CancerLinQ Will Transform Cancer Care That’s why ASCO is building CancerLinQ™, an ambitious “big data” initiative to transform cancer care and improve patient outcomes through the generation of new knowledge based on real-world patients and learning tools that aid in the application of that knowledge to patient care. When complete, it will seamlessly and securely aggregate and analyze data from electronic health records and other sources in order to do three things: CancerLinQ will provide clinical decision support to help physicians

Peter Paul Yu, MD, FACP, FASCO, Director of Cancer Research, Palo Alto Medical Foundation

choose the right therapy at the right time for each patient. This functionality will draw on published guidelines from ASCO and other expert groups and eventually on conclusions drawn from real-world patient care. The system will provide rapid, quality feedback to allow providers to compare their care against guidelines and against the care of their peers. We will be able to see, right away, if there are ways to improve the care we’re provid-

ly be available to all oncology practices in the United States, no matter their affiliations or choice of electronic health record systems. As excited as we are about CancerLinQ’s progress and potential, important challenges lie ahead. For one, CancerLinQ is an extremely ambitious and complex technical project. We will need to overcome a host of technological challenges as we seek to build a platform that is powerful, versatile, and easy to use.

The promise of CancerLinQ is, at its core, the promise of precision medicine. More than ever, our nation is expecting us to deliver on this promise. —Peter Paul Yu, MD, FACP, FASCO

ing and to monitor that care in real time as we work to close those gaps. CancerLinQ’s analytic tools will help improve care by uncovering hidden patterns in patient characteristics, treatments, and outcomes. These kinds of insights will generate strong new hypotheses for clinical research and help us improve trial designs.

Rollout Later This Year Building this system will take several years and require substantial, ongoing investments. But I believe that CancerLinQ is well on its way to becoming the platform of choice for oncologists by the end of this decade. We recently announced that CancerLinQ will be built on a big data software platform developed by SAP, a leading data processing and database management company. This technology, known as HANA, is already being used by thousands of institutions worldwide, including many health and medical organizations. With the technology platform selected, we are on a fast track to roll out the first version of CancerLinQ by the end of this year with at least 12 oncology practices nationwide, which collectively serve about 500,000 cancer patients. Insights from this first phase will allow us to develop smarter, more advanced versions, which will ultimate-

Like any health data initiative, CancerLinQ will need to guarantee the security and privacy of patient information. We are deeply committed to doing so and have engaged patient advisors and other experts to make sure we maintain patients’ trust every step of the way.

Fulfilling the Promise of Precision Medicine There are also a number of other health data initiatives competing for oncologists’ attention and patients’ data. As the only nonprofit, physicianled initiative in this arena, I believe CancerLinQ is well positioned to succeed. But its impact on patient care will ultimately depend on the participation of ASCO’s members and other physicians nationwide. In the coming months, we will have exciting news and updates to share as we continue to bring CancerLinQ from vision to reality. I invite you to visit our newly revamped website, CancerLinQ. org, for more information. More important, I ask my fellow oncologists to join us as we roll out CancerLinQ in the years ahead. The promise of CancerLinQ is, at its core, the promise of precision medicine. More than ever, our nation is expecting us to deliver on this promise. n Disclosure: Dr. Yu is the President of ASCO for 2014–2015.

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Residual disease in myeloma goes deep.1-5 shouldn’t we stRive to go deepeR? Even after achieving complete response, myeloma cells can persist.1-5 It’s time to reconsider the way we approach myeloma: Growing evidence supports using a long-term treatment approach for continuous disease suppression and improved outcomes.6-8 Proteasomes regulate intracellular protein degradation. Their inhibition induces endoplasmic reticulum stress within myeloma cells and impacts support mechanisms within the bone marrow microenvironment.9-11 At Takeda, we’re committed to achieving a deeper understanding of multiple myeloma and helping to address the challenges patients face today and tomorrow.

ReFeRenCes: 1. Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol. 2013;31(20):2540-2547. 2. Paiva B, Vidriales MB, Cerveró J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112(10):4017-4023. 3. Biran N, Ely S, Chari A. Controversies in the assessment of minimal residual disease in multiple myeloma: clinical significance of minimal residual disease negativity using highly sensitive techniques [published online ahead of print September 16, 2014]. Curr Hematol Malig Rep. doi:10.1007/s11899-014-0237-y. 4. Munshi NC, Anderson KC. Minimal residual disease in multiple myeloma. J Clin Oncol. 2013;31(20):2523-2526. 5. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014;123(20):3073-3079. 6. Palumbo A, Niesvizky R. Sustained disease control in transplant-ineligible patients: the role of continuous therapy. Leuk Res. 2012;36(suppl 1):S19-S26. 7. Girnius S, Munshi NC. Challenges in multiple myeloma diagnosis and treatment. Leuk Suppl. 2013;2(suppl):S3-S9. 8. Palumbo A, Gay F, Musto P, et al. Continuous treatment (CT) versus fixed duration of therapy (FDT) in newly diagnosed myeloma patients: PFS1, PFS2, OS endpoints. J Clin Oncol. 32:5s, 2014 (suppl; abstr 8515). 9. Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004;4(5):349-360. 10. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10(11):2034-2042. 11. Borrello I. Can we change the disease biology of multiple myeloma? Leuk Res. 2012;36(suppl 1):S3-S12. Takeda Oncology and are registered trademarks of Takeda Pharmaceutical Company Limited. Other trademarks are the property of their respective owners. Copyright © 2015, Millennium Pharmaceuticals, Inc.

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