TAP Vol 5 Issue 16 by Harborside Press LLC

Rituximab Retreatment vs Maintenance

| The Mentor/Mentee Relationship

126, 127

| Years of Progress

146

VOLUME 5, ISSUE 16

OCTOBER 15, 2014

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

ASTRO Annual Meeting

Chest Radiation Improves Survival and Intrathoracic Recurrence Rates in Extended-Stage Small Cell Lung Cancer

Relevance of the Hippocratic Oath in the 21st Century By Hagop Kantarjian, MD, and David P. Steensma, MD

By Alice Goodman

horacic radiotherapy extended progression-free survival, reduced intrathoracic recurrences, and improved overall survival at 2 years when added to prophylactic cranial irradiation in patients with extended-stage small cell lung cancer in an international randomized controlled trial.1 “Thoracic radiation should be added to prophylactic cranial irradiation and be offered to all extendedstage small cell lung cancer patients with a response to initial chemotherapy to improve outcomes,” stated lead author Ben Slotman, MD, Professor and Chairman of Radiation Oncology at VU University Medical Center, Amsterdam. Dr. Slotman presented these results at the 56th Annual Meeting of the American Society for Radiation Oncology (ASTRO) in San Francisco. The work was simultaneously published in The Lancet. 2

CREST Trial The multinational CREST trial enrolled 498 patients with extendedstage small cell lung cancer who had a complete, partial, or good response to initial platinum/etoposide chemotherapy. Patients Ben Slotman, MD were randomly assigned 1:1 to receive prophylactic cranial irradiation with or without thoracic radiotherapy within 2 to 7 weeks of chemotherapy. Thoracic radiotherapy was delivered in 10 fractions of 3 Gy. “We know prophylactic cranial irradiation improves symptomatic brain metastases and overall survival at 1 year. We also know that persistent intrathoraccontinued on page 4

Best of ASCO

Health-Care Reform Is Changing the Oncology Landscape alue-based health-care reform is happening. We have to get on board,” Rena Conti, PhD, a health economist at the University of Chicago, advised attendees of the Best of ASCO Seattle meeting. She discussed highlights from Annual Meeting sessions that addressed the impact of the Affordable Care Act on the field of oncology and on disparities in care.1,2

n the face of it, the idea that a code of professional conduct dating to the ancient Iron Age could possibly retain any relevance in the current era of “Big Data,” religious and cultural pluralism, trillion-dollar government budgets, and nanotechnology seems preposterous. Yet the well-publicized challenges of contemporary health care mean that the ideals of the Hippocratic Oath (see sidebar on page 104)1— continued on page 101

Dr. Kantarjian is Chairman of the Leukemia Department at The University of Texas MD Anderson Cancer Center and a Baker Institute Scholar for Health Policies at Rice University, Houston. Dr. Steensma is a physician in the Dana-Farber Cancer Institute Adult Leukemia Program and Associate Professor of Medicine at Harvard Medical School, Boston. Disclaimer: This commentary represents the views of the authors and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE

By Susan London

“V

Imperative for Reform

High and persistently rising national spending on cancer care underscores the urgent need for reform, according to Dr. Conti. “Spending on cancer care outpaces [gross domestic product] growth in the United States, but also spending growth in health care more generally,” she noted. Contributors to this phenomenon include agWe can keep the current system ing of the population and as it is, but we need to make breakthroughs in therapy in the past few decades. reimbursement more closely match While survival for the acquisition costs of these drugs, many cancers has improved in recent decades, essentially wringing out the profit overuse and underuse of that chemotherapy provides in the effective cancer treatments also coexist in our system. outpatient setting. There are also stark racial —Rena Conti, PhD

Oncology Meetings Coverage ASTRO Annual Meeting ....... 3–6, 15–21 Best of ASCO .................................... 21–28 Debates and Didactics in Hematology/Oncology .......................30, 34 Breast Cancer Symposium ............... 38–53 Eileen M. O’Reilly, MD, on Pancreatic Cancer .......................................54 D. Ross Camidge, MD, PhD, on REVEL Trial in NSCLC .......................56 David Fishman, MD, on Preventing Ovarian Cancer ........................69 Direct From ASCO ........................ 97–100 George D. Demetri, MD, on Sarcoma 2014 .......................................117

continued on page 27

October Is Breast Cancer Awareness Month

A Harborside Press® Publication

The ASCO Post | OCTOBER 15, 2014

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

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ASCOPost.com | OCTOBER 15, 2014

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ASTRO Annual Meeting Thoracic Oncology

Stereotactic Body Radiation Therapy Benefits Patients With Early-Stage Inoperable or Advanced Oligometastatic Lung Cancer By Alice Goodman

he door is open for expanded use of stereotactic body radiation therapy (SBRT) in patients with inoperable early-stage lung cancer and for patients with oligometastatic stage IV non-small cell lung cancer (NSCLC), according to results of two studies presented at the 56th Annual Meeting of the American Society for Radiation Oncology (ASTRO).

Early-Stage Inoperable Lung Cancer In one of the two studies, a cooperative group trial (RTOG 0236) using stereotactic body radiation therapy (SBRT), 5-year follow-up of a cohort of 59 frail elderly patients with inoperable lung cancer showed a low recurrence rate at the primary tumor site (the radiated field) and no progressive late toxicity.1 These findings confirmed and extended 3-year results presented

earlier at the 2009 ASTRO Annual Meeting and published in JAMA,2 noted lead author Robert Timmerman, MD, Professor and Vice-Chair of the Department of Radiation Oncology at the University of Texas Southwestern Medical Center in Dallas. Dr. Timmerman noted that SBRT has not been universally adopted in this setting despite the positive results presented earlier because of concerns about late toxicity. He indicated that these longer-term data could shift the standard of care to SBRT for patients with early-stage inoperable lung cancer.

Oligometastatic NSCLC A second study was a large, international, individual patient data metaanalysis showing that SBRT or surgery can achieve long-term survival in some patients with oligometastatic stage IV NSCLC (ie, only a few metastatic le-

This study [RTOG 0236] should hold weight because it was done within the cooperative groups and the data were presented at [major oncology] meetings. The original data were practice-changing, and these longer-term results are more practice-changing. —Robert Timmerman, MD

sions, primarily in the lung and brain).3 Results of this study were used to develop a risk-stratification model that could prove helpful in identifying which patients are the best candidates for SBRT or surgery. “We observed a 29.4% 5-year overall survival, which is much higher than what is usually seen in stage IV patients. In our study,4 which included patients

with one to five metastatic sites, we found that the longest survival was associated with metachronous metastases [appearing after the original lung cancer],” said lead author Allison Ashworth, MD, a Radiation Oncologist who completed the study as part of her training at the London Health Sciences Centre at Western University in London, Ontario, Canada.

EXPERT POINT OF VIEW

enjamin Movsas, MD, Chair of Radiation Oncology at Henry Ford Hospital in Detroit, served as moderator at a press conference where the two SBRT studies by Timmerman et al and Ashworth et al were reported.1,2 Dr. Movsas said that SBRT is a promising approach, noting that the therapy facilitates delivery of precise local radiation therapy which

ily for patients with medically inoperable lung cancer. “However, we also offer SBRT as a secondary alternative for patients who decline surgery. These cases are presented to a multidisciplinary tumor board,” he said. Dr. Movsas said that an estimated 40% to 50% of all centers in the United States are poised to use SBRT. “The data from both of these stud-

[Stereotactic body radiation therapy] is a complex treatment requiring physics support and imaging, but it opens a completely new therapeutic strategy for patients with no other options. —Benjamin Movsas, MD

is generally well tolerated. For example, Dr. Movsas said “I treated one of my NSCLC patients with SBRT when he was 85 years old; he is now 88 years old and playing golf. This patient, and those in Dr. Timmerman’s trial, would never have had surgery.” Dr. Movsas noted that at Henry Ford Hospital SBRT is used primar-

ies should help guide radiation oncologists as to which patients would be most likely to benefit from SBRT,” Dr. Movsas said. “SBRT is a complex treatment requiring physics support and imaging, but it opens a completely new therapeutic strategy for patients with no other options,” Dr. Movsas said.

“This is an opportunity to expand the use of SBRT to appropriately selected patients. We have the technology and can thoughtfully apply it. However, there may be several treatment options and we need to be careful to offer the right treatment. That’s why multidisciplinary tumor boards are so important,” Dr. Movsas stated. “A decade ago, patients would get radiation once a day 5 days per week for 7 weeks. SBRT is offered in three precise treatments. The 5-year survival [in Dr. Ashworth’s study] is a very positive result, and we still want to improve on that,” he said. n Disclosure: Dr. Movsas reported no potential conflicts of interest.

References 1. Timmerman R, Hu C, Michalski J, et al: Long-term results of RTOG 0236: A phase II trial of SBRT in the treatment of patients with medically inoperable stage I non-small cell lung cancer. 56th Annual Meeting of ASTRO. Abstract 56. Presented September 15, 2014. 2. Ashworth AB, Senan S, Palma DA, et al: Can we identify long-term, survivors in oligometastatic non-small cell lung cancer? ASTRO Annual Meeting. Presented September 16, 2014. Abstract 168.

Allison Ashworth, MD

“We hope this study will be used to select which patients with stage IV NSCLC are most likely to benefit from aggressive treatments,” Dr. Ashworth said. “One limitation of our study is a selection bias with younger, healthier patients than those typically diagnosed with stage IV NSCLC. Ultimately, we need randomized clinical trials to determine whether the longer survival is due to the treatments or because the patients have less aggressive disease,” she added.

RTOG 0236 The phase II trial reported by Dr. Timmerman was conducted from May 2004 until October 2006 and included 59 frail elderly patients with medically inoperable stage I NSCLC (median age, 72). These patients had multiple comorbidities that precluded surgery. All patients received SBRT in three fractions of 18 Gy (total of 54 Gy) over continued on page 4

The ASCO Post | OCTOBER 15, 2014

PAGE 4

ASTRO Annual Meeting SBRT in Lung Cancer continued from page 3

1.5 to 2 weeks. SBRT requires image guidance to deliver high doses of radiation to the tumor site in less time than standard radiation, minimizing exposure to healthy tissues. At 5 years, the rates of disease-free survival and overall survival were 26% and 40%, respectively. Median overall survival was 4 years. “Primary tumor recurrence in the treated area remained very low owing to the potent SBRT regimen,” Dr. Timmerman said. Four patients had recurrences at the primary tumor site, yielding an estimated 5-year primary tumor failure rate of 7%; nine additional patients had recurrences within the involved lobe, posing a 5-year primary tumor and involved lobe (local) failure rate of 20%. The 5-year local-regional failure rate was 38% (n = 7); 5-year disseminated failure rate was 31% (n = 15). These failures occurred mostly at untreated sites, Dr. Timmerman noted. Treatment-related grade 3 and 4 adverse events occurred in 17 patients, which was similar to the initial report at 3 years’ follow-up. Dr. Timmerman noted that the fact that severe toxicity remained relatively unchanged with longer follow-up should allay concerns about increased long-term toxicity with SBRT.

CREST Trial continued from page 1

ic disease is seen in about three-quarters of extended-stage small cell lung cancer patients and intrathoracic progression in almost 90%,” Dr. Slotman told listeners. The present study was conducted to see if thoracic radiotherapy could improve intrathoracic and general outcomes. No significant differences in baseline characteristics were seen between the two groups. Median age was 63 years; 55% were male and 45% were female. Median follow-up was 24 months. Eighty-nine percent of all patients were World Health Organization (WHO) performance status 0 or 1. Eighty-eight percent had persistent intrathoracic disease after chemotherapy. Additionally, no significant differences in grades 3 and 4 toxicities were observed between the two treatment arms.

Survival and Recurrence Data Over the first 9 to 12 months following treatment, survival curves were similar for the two arms, Dr. Slotman said. But by 24 months, survival was 13% in the group treated with thoracic radiotherapy vs 3% for prophylactic cranial

“This study [RTOG 0236] should hold weight because it was done within the cooperative groups and the data were presented at [major oncology] meetings. The original data were practice-changing, and these longer-term results are more practice-changing,” Dr. Timmerman said. A phase III trial comparing SBRT to surgery for operable patients will be done as a multicenter, multinational trial through the ACCRU Foundation (an affiliate of the National Institutes of Health cooperative group Alliance), and at the University of Texas Southwestern Medical Center in Dallas. “We want to get high-level evidence in operable patients,” Dr. Timmerman said.

Individual Patient Data The individual patient data metaanalysis reported by Dr. Ashworth included 757 patients diagnosed with stage IV NSCLC at 20 cancer centers worldwide. All patients had one to five oligometastases treated with surgery and SBRT; in all cases, the original lung tumor was treated aggressively. Overall survival at 5 years was 29.4%, which is higher than typical for stage IV patients. Factors that predicted for survival included synchronous vs metachronous metastasis and presence of nodal disease, she said. Based on these results, the following irradiation alone (P = .004). Subgroup analysis showed no significant differences in the effect of thoracic radiotherapy in survival related to age, degree of response to chemotherapy, or WHO status. Progression-free survival was significantly longer in the group receiving thoracic radiotherapy, with a 27% reduced risk of recurrence compared with prophylactic cranial irradiation alone (P = .001). Among all patients, the rate of intrathoracic progression was 43.7% in the thoracic radiotherapy group vs 79.8% in the prophylactic cranial irradiation-only group (P < .001). Intrathoracic progression as the first site of relapse was observed in 41.7% and 77.8%, respectively (P < .001). Intrathoracic progression was the only site of progression in 19.8% and 46% of patients, respectively (P < .001). Progression elsewhere, with or without progression in the thorax or brain, occurred in 60.3% of the thoracic radiotherapy group compared to 40.3% in the prophylactic cranial irradiation–alone group (P < .001). There was no significant difference between treatment arms in the risk of brain metastasis as site of first relapse.

Stereotactic Body Radiation Therapy for Non–Small Cell Lung Cancer ■ Stereotactic body radiation therapy (SBRT) improved overall survival in frail elderly patients with inoperable early-stage lung cancer. ■ SBRT improved survival in patients with stage IV NSCLC with few metastases, particularly those patients with metachronous metastases and no nodal involvement. Appropriate treatment for these patients should be discussed by a multidisciplinary tumor board.

risk stratification model was developed for survival: • Low risk/best survival: metachronous metastases (5-year overall survival of 47.5%) • Intermediate risk: synchronous metastases and node negativity (5-year overall survival 36.2%) • High-risk/worst survival: synchronous metastases and node positivity (5-year overall survival of 13.8%). Dr. Ashworth noted that the most appropriate treatment for these patients should be discussed by a multidisciplinary tumor board. “Selection of patients for the right treatment is critical.… This study should help pave the way for optimal treatment selection for this group of patients,” Dr. Ashworth said. n Disclosure: Dr. Timmerman’s institution has a research grant to study image-guided hypofractionated radiotherapy from Varian Medical Systems, for which he is a principal

investigator. Dr. Ashworth reported no potential conflicts of interest.

References 1. Timmerman R, Hu C, Michalski J, et al: Long-term results of RTOG 0236: A phase II trial of SBRT in the treatment of patients with medically inoperable stage I non-small cell lung cancer. ASTRO Annual Meeting. Abstract 56. Presented September 15, 2014. 2. Timmerman R, Paulus R, Choy H: SBRT for early stage lung cancer. JAMA 303:1070-1076, 2010. 3. Ashworth AB, Senan S, Palma DA, et al: Can we identify long-term, survivors in oligometastatic non-small cell lung cancer? ASTRO Annual Meeting. Presented September 16, 2014. Abstract 168. 4. Ashworth AB, Senan S, Palma DA, et al: An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non–small-cell lung cancer. Clin Lung Cancer 15:346-355, 2014.

EXPERT POINT OF VIEW

ommenting on this study, Benjamin Movsas, MD, of Henry Ford Hospital in Detroit, said that the CREST study confirmed the value of adding a short course of thoracic radiotherapy to patients with metastatic extended-stage small cell lung cancer who responded to initial chemotherapy. “Adding radiation to the chest extended survival. These results show that local radiation therapy not only improves local control but also improves overall survival. These patients may not typically get thoracic radiation, because it is not the standard of care. The study results should change that paradigm,” Dr. Movsas said. “In the past, we have considered patients with an excellent response to chemotherapy for radiation. This study extends the benefits of thoracic radiation to any patient with some response to chemotherapy, because they have a survival benefit,” he continued. “This message is important for both radiation oncologists and medical oncologists. Extended-stage small cell lung cancer should be managed in a multidisciplinary setting,” Dr. Movsas stated. n Disclosure: Dr. Movsas reported no potential conflicts of interest.

Dr. Slotman said that the higher rate of progression outside the thorax in the thoracic radiotherapy arm warrants studies on consolidative radiation therapy to other sites of distant disease. n Disclosure: Dr. Slotman reported no potential conflicts of interest.

References 1. Slotman B, Faivre-Finn C, van Tinteren H, et al: ASTRO Annual Meeting.Abstract CT-05. Presented Sept 14, 2014. 2. Slotman BJ, van Tinteren H, Praag JO, et al: Lancet. Sept 12, 2014 (early release online).

ASCOPost.com | OCTOBER 15, 2014

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ASTRO Annual Meeting Hematology

Radiation Therapy Improves 10-Year Survival for Patients With Early Hodgkin Lymphoma, but Frequently Omitted in Treatment Plans Study Reveals Gaps in Care of Early-Stage Disease By Alice Goodman

dding consolidation radiation therapy to chemotherapy significantly improves 10-year survival in patients with stage I and II Hodgkin lymphoma, according to a large observational study based on the National Cancer Database (NCDB). Yet over that same 10-year period, radiation therapy use declined by 15%, and oncologists are not including radiation therapy as part of the treatment plan. The findings were presented at the American Society for Radiation Oncology’s 56th Annual Meeting in San Francisco.1

‘Practice-Changing’ Findings The study shows that early-stage Hodgkin lymphoma patients with higher socioeconomic status, health insurance, and treatment at comprehensive cancer centers are more likely to get radiation therapy as part of management than their counterparts. The authors hope that the message from this study will affect clinical management of this potentially curable disease. “The standard of care for treatment of early-stage Hodgkin lymphoma is combined modality chemotherapy followed by consolidation radiotherapy.

The study highlighted disparities in care and access to care. We need to believe in the potential use of radiation in this setting and work with our medical oncology colleagues of the benefit of consolidation radiation. —Rahul R. Parikh, MD

Most randomized trials conducted to date have been underpowered to show a survival benefit. This large analysis based on the NCDB showed an overall survival benefit at 10 years for combined modality therapy. Yet radiotherapy has declined in use,” stated lead author Rahul R. Parikh, MD, of Mount Sinai Beth Israel Medical Center and Mount Sinai St. Luke’s–Roosevelt Hospital in New York City. “We have identified specific factors associated with omission of radiation. This study should be practice-changing,” Dr. Parikh stated. Dr. Parikh noted that the study is the largest contemporary dataset of patients with early-stage Hodgkin lymphoma and reflects contemporary

EXPERT POINT OF VIEW

“T

he goal of therapy is to maximize cure. Limiting radiation therapy and other types of cancer therapies is reasonable to minimize side effects, but at times this path might lead to increased risk of cancer recurrence,” said Theodore DeWeese, MD, Chairman of the Department of Radiation Oncology and Molecular Radiation Science at the James Buchanan Brady Urology Institute at Johns Hopkins University Theodore DeWeese, MD School of Medicine in Baltimore. “Dr. Parikh’s study shows that to maximize cure, early-stage Hodgkin lymphoma patients need radiation and chemotherapy. We always seek to maximize cure and minimize side effects. The belief that radiation has long-term consequences leads to omission of radiation therapy, perhaps inappropriately. Dr. Parikh has shown that perhaps these fears may lead some to inappropriately exclude radiation from the treatment plan,” Dr. DeWeese stated. n Disclosure: Dr. DeWeese reported no potential conflicts of interest.

treatment programs with radiationspecific data. The study prospectively collected outcomes data covering 41,420 patients with newly diagnosed Hodgkin lymphoma in more than 1,500 U.S. hospitals. Of these, 20,523 (49%) received radiation at a mean dose of 30.6 Gy, while 20,897 did not. Multiagent chemotherapy was given to 39,842 patients (96%). Inclusion of radiation therapy in the treatment plan boosted 10-year overall survival from 76% in those who did not get radiation therapy to 84% in those who received radiation therapy. This difference was highly statistically significant (P < .00001). Also, patients who did not get radiation therapy had an increase in the rate of salvage transplant procedures.

Factors Associated With Omission of Radiotherapy “Patients with B symptoms and higher comorbidity status were less likely to get radiation,” Dr. Parikh told the audience. Factors significantly associated with not receiving radiation therapy included uninsured status (P < .001),

being treated at an academic/research facility rather than a comprehensive cancer center (P < .001), and having lower educational and income status (P < .001). A multivariate analysis controlling for several factors showed that receiving radiation and chemotherapy remained significant predictors of overall survival. “Despite this overall survival benefit, utilization of radiation therapy decreased from 1998 to 2011 by 15%. When we looked at reasons why radiation was not given, 86% of oncologists said it was not part of the treatment plan,” said Dr. Parikh. “We like to treat patients in a multidisciplinary setting where medical oncologists and radiation oncologists confer at time of diagnosis. The study highlighted disparities in care and access to care. We need to believe in the potential use of radiation in this setting and work with our medical oncology colleagues of the benefit of consolidation radiation,” he continued. “We recommend that radiation remain standard of care combined with chemotherapy for this curable disease,” he concluded. n Disclosure: Dr. Parikh reported no potential conflicts of interest.

Reference 1. Parikh RR, Yahalom J, Talcott JA, et al: Early-stage Hodgkin’s disease: The utilization of radiation therapy and its impact on overall survival. 56th Annual Meeting of ASTRO. Abstract CT-08. Presented September 14, 2014.

Radiation in Early-Stage Hodgkin Lymphoma ■ Chemotherapy followed by consolidation radiation extended 10-year survival in with early-stage Hodgkin lymphoma. ■ Radiation therapy is omitted in approximately 50% of patients with earlystage Hodgkin lymphoma. ■ Factors associated with omission of radiation therapy from the treatment plan included lower socioeconomic status, uninsured status, and not being treated at a comprehensive cancer center.

The ASCO Post | OCTOBER 15, 2014

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ASTRO Annual Meeting Breast Cancer

Hypofractionated Radiation Much Less Toxic Than Conventionally Fractionated Radiation in Early Breast Cancer By Alice Goodman

ypofractionated whole-breast irradiation was associated with much less acute toxicity during radiation therapy compared with conventionally fractionated whole-breast irradiation and also led to improved physical well-being and less physicianreported and patient-reported fatigue 6 months later, according to results of a randomized controlled trial. This is one of the first trials to compare these treatments in patients given contemporary radiation therapy with a tumor bed boost. “Hypofractionated whole-breast irradiation results in less toxicity than

tionally fractionated whole-breast irradiation (n = 149). Hypofractionation was delivered at 42.56 Gy in 16 fractions over 20 to 21 days, followed by a tumor bed boost of 10 to 12.5 Gy in 4 to 5 fractions; conventional fractionation was delivered at 50 Gy in 25 fractions over 30 to 32 days, followed by a tumor bed boost of 10 to 14 Gy in 5 to 7 fractions. The primary objective of the present trial was cosmesis at 3 years; secondary endpoints included maximal acute toxicities and quality of life assessed by the FACT-B questionnaire, which includes fatigue, nausea, caring for family, pain, and feelings of distress.

Hypofractionated whole-breast irradiation results in less toxicity than conventionally fractionated whole-breast irradiation, even when a tumor bed boost is delivered. —Simona F. Shaitelman, MD, EdM

conventionally fractionated wholebreast irradiation, even when a tumor bed boost is delivered,” stated lead author Simona F. Shaitelman, MD, EdM, of The University of Texas MD Anderson Cancer Center, Houston, Texas, who presented the results at the 56th Annual Meeting of the American Society for Radiation Oncology (ASTRO). At least four large randomized trials have compared hypofractionated vs conventionally fractionated wholebreast irradiation, she said, showing equivalent rates of local control, overall survival, and cosmesis. “But none of these trials mandated a tumor bed boost, which is widely used in the United States and Europe and reflects contemporary treatment,” she said.

Of 432 patients screened, 287 were randomly assigned. Patients were excluded if they had a history of breast cancer, concurrent bilateral breast cancer, or were pregnant. They were assessed for acute toxicity during radiation treatment and then followed for 6 months. Prior to starting treatment, 91% in the conventional fractionation arm and 95% in the hypofractionated arm had good to excellent cosmesis. Most of the women were between the ages of 50 and 70, 88% were postmenopausal, and 75% were overweight or obese. Threequarters had invasive breast cancer; 25% were grade 3; the majority were estrogen receptor–positive and progesterone receptive–positive; and 8% were HER2-positive.

Study Details

Greater Toxicity With Conventional Fractionation

Patients with early-stage breast cancer (stage 0–II) treated with breast-conserving surgery with negative margins who were eligible for whole-breast irradiation were randomly assigned to either hypofractionated (n = 138) or conven-

Acute toxicity was significantly worse on conventionally fractionated whole-breast irradiation vs hypofractionated whole-breast irradiation, as assessed by physicians. Grade 2 or

Hypofractionated Whole-Breast Irradiation in Early Breast Cancer ■ Several large randomized trials have demonstrated equivalent rates of local control, overall survival, and cosmesis with hypofractionated vs conventionally fractionated whole-breast irradiation. ■ Compared with conventionally fractionated whole-breast irradiation, hypofractionated radiation following breast-conserving surgery causes much less acute toxicity during radiation therapy and fatigue 6 months after completion of radiation. ■ These findings should encourage radiologists to use a radiation schedule that is completed more quickly and is more convenient for patients.

higher acute toxicity was reported in 46.4% of the hypofractionated patients vs 77.9% of the conventionally fractionationated group (P < .001); grade 3 or higher acute toxicity occurred in 0% vs 5.4%, respectively (P = .006). Acute fatigue was reported in 8.7% vs 16.7%, respectively (P = .02). Results also strongly favored hypofractionation over conventional fractionation for acute pruritus, breast pain, dermatitis, and hyperpigmentation. At 6 months after completion of radiation, patients randomly assigned to hypofractionated whole-breast irradiation showed a strong trend toward better physical well-being on FACT-B scoring than those treated

with conventionally fractionated whole-breast irradiation (P = .07), as well as less patient- and physician-reported fatigue (P < .001 and P = .009, respectively). n

Disclosure: Dr. Shaitelman received a research grant from Elekta, and Dr. Smith (the senior author in the study) has a research grant from Varian.

Reference 1. Shaitelman S, Buchholz TA, Hunt KK, et al: Hypofractionated whole breast irradiation results in less acute toxicity and improved quality of life at 6 months compared to conventionally fractionated whole breast irradiation: Results of a randomized trial. ASTRO Annual Meeting. Abstract LBA3. Presented September 14, 2014.

EXPERT POINT OF VIEW

“T

his is a provocative study, showing unexpected differences in acute skin reactions with conventional fractionation vs hypofractionation. Some studies have failed to show differences in acute toxicities between these two types of radiation therapy,” said Kenneth B. Roberts, MD, Professor of Therapeutic Radiology at Yale University School of Medicine, New Haven, Connecticut. “In the past, there has been some undue conKenneth B. Roberts, MD cern about hypofractionation causing more toxicity. The concept behind this is that higher doses per fraction would be theorectically associated with greater toxicity. In fact, this study showed less acute toxicity and less skin reaction with hypofractionated radiation therapy. And a striking aspect of this study is that all patients received a breast boost. This study lends support that we can use a radiation regimen that is completed more quickly and is more convenient for patients. We are giving an equivalent therapy in terms of disease control and the patient is getting radiation within 4 weeks instead of 6½ weeks,” Dr. Roberts stated. n Disclosure: Dr. Roberts reported no potential conflicts of interest.

The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1,2

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

as a single agent

overall response rate1 overall response rate1

76 54%

% (95% CI: 62, 87)

median duration of response1

(95% CI: 40, 67)

median duration of response1

10.5 5.6

months

(95% CI: 7, 15)

months

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1 Major efficacy outcome: Investigator-assessed response rate1 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

50 40 30 20 10 0

Complete Response

Partial Response

TAFINLAR as a single agent (N=54)

Complete Response

TAFINLAR

150 mg twice daily

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1 Efficacy outcome: Investigator-assessed median duration of response1

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months Months TAFINLAR as a single agent (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

(dabrafenib) 50 mg, 75 mg capsules

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination. Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%). The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%). Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions. To learn more, visit TAFINLARMEKINISTHCP.com Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages. Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703. TAFINLARMEKINISTHCP.com TAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014

(dabrafenib) 50 mg, 75 mg capsules

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)]. 5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. 5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. 5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. 5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)]. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. 5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination. 5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. 5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white. Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent. In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination. Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades Adverse Reactions Gradesa 3 and 4 Gradesa General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders 45 0 43 Rashc Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute. Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness. Gastrointestinal Disorders: Stomatitis, pancreatitis. General Disorders and Administration Site Conditions: Asthenia. Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular. Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma. Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension. Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

All All All Grades Grades Grades Grades 3 and 4 Grades 3 and 4 Grades 3 and 4a Tests Hematology Leukopenia 62 5 46 4 21 0 Lymphopenia 55 22 59 19 40 6 Neutropenia 55 13 37 2 9 2 Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0 Liver Function Tests Increased AST 60 5 54 0 15 0 Increased alkaline 60 2 67 6 26 2 phosphatase Increased ALT 42 4 35 4 11 0 Hyperbilirubinemia 15 0 7 4 0 0 Chemistry Hyperglycemia 58 5 67 6 49 2 Increased GGT 56 11 54 17 38 2 Hyponatremia 55 11 48 15 36 2 Hypoalbuminemia 53 0 43 2 23 0 Hypophosphatemia 47 5 41 11 40 0 Hypokalemia 29 2 15 2 23 6 Increased creatinine 24 5 20 2 9 0 Hypomagnesemia 18 2 2 0 6 0 Hyperkalemia 18 0 22 0 15 4 Hypercalcemia 15 0 19 2 4 0 Hypocalcemia 13 0 20 0 9 0 a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase. QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent. 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. 7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)]. Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight. MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)]. Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss. In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals. 8.3 Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1. Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older. 8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)]. Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients. Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)]. MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)]. Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)]. Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)]. MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment. 8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated. • TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)]. • TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal. TAFINLAR is a registered trademark of GlaxoSmithKline. MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

ASCOPost.com | OCTOBER 15, 2014

PAGE 15

ASTRO Annual Meeting Palliative Care

Radiation Alone Is as Effective as and Less Toxic Than Chemoradiation for Advanced Esophageal Cancer By Alice Goodman

adiation therapy alone was found to be as effective as chemoradiation in reducing dysphagia associated with advanced esophageal cancer in the palliative setting and was less toxic, according to results of a multinational phase III trial called the Trans-Tasman Radiation Oncology Group (TROG)

tice is to prescribe chemotherapy for patients with advanced esophageal cancer, presumably based on the standard use of [chemoradiotherapy] in patients with less advanced disease,” Dr. Penniment said. “These results will allow us to simplify treatment for patients [whose disease is incurable]

There is a small group of patients with primary advanced esophageal cancer who can have longer-term survival, and radiation can improve swallowing and potentially lengthen the time without symptoms in this group.

the chemoradiotherapy group, a difference that was not statistically significant. However, chemoradiotherapy resulted in a significant increase in toxicity, namely, nausea and vomiting (P < .01), compared with radiotherapy alone. Median survival was not significantly different between the two treatment arms. One potentially important finding of the trial was that about 10% (n = 21) of patients were alive 2 years post-treatment. “This tail in the curve shows us that there is a small group of patients with primary advanced esophageal cancer who can have longer-term survival, and radiation can improve swallowing and potentially lengthen the time without symptoms in this

group,” Dr. Penniment said. “We think all patients with esophageal cancer can potentially benefit from radiation,” he said. n

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

Reference 1. Penniment MG, Harvey JA, Wong R, et al: Best practice in advanced oesophageal cancer: A report on TROG 03.01 NCIC CTG ES.2 multinational phase III study in advanced oesophageal cancer comparing quality of life and palliation of dysphagia in patients treated with radiotherapy or chemo-radiotherapy. ASTRO Annual Meeting. Abstract CT-03. Presented September 14, 2014.

—Michael Gordon Penniment, MBBS

03.01 and National Cancer Institute of Canada (NCIC) CTG ES.2. Results of the study were presented at the 56th Annual Meeting of the American Society for Radiation Oncology (ASTRO).1

Radiation an Excellent Tool in Palliation “Overall, radiation remains an excellent tool for palliation of patients with advanced esophageal cancer and should remain the standard of care,” said lead author Michael Gordon Penniment, MBBS, Director of Radiation Oncology at Royal Adelaide Hospital in South Australia and the Director of Radiation Oncology at the Alan Walker Cancer Chemotherapy Care Centre in Darwin, Australia. Researchers found that chemotherapy increased toxicity significantly without additional symptom control or improved survival in this patient population. “The study focused on the best, yet simplest and least toxic treatment to alleviate pain,” Dr. Penniment said. “There is no gold standard for palliation [in this setting]. Current prac-

but who can expect an improvement in swallowing and quality of life with radiation alone, sparing them the extra toxicity and cost of chemotherapy.”

Study Details This is the largest randomized phase III trial in advanced esophageal cancer. The study enrolled 220 patients, the majority with metastatic disease, and randomized them to receive palliative radiation (35 Gy in 15 fractions in Australia and New Zealand or 30 Gy in 10 fractions in Canada and the United Kingdom) or concomitant chemoradiotherapy with cisplatin and fluorouracil. Dysphagia was measured with the Mellow score; toxicity with the Common Terminology Criteria for Adverse Events (CTCAE) version 2, and quality of life (QOL) using the European Organization for Research and Treatment of Cancer (EORTC) QLQ 30 and esophagus module (OES-18).

Results A dysphagia response at any time was reported in 67.89% of patients in the radiotherapy-alone group vs 73.8% in

Radiation Therapy for Advanced Esophageal Cancer ■ Radiation therapy alone was as effective as chemoradiation for alleviating dysphagia in patients with advanced esophageal cancer. ■ Chemoradiation had greater toxicity than radiation alone in the palliative setting. ■ Radiation alone should remain the standard of care for advanced esophageal cancer.

EXPERT POINT OF VIEW

racy Balboni, MD, moderated the press conference where data from the Trans-Tasman Radiation Oncology Group (TROG) 03.01 and National Cancer Institute of Canada (NCIC) CTG ES.2 trial were discussed during ASTRO’s Annual Meeting.1 Dr. Balboni, a Radiation Oncologist at Harvard Medical School and Dana-Farber Cancer Institute in Boston, noted that trials in the palliative setting such as that reported by Dr. Penniment and

We need to care about patients’ quality of life throughout this increasing time that they are living with their cancers. —Tracy Balboni, MD

colleagues “become all the more relevant as patients live longer with their incurable disease. We need to care about patients’ quality of life throughout this increasing time that they are living with their cancers. Research that informs how best to uphold our patients’ quality of life is critical.”

Focus on Quality Commendable Dr. Balboni commended Dr. Penniment et al for their study on quality of life in incurable patients. “Our international colleagues have spearheaded efforts at the intersection of palliative care and radiation oncology. In the United States, we are just beginning to follow in their footsteps and emulate the good research they have contributed in this area,” she added. n Disclosure: Dr. Balboni reported no potential conflicts of interest.

The ASCO Post | OCTOBER 15, 2014

PAGE 16

ASTRO Annual Meeting Genitourinary Oncology

Duration of Androgen-Deprivation Therapy for Patients With High-Risk Prostate Cancer By Alice Goodman

ptimal duration of androgen-deprivation therapy as part of primary therapy for prostate cancer continues to be an important question. Two wellconducted studies reported recently at the 56th Annual Meeting of the Ameri-

was apparent mainly in men with highrisk prostate cancer. The second study showed that quality of life was superior with 18 months of androgen-deprivation therapy vs 36 months, and clinical outcomes were similar.

The 5-year results of our study show that modern high-dose radiotherapy with 28 months of hormone therapy is a successful combination to control prostate cancer, with good quality of life for patients with high-risk prostate cancer. —Almudena Zapatero, MD, PhD

can Society for Radiation Oncology (ASTRO) provide data that can help inform decision-making, especially for patients with high-risk disease. The first study showed that 28 months of androgen-deprivation therapy plus high-dose radiotherapy (78 Gy) was superior to 4 months plus the same radiation treatment in extending overall survival and disease-free survival, but the benefit of longer treatment

Long-Term vs Short-Term Hormonal Therapy The addition of 28 months of androgen-deprivation therapy (long-term androgen deprivation) to high-dose radiotherapy improved 5-year biochemical disease-free survival, metastasis freesurvival, and overall survival compared with 4 months of androgen-deprivation therapy (short-term androgen deprivation) and high-dose radiotherapy as pri-

Duration of Androgen-Deprivation Therapy in Prostate Cancer ■ The optimal duration of androgen-deprivation therapy remains uncertain for patients with high-risk prostate cancer. ■ In terms of survival, a large randomized trial found that 28 months of androgendeprivation therapy plus high-dose radiotherapy is superior to 4 months of hormonal treatment plus the same radiotherapy in patients with high-risk prostate cancer. ■ A second randomized trial found that, in men with high-risk prostate cancer, 18 months of androgen-deprivation therapy yielded better quality of life than 36 months of androgen-deprivation therapy. ■ Final results of the ongoing phase III PCS IV trial cancer comparing 18 vs 36 months of androgen-deprivation therapy in men with high-risk prostate cancer are awaited.

mary treatment of men with intermediate- and high-risk prostate cancer, with most of the benefit seen in men with high-risk disease.1 “Optimal timing and sequence of hormone therapy are extremely challenging for management of patients with intermediate-risk and high-risk prostate cancer,” noted lead author Almudena Zapatero, MD, PhD, Hospital Universitario de la Princesa, Madrid. “The 5-year results of our study show that modern high-dose radiotherapy with 28 months of hormone therapy is a successful com-

bination to control prostate cancer, with good quality of life for patients with high-risk prostate cancer,” she said.

DART 01/05 Study The multicenter DART 01/05 study, selected as a Plenary Session presentation, enrolled 362 men with intermediaterisk and high-risk prostate cancer at nine centers in Spain between 2006 and 2010. None of the patients had lymph node involvement or metastases at baseline. All patients were treated with 4 months of concomitant androgen-

Determining Androgen-Deprivation Therapy By Phillip J. Gray, MD

etermining an appropriate course of androgen-deprivation therapy in patients with prostate cancer is complex. For patients with high-risk features, 4 to 6 months of androgen-deprivation therapy helps, but 28 to 36 months is better in terms of disease control and overall survival. In the study by Nabid et al, an intermediate-length 18-month course of androgen-deprivation therapy was associated with reduced toxicity and impact on patient quality of life compared to a 36-month course. The other unanswered question is, how much androgen-deprivation therapy is needed when dose-escalated radiation therapy is given, if needed at all? Previous studies for intermediate- and high-risk patients all

We need to get more granular in our approach to defining risk so that we know which patients can get by with shorter courses of androgen-deprivation therapy and which patients need longer durations.

used lower radiation doses and so the waters have been muddied somewhat in terms of our ability to interpret the outcomes of these studies in the modern era. The study by Zapatero et al showed us that for patients receivDr. Gray is a radiation oncologist at Massa- ing high-dose radiotherapy, hormone chusetts General Hospital in Boston. therapy is still advantageous and lon-

—Phillip J. Gray, MD

ger courses were still the best in patients with the highest-risk cancers.

How Long Is Long Enough? The question is then how long is long enough? It is not clear yet that 18 months is enough, but 36 months may indeed be too long for some patients,

especially given the impacts on patientreported quality of life. Ideally, we need to offer the shortest course of hormone therapy to our patients that will still maximally impact their chance for cure while maintaining adequate quality of life. We need to get more granular in our approach to defining risk so that we know which patients can get by with shorter courses of androgen-deprivation therapy and identify which patients may need longer durations. Currently, we end up both overtreating and undertreating some patients, because we still don’t have a perfect way to predict outcome. Ongoing work in the area of molecular biomarkers will no doubt help us with these difficult treatment decisions in the future. n

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

ASCOPost.com | OCTOBER 15, 2014

PAGE 17

ASTRO Annual Meeting deprivation therapy and high-dose radiotherapy at a median dose of 78 Gy. Patients were then randomized to two groups: adjuvant goserelin (Zoladex) for an additional 24 months (long-term) or no additional androgen-deprivation therapy (short-term). There were a total of 166 patients with intermediate-risk disease and 189 patients with high-risk disease who were evenly balanced between the two treatment arms. At a median follow-up of 63 months, 5-year biochemical disease-free survival was 89.8% in the long-term androgendeprivation group vs 81.3% in the shortterm group (P = .019). Metastasis-free survival at 5 years was also significantly higher for the long-term androgendeprivation group: 93.6% vs 83.4%, respectively (P = .009). Overall survival was statistically superior as well for longterm androgen deprivation: 94.8% vs 86.1%, respectively (P = .009).

18 vs 36 months of AndrogenDeprivation Therapy Testosterone levels recovered more quickly and quality of life was improved in men with high-risk prostate cancer treated with 18 months of androgendeprivation therapy vs 36 months in a large randomized phase III trial (PCS IV).2 At an interim analysis reported pre-

viously in The ASCO Post (July 25, 2013; bit.ly/1rrLBf0), overall and disease-free survival rates from this trial were comparable between the two arms. Final survival results from the ongoing PCS IV trial comparing 18 vs 36 months of androgendeprivation therapy are awaited. At the ASTRO meeting, lead author Abdenour Nabid, MD, Centre Hos-

pitalier Universitaire de Sherbrooke Canada, presented new data from the PCS IV trial on testosterone levels and quality-of-life data from the trial. The study enrolled 561 men with high-risk prostate cancer and randomized them to either 18 months of androgen-deprivation therapy plus radiation continued on page 18

After progression following initial antiestrogen therapy in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer (mBC)...

Go with FASLODEX. Now Availa b

p d ate d D

Primary Endpoint: Progression-Free Survival (PFS)1,*

A Secondary Endpoint: Overall Survival (OS)1

Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg in CONFIRM2,†

Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg in CONFIRM2

At minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006) 2

m .c o

These benefits in outcomes were mainly in patients with high-risk disease. Five-year biochemical disease-free survival in patients with high-risk disease was 88% for long-term androgen deprivation vs 75.3% in the short-term group; 5-year overall survival was 96.1% with long-term androgen deprivation therapy and 81.5% with short-term androgen deprivation therapy for patients with high-risk disease, respectively. The magnitude of difference between the two treatment arms was much smaller among patients with intermediate-risk disease; the absolute difference for biochemical disease-free survival was 4% and for overall survival 2%. Acute and late radiation toxicities were low, Dr. Zapatero reported, with no significant differences between treatment arms.

—Abdenour Nabid, MD

w w w.F asl

Before we have final results of the ongoing phase III PCS IV trial, it is a good idea to treat [high-risk prostate cancer] with androgen-deprivation therapy for 2 years instead of 3.

Final O Analy S sis From CONFI RM*

• Not statistically significant as no adjustments were made for multiplicity2

At minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96) 2

Important Safety Information About FASLODEX • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema have been reported in association with FASLODEX • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants • FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) Please see additional Important Safety Information on reverse and brief summary of full Prescribing Information for FASLODEX on following pages. * PFS is defined as the time between randomization and the

earliest evidence of progression or death from any cause. 2 † COmparisoN of FASLODEX In Recurrent or Metastatic Breast Cancer.1

Go with Confidence Learn more at www.FaslodexUpdatedData.com

The ASCO Post | OCTOBER 15, 2014

PAGE 18

ASTRO Annual Meeting Androgen-Deprivation Therapy continued from page 17

therapy or 36 months of androgen-deprivation therapy plus radiation therapy. For both groups, radiation therapy was given 4 months after the initiation of androgen-deprivation therapy. Measurements of serum testosterone

were obtained at baseline and at each follow-up visit. At a median follow-up of 84 months, testosterone levels recovered to normal in 55.7% of patients treated with 18 months of androgen-deprivation therapy vs 44.9% in the 36-month androgen-deprivation therapy group. Time to recovery of normal testosterone levels was shorter in the 18-month group compared

with the 36-month group: a median of 47.2 months vs 73.2 months, respectively. Using two validated quality-of-life tools (EORTC30 and EORTC25) totaling 55 items grouped into 21 scales (evaluated from 0–100 points), patients were assessed prior to treatment, every 6 months during androgen-deprivation therapy, 4 months post–androgen-

deprivation therapy, and once a year for 5 years after treatment. Quality of life was more improved in patients whose testosterone levels recovered to normal compared with those whose levels did not reach this benchmark. In fact, 26 of the 55 items, as well as 12 of the 21 scales were significantly improved in those with testosterone

FASLODEX is indicated for the treatment of hormone receptor-positive (HR+) metastatic breast cancer (mBC) in postmenopausal women with disease progression following antiestrogen therapy. See more a t

FASLODEX 500 mg vs 250 mg in the Updated OS Analysis in CONFIRM2,§ • Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg at minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2 • Not statistically significant as no adjustments were made for multiplicity.2 • In the initial OS analysis after a minimum duration of 18 months, there was no statistically significant difference in OS between the 2 treatment groups2 * The CONFIRM trial was a randomized, double-blind, controlled phase III

study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1 † PFS was the primary endpoint.1 ‡ ORR is defined as the number of patients with complete response or partial response.2 § OS was a secondary endpoint.1

em FASLODEX 500 mg Showed 4 b er 01 9-1 3, 2 a Comparable Safety Profile to FASLODEX 250 mg in CONFIRM1 c

• Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg at minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2 • Objective response rates (ORRs)‡ were not significantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2 — Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261)2 — ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

Prolonged PFS With FASLODEX 500 mg vs 250 mg in CONFIRM2,*,†

SABC BoothS #465

Additional Important Safety Information About FASLODEX

• Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX • The most common, clinically significant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent Indication For FASLODEX • FASLODEX is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

Please read brief summary of full Prescribing Information for FASLODEX on following pages.

References: 1. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594-4600. 2. Full Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

Go with Confidence FASLODEX is a registered trademark of the AstraZeneca group of companies.

3017912

8/14

ASCOPost.com | OCTOBER 15, 2014

PAGE 19

ASTRO Annual Meeting recovery vs those with no testosterone recovery. These scales were clinically relevant and included sexual activity, ability to exercise, fatigue, pain, emotional functioning, and global health status, Dr. Abdenour said. “These results are not surprising, considering the side effects of [androgen-deprivation therapy] and the fact

that testosterone recovery has a significant impact on improved quality of life. In high-risk prostate cancer, the current guideline for [androgen-deprivation therapy] duration is 2 to 3 years. Before we have final results of the ongoing phase III PCS IV trial, it is a good idea to treat with androgen-deprivation therapy for 2 years instead of 3,” he said. n

FASLODEX® (fulvestrant) Injection

Disclosure: Drs. Zapatero and Abdenour reported no potential conflicts of interest.

References 1. Zapatero A, Guerrero A, Maldonado J, et al: Randomized phase III trial of adjuvant androgen deprivation in combination with high-rose conformal radiotherapy in intermediate- and high-risk localized prostate cancer. 56th ASTRO Annual Meeting.

Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population Body System Number (%) of Patients Fulvestrant 500 mg N=361

Fulvestrant 250 mg N=374

Injection Site Pain

42 (11.6)

34 (9.1)

Headache

28 (7.8)

25 (6.7)

DOSAGE AND ADMINISTRATION

Back Pain

27 (7.5)

40 (10.7)

Recommended Dose

Fatigue

27 (7.5)

24 (6.4)

Pain in Extremity

25 (6.9)

26 (7.0)

Asthenia

21 (5.8)

23 (6.1)

24 (6.6)

22 (5.9)

Nausea

35 (9.7)

51 (13.6)

Vomiting

22 (6.1)

21 (5.6)

Anorexia

22 (6.1)

14 (3.7)

Constipation

18 (5.0)

13 (3.5)

Bone Pain

34 (9.4)

28 (7.5)

Arthralgia

29 (8.0)

29 (7.8)

Musculoskeletal Pain

20 (5.5)

12 (3.2)

Cough

19 (5.3)

20 (5.3)

Dyspnea

16 (4.4)

19 (5.1)

BRIEF SUMMARY For full Prescribing Information, see package insert. INDICATIONS AND USAGE FASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter [see Clinical Studies (14) in full Prescribing Information].

Dose Modification Hepatic Impairment: A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions and Use in Specific Populations].

Administration Technique

The proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged. 2. Remove perforated patient record label from syringe. 3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions refer below to the “Directions for Use of SafetyGlide™.” 4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap. 5. Twist to lock the needle to the luer connector. 6. Remove needle sheath. 7. Remove excess gas from the syringe (a small gas bubble may remain). 8. Administer intramuscularly slowly in the buttock. 9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered. 10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector. 11. Repeat steps 1 through 10 for second syringe. For additional directions for use, see Administration Technique (2.3) in full Prescribing Information.

CONTRAINDICATIONS FASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX.

WARNINGS AND PRECAUTIONS Blood Disorders Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.

Hepatic Impairment The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended [see Dosage and Administration]. FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations].

Use in Pregnancy Based on its mechanism of action and findings in animals, FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area. There are no adequate and wellcontrolled studies in pregnant women using FASLODEX. Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients). Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month.

and Adverse Reaction Body as a Whole

Vascular System

Hot Flash Digestive System

Musculoskeletal System

Respiratory System

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms. Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3) The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups, regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis. Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2). Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day. Table 2: Combined Data from Studies 2 and 3, Adverse Reactions ≥ 5% Body System FASLODEX 250 mg Anastrozole 1 mg N=423 N=423 and Adverse Reactiona (%) (%) Body as a Whole Asthenia Pain Headache Back Pain Abdominal Pain Injection Site Painb Pelvic Pain Chest Pain Flu Syndrome Fever Accidental Injury Cardiovascular System Vasodilatation Digestive System Nausea Vomiting Constipation Diarrhea Anorexia Hemic and Lymphatic Systems Anemia

68.3 22.7 18.9 15.4 14.4 11.8 10.9 9.9 7.1 7.1 6.4 4.5 30.3 17.7 51.5 26.0 13.0 12.5 12.3 9.0 13.7 4.5

67.6 27.0 20.3 16.8 13.2 11.6 6.6 9.0 5.0 6.4 6.4 5.7 27.9 17.3 48.0 25.3 11.8 10.6 12.8 10.9 13.5 5.0

—continued

Abstract PL-02. Presented September 15, 2014. 2. Nabid A, Carrier N, Martin A, et al: Quality of life in patients with testosterone recovery after long-term androgen deprivation therapy for high-risk prostate cancer. Annual Meeting of ASTRO. Abstract 24. Presented September 15, 2014.

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ASTRO Annual Meeting Thoracic Oncology

Study in Survivors of NSCLC Reports Lower Risk of Developing Secondary Primary Lung Cancers in Never and Former Smokers vs Current Smokers

urvivors of non–small cell lung cancer (NSCLC) who never smoked or who are former smokers at the time of

diagnosis have a lower risk of developing secondary primary lung cancers compared to those who are current smokers,

suggesting that increased tobacco exposure is associated with a higher risk of secondary primary lung cancers, accord-

FASLODEX® (fulvestrant) Injection Body System and Adverse Reactiona

FASLODEX 250 mg N=423 (%) Metabolic and Nutritional Disorders 18.2 Peripheral Edema 9.0 Musculoskeletal System 25.5 Bone Pain 15.8 Arthritis 2.8 Nervous System 34.3 Dizziness 6.9 Insomnia 6.9 Paresthesia 6.4 Depression 5.7 Anxiety 5.0 Respiratory System 38.5 Pharyngitis 16.1 Dyspnea 14.9 Cough Increased 10.4 Skin and Appendages 22.2 Rash 7.3 Sweating 5.0 Urogenital System 18.2 Urinary Tract Infection 6.1

Anastrozole 1 mg N=423 (%) 17.7 10.2 27.9 13.7 6.1 33.8 6.6 8.5 7.6 6.9 3.8 33.6 11.6 12.3 10.4 23.4 8.0 5.2 14.9 3.5

a A patient may have more than one adverse reaction. b All patients on FASLODEX received injections, but only those anastrozole patients who were in the North American Study 2 received placebo injections.

Post-Marketing Experience For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions including angioedema and urticaria. Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered. Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

DRUG INTERACTIONS There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro, drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics. Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area (BSA). Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed. Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.

Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26. Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known. Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died. Pharmacokinetics The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis. In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively.

Geriatric Use For FASLODEX 250 mg, when tumor response was considered by age, objective responses were seen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years of age and older, who were treated with FASLODEX in Study 2 and Study 3, respectively.

Pediatric Use A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCuneAlbright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8). The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.

These findings confirm that smoking cessation is crucial and should be an integral component of patient care for patients without a prior cancer diagnosis as well as for cancer survivors. —John Michael Boyle, MD

Hepatic Impairment FASLODEX is metabolized primarily in the liver. The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (ChildPugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C). A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (ChildPugh class B) [see Dosage and Administration and Warnings and Precautions].

Renal Impairment Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine.

OVERDOSAGE Animal studies have shown no effects other than those related directly or indirectly to antiestrogen activity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

Nursing Mothers It is not known if fulvestrant is excreted in human milk. Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FASLODEX, 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.

ing to research presented recently at the American Society for Radiation Oncology (ASTRO) 56th Annual Meeting.1 The analysis studied the association between patients’ smoking histories and their risks of developing secondary primary lung cancers, which is defined as a new lung cancer unrelated to the initial tumor based on histology and location in the lung. The study analyzed 1,484 patients (372 current smokers, 1,014 former smokers, and 98 never smokers) who underwent surgery, with or without adjuvant chemotherapy or radiation therapy,

SafetyGlide™ is a trademark of Becton Dickinson and Company. FASLODEX is a trademark of the AstraZeneca group of companies. © AstraZeneca 2013 Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, England By: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany Rev. 11/12 2355400 2/13

for stage I to IIIA NSCLC at Duke University Medical Center between 1995 and 2008. Baseline covariates and oncologic outcomes including local control, development of distant metastases, overall survival, and rates of secondary primary lung cancers were assessed. Secondary primary lung cancers were distinguished from metastases based on histologic evaluation supplemented with clinical presentation, including the anatomic site and chronological onset of diagnosis. Hazard ratios were calculated with 95% confidence intervals, and multivariate analyses were performed using a Cox regression model. The study found that 5 years after the initial diagnosis, current smokers were more likely to develop secondary primary lung cancers. The 5-year incidence of secondary primary lung cancers was 13% for current smokers, 7% for former smokers, and 0% for patients who had never smoked. In the follow-up period, only one patient who had never smoked developed a secondary primary lung cancer, 7 years after surgery for the first cancer. Furthermore, when restricting the analysis to continued on page 21

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Best of ASCO® Best of ASCO Seattle Proves Engaging, Provocative By Susan London

his year’s Best of ASCO meeting held in Seattle featured topics that both riveted attendees and pushed their buttons, according to program chair Alan P. Venook, MD, of the University of California, San Francisco. “I am extremely pleased with the quality of the presentations from the faculty, but more so, the questions from the participants in the audience. I think their level of engagement is really striking,” he commented in an interview. “Of course, this is a bit of a biased sampling; the people who come to this meeting are motivated. But this is ASCO at its best, which is with really good speakers, getting down to the details of the information that was presented.”

sible solutions—got many meeting attendees out of their chairs. “That is an underlying theme that we have to be cognizant of, and certainly this coming year, at the 2015 ASCO Annual Meeting, this will also be a featured issue, because I do think we are going to break the bank pretty soon, and there has to be much more acknowledgment of that,” he said. “That was interesting

We are really trying to get at the more practical issues in closing the education gap, which is really a matter of integrating the scientific and clinical data. So we are tackling a much tougher topic.

Animated Discussion At the meeting, which drew approximately 400 attendees, topics that garnered particularly animated discussion during question-and-answer periods included genitourinary cancers, survivorship, and rising costs of oncology care. Although major advances were made in many cancers this year, according to Dr. Venook, “I think we can’t be satisfied with the progress in any of these diseases.” Issues surrounding the costs of care—their causes, impacts, and pos-

Smoking and Second Lung Cancers continued from page 20

continuing smokers with pack-years as a continuous variable, the risk of secondary primary lung cancers increased with the number of years of tobacco exposure, corresponding to an 8% increased risk per 10 pack-years. For all patients, there were no differences in local control or distant metas-

of research in various cancers and how to apply it in practice. “We’re trying to be less conventional. The educational components have historically been less disease oriented and pretty straightforward—for example, stage II colon cancer, this is what you do,” Dr. Venook elaborated. “And [now] we are really trying to get at the more practical issues in closing the education gap, which is

—Alan P. Venook, MD

because it divided up the participants. Some people were really into it, and others—you could just see their skin on fire because they were so unhappy with the discussion. But I think that’s a discussion we need to have.” This year’s program also incorporated a number of 50th anniversary– themed education sessions from the Annual Meeting, recapping the history tases based on smoking status. When comparing patients who were current smokers to those who had never smoked or had quit smoking more than 5 years prior to surgery, overall survival was significantly worse for current smokers. “In conducting the study, which is one of the largest of its kind, we were particularly interested in how smoking history related to the risk of developing a second lung cancer,” said John

really a matter of integrating the scientific and clinical data. So we are tackling a much tougher topic.”

Reaching More Oncologists A show of hands suggested that few attendees had been to the Annual Meeting in Chicago, but those would be the people expected to attend, Dr. Venook observed. “What is Michael Boyle, MD, Lead Author of the study and a Radiation Oncology Resident at the Duke Cancer Institute in Durham. “While we believed those who have never smoked would have a low risk of developing a second lung cancer, which was confirmed, we were encouraged to find that smoking cessation led to a lower risk of developing a second lung cancer and overall survival rates similar to nonsmokers. These findings confirm that smoking

unique here is that this is the crème de la crème of the oncology community, the most motivated of the oncologists. It may be that we are preaching to the choir because they are interested and they may already know a lot of this stuff,” he acknowledged. “What we have to do is reach out to the doctors who don’t come to this meeting and don’t go to ASCO, but make sure we have a venue for them to learn this,” he continued. “That’s what ASCO University is trying to do, certainly in trying to create these modules for educating.” Clinicians who were unable to attend the meeting will indeed be able to access its session through ASCO’s Virtual Meeting, Dr. Venook noted. Even so, “we need to do more to reach more oncologists. The deficit in education is getting greater and greater because it’s much harder to do what we do. I’m not sure how to go about doing that, but we have to figure that out. That’s a challenge to all of us at ASCO. The materials are great, but if you can’t disseminate them,” they won’t have impact, Dr. Venook concluded. “Getting to the folks who don’t come to these meetings is really where our challenge is.” n Disclosure: Dr. Venook reported no potential conflicts of interest.

cessation is crucial and should be an integral component of patient care for patients without a prior cancer diagnosis as well as for cancer survivors.” n Reference 1. Boyle JM, Chino JP, Tandberg D, et al: Tobacco use and secondary lung malignancies after surgery for non-small cell lung cancer. Abstract 170. ASTRO Annual Meeting. Presented September 16, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Fadlo R. Khuri, MD, FACP, on the Future of NSCLC Therapy see page 30

Harold Burstein, MD, on Pathologic Assessment of the Partial Mastectomy Specimen see page 38

Visit The ASCO Post online at ASCOPost.com

Eileen M. O'Reilly, MD, on BRCA-Mutated Pancreatic Cancer see page 54

The ASCO Post | OCTOBER 15, 2014

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Best of ASCO® Hematology

Exciting Highlights in Several Types of Lymphoma Presented at Best of ASCO By Charlotte Bath

ntibody-drug conjugates are being tested against several types of lymphomas and for some of these agents, “activity is quite impressive,” Andrew M. Evens, DO, MSc, reported at the recent Best of ASCO meeting in Chicago. Dr. Evens, Professor of Medicine, Chief, Division of Hematology/Oncology, and Director, Tufts Cancer Center, at Tufts Medical Center in Boston, summarized three studies involving antibody-drug conjugates, as well as several other trials originally presented at the 2014 ASCO Annual Meeting in Chicago. Two of the antibody-drug conjugates bind to CD19, which Dr. Evens noted, “is the most widely expressed antigen in B-cell malignancies.” There are “still unmet needs” for patients with these malignancies, he said, with many not responding to salvage therapy or third-line treatment following salvage therapy.

SGN-CD19A in B-Lineage NHL SGN-CD19A showed evidence of clinical activity in patients with relapsed or refractory, aggressive Blineage non-Hodgkin lymphoma, according to an interim analysis of a phase I study.1 The objective response rate was 30% (11 of 37 patients), and the complete response rate was 16% (6 patients). All patients had at least one prior systemic regimen, and patients with diffuse large B-cell lymphoma or grade 3 follicular lymphoma must have received intensive salvage therapy. SGN-CD19A was administered intravenously on day 1 of 21-day cycles. Adverse events were an issue with this study, Dr. Evens stated, with 31 patients (84%) experiencing adverse events involving the eye. “This was not just mild visual changes but keratopathy was diagnosed in several patients,” Dr. Evens said. Treatment with steroid eye drops as well as dose modifications resolved most cases, but “not all patients had complete resolution of the symptoms,” he noted. Overall, blurred vision occurred in 19 patients (51%), dry eye in 13 patients (35%), keratopathy in 11 patients (30%), corneal deposits in 5 patients (14%) and keratitis in 5 patients. Most patients had grade 1/2 symptoms. “It is unclear why eye problems de-

veloped,” and further investigation is needed to address these problems and determine if there are different patterns of dosing that could avoid these side effects, Dr. Evens said. “These data show why, in part, you still need phase I studies.” Other grade 3 adverse events were thrombocytopenia, neutropenia, and anemia, each occurring in < 10% of patients. The maximum tolerated dose has not yet been established.

‘Efficacy Was Good’ in Starlyte Study Another anti-CD19 antibody-drug conjugate, coltuximab ravtansine (CoR, SAR3419), was used to treat patients with relapsed or refractory diffuse large B-cell lymphoma in the phase II Starlyte study.2 All patients had received at least one standard treatment including rituximab (Rituxan) and were not candidates for transplantation. The median age was 71,

back pain (11.5%). Four patients discontinued treatment due to treatmentemergent adverse events. Hematologic toxicity was moderate, although 26.4% of patients experienced grade 3/4 neutropenia, 9.9% thrombocytopenia, and 6.6% anemia.

Brentuximab Vedotin Displays ‘Striking Activity’ In a pilot phase II study involving 12 patients, brentuximab vedotin (Adcetris) showed “striking activity” in patients with previously untreated, limited-stage Hodgkin lymphoma, Dr. Evens remarked.3 All patients also received ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Brentuximab vedotin is an anti-CD30 antibody drug conjugate and has been approved by the U.S. Food and Drug Administration for relapsed/refractory Hodgkin lymphoma and anaplastic large cell lymphoma. Eligible patients had previously un-

This is impressive clinical activity [seen with coltuximab ravtansine], because with relapsed/refractory aggressive B-cell lymphoma, [it] is very difficult to obtain complete response with a single agent. —Andrew M. Evens, DO, MSc

and 53.7% were male. Primary refractory patients were excluded. The overall response rate was 43.9%, with a complete response rate of 14.6%. “This is impressive clinical activity, because with relapsed/refractory aggressive B-cell lymphoma, [it] is very difficult to obtain complete response with a single agent,” Dr. Evens said. “Efficacy was good,” Dr. Evens said, but these ocular disorders did raise a “red flag.” Eye disorders were not as problematic as in the previously described SGN-CD19A study, and adverse events were limited to grade 1/2 with no keratitis. “But we’ll need to know more about these ocular side effects as time goes on,” Dr. Evens stated. Other common nonhematologic treatment-emergent adverse events were nausea (23.0%), diarrhea (19.7%), fatigue and cough (18.0%), vomiting and decreased appetite (13.1%), asthenia, and abdominal and

treated stage IA, IIA, or III CD30-positive Hodgkin lymphoma and absence of bulky disease (defined as a mediastinal mass greater than one-third of the maximum chest diameter or any mass ≥ 10 cm). Patients received two cycles of brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks over 30 minutes, followed by three to six cycles of ABVD depending on stage, according to the study abstract. The median age of the patients was 36 years (range, 19–70 years). Eleven of the 12 patients enrolled had stage II disease, and one patient had stage III disease. After the two cycles of brentuximab vedotin, the 11 patients with stage II disease responded (92%), 10 with complete responses (83%), and 1 patient (8%) with partial metabolic response. Only the patient with stage III disease did not respond, and a new lesion was found.

Encouraging Results With Sequential Therapy “This was an interesting trial with a window study design,” as patients received two cycles of brentuximab vedotin before standard treatment with ABVD had “encouraging results,” Dr. Evens said. “No relapses have been observed during subsequent therapy with ABVD with or without radiotherapy,” he added. “Sequential brentuximab vedotin–ABVD (without radiotherapy) warrants further investigation, as in a similar ongoing clinical trial in older patients with untreated Hodgkin lymphoma.” Two cycles of brentuximab vedotin were well tolerated. Grade 3 adverse events were limited to a transient and asymptomatic increase in liver transaminases in three patients and gammaglutamyl transpeptidase in two patients. Dr. Evens also cautioned the brentuximab vedotin should not be given concurrently with bleomycin or gemcitabine. In a recent letter to the editor in Blood, Dr. Evens and several coauthors noted that pancreatitis in patients treated with brentuximab vedotin is “a rare, yet previously unrecognized serious event.”4

Increasing Rituximab Dosing in Elderly Males In the randomized phase II SEXIER-CHOP-14 trial, increasing the dose of rituximab from 375 mg/m2 to 500 mg/m2 significantly improved the outcome for elderly male patients with aggressive CD20-positive B-cell lymphomas also receiving cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP).5 Previous trials had found that at the 375 mg/m2 dose, female patients over 60 years of age had higher rituximab serum levels and better outcomes than males in that age group. With some additional analyses, including those with younger patients (male and female) treated with rituximab, the difference in responses “probably isn’t so much a male disadvantage, as an elderly female advantage,” Dr. Evens noted, explaining that “elderly women have a much slower [rituximab] clearance than … everyone else.” Although “rituximab was FDA-approved 17 years ago in 1997, we’re still trying to figure out the dose,” Dr. Evens noted. The SEXIE-R-CHOP-14 was conducted by the German High-Grade

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Best of ASCO® Non-Hodgkin Lymphoma Study Group. Three previous trials finding inferior outcomes for elderly men used the same German standard of R-CHOP over 14 days. To test increasing the effect of increasing rituximab doses, 148 male patients in the trial received 500 mg/m2 while the 120 females received 375 mg/m2. The trial also tested different dosing schedules, but those results have not yet been reported.

Toxicity Didn’t Rise With Dose During the treatment period, the increased rituximab dose in males resulted in slightly higher trough serum levels than in females, but the levels dropped faster in males resulting in nearly identical serum levels and a very similar overall rituximab exposure time. The increased dose of rituximab in males was not associated with increased toxicities. The difference in outcome between elderly males and females “appeared to be abrogated by giving higher doses to male patients, as were trough serum rituximab levels,” Dr. Evens noted. The trial results showed that at 3 years, progression-free survival was 74% in males vs 68% in females (P = .396) and overall survival was 80% in males and 72% in females (P = .111). “It is not quite practice-changing yet,” Dr. Evens said, “but definitely very interesting” and more data, including results of the dosing schedule portion of the trial, are eagerly anticipated. “Whether 375 mg/m2 for elderly females is optimal is unclear,” Dr. Evens noted. “Since both young male and female patients also have unfavorable rituximab pharmacokinetics compared with elderly females, increasing the dose in these population may also result in a better outcome,” Dr. Evens added. “Additionaly, to compare rituximab with novel CD20 antibodies, bona fide

head-to-head comparisons using the same dose and schedule are necessary.”

Previously Reported Studies Dr. Evens also summarized a phase II study suggesting that the addition of lenalidomide (Revlimid) to R-CHOP among patients with newly diagnosed diffuse large B-cell lymphoma may overcome the negative prognostic impact associated with the non–germinal center B-cell phenotype.6 Outcomes were similar, with 2-year progression-free survival rates of 60% in the germinal center B-cell phenotypes patients vs 50% in the non–germinal center B-cell patients and 2-year survival rates of 83% vs 75%. (Details of the study are reported in the July 10, 2014, issue of The ASCO Post.) Summaries of two multiple myeloma studies also were presented at

placebo.7 Median overall survival was similar, 33.6 months vs 30.4 months, although data for this endpoint were still immature. The other multiple myeloma study found that either thalidomide (Thalomid) or lenalidomide combined with melphalan/prednisone maintenance therapy produced similar results when administered to newly diagnosed patients ineligible for high-dose therapy.8 Response rates were 75% for patients receiving thalidomide vs 72% for patients receiving lenalidomide. Corresponding complete response rates were 25% and 32%. (Details of both multiple myeloma studies are reported in the July 25, 2014, issue of The ASCO Post.) n Disclosure: Dr. Evens is on the advisory board for and has received research funding from Seattle Genetics and is on the advisory board and speakers bureau for Celgene.

New Data in Lymphoma ■ SGN-CD19A showed signs of clinical activity in relapsed or refractory aggressive B-lineage non-Hodgkin lymphoma, but ocular toxicity was common, with 84% of patients experiencing adverse events involving the eye. ■ Treating patients with relapsed or refractory diffuse large B-cell lymphoma with coltuximab ravtansine resulted in an overall response rate of 43.9%. ■ Brentuximab vedotin followed by ABVD showed striking activity in patients with previously untreated Hodgkin lymphoma, with 92% of patients responding (83% with complete responses). ■ Increasing the dose of rituximab from 375 mg/m2 to 500 mg/m2 significantly improved the outcome without increasing toxicities for elderly male patients with aggressive CD20-positive B-cell lymphomas also receiving CHOP.

Best of ASCO meeting in Chicago. The phase III PANORAMA 1 trial showed that adding the investigational agent panobinostat to bortezomib (Velcade) and dexamethasone in patients with previously untreated advanced disease resulted in a near doubling of complete and nearly complete responses, 27.6% vs 15.7% for bortezomib with

References 1. Forero-Torres A, Moskowitz C, Advani RH, et al: Interim analysis of a phase 1, open-label, dose-escalation study of SGNCD19A in patients with relapsed or refractory B-lineage non-Hodgkin lymphoma (NHL). ASCO Annual Meeting. Abstract 8505. Presented June 1, 2014. 2. Trneny M, Verhoef G, Dyer MJS, et al:

Starlyte phase II study of coltuximab ravtansine (CoR, SAR3419) single agent: Clinical activity and safety in patients (pts) with relapsed/refractory (R/R) diffuse large Bcell lymphoma (DLBCL; NCT01472887). ASCO Annual Meeting. Abstract 8506. Presented June 1, 2014. 3. Federico M, Pesce EA, Merli F, et al: A pilot phase II study with brentuximab vedotin followed by ABVD in patients with previously untreated Hodgkin lymphoma: A preliminary report. ASCO Annual Meeting. Abstract 8507. Presented June 1, 2014. 4. Gandhi MD, Evens AM, Fenske TS, et al: Pancreatitis in patients treated with brentuximab vedotin: A previously unrecognized serious event. Blood 123:28952897, 2014. 5. Pfreundschuh M, Held G, Zeynalova S, et al: Increased rituximab (R) doses and effect on risk of elderly male patients with CD20+ B-cell lymphomas: Results from the SEXIE-R-CHOP-14 trial of the DSHNHL. ASCO Annual Meeting. Abstract 8501. Presented June 1, 2014. 6. Nowakowski GS, LaPlant B, Macon WR, et al: Effect of lenalidomide combined with RCHOP (R2CHOP) on negative prognostic impact of nongerminal center phenotype in newly diagnosed diffuse large B-cell lymphoma: A phase 2 study. ASCO Annual Meeting. Abstract 8520. Presented June 1, 2014. 7. Richardson PG, Hungria VT, Yoon S, et al: Panorama 1: A randomized, doubleblind, phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed and refractory multiple myeloma. ASCO Annual Meeting. Abstract 8510. Presented June 2, 2014. 8. Stewart AK, Jacobus SJ, Fonseca R, et al: E1A06: A phase III trial comparing melphalan, prednisone, and thalidomide (MPT) versus melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed multiple myeloma (MM). ASCO Annual Meeting. Abstract 8511. Presented June 1, 2014.

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NEW INDICATION

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

sion s e r g o r p e diseas your patients t a I D N A Start XT static CRPC fo1 r to meta therapy* on GnRH

*Or af

1 omy. chiect r o l a r e r bilat

Important Safety Information Contraindications XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In Study 1, conducted in patients

with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Adverse Reactions The most common adverse reactions (≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Other Adverse Reactions include: • Laboratory Abnormalities: In the two studies, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). • Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Significantly extended radiographic progression-free survival†1

Significantly improved overall survival†1 • 29% reduction in risk of death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.71 [95% CI, 0.60-0.84]; P < 0.0001)

• 83% reduction in risk of radiographic disease progression or death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.17 [95% CI, 0.14-0.21]; P < 0.0001)

• Estimated median overall survival was 32.4 months (95% CI, 30.1-not reached) for XTANDI + GnRH therapy* and 30.2 months (95% CI, 28.0-not reached) for placebo + GnRH therapy*1

• Estimated median radiographic progression-free survival was not reached (95% CI, 13.8-not reached) for XTANDI + GnRH therapy* and was 3.7 months (95% CI, 3.6-4.6) for placebo + GnRH therapy*1

Oral, once-daily dosing with no required steroid coadministration1

Significantly delayed time to chemotherapy initiation†1 • Delayed time to chemotherapy initiation by a median of 28.0 months with XTANDI + GnRH therapy* vs 10.8 months with placebo + GnRH therapy* (HR = 0.35 [95% CI, 0.30-0.40]; P < 0.0001)

• Dosage: XTANDI 160 mg (four 40 mg capsules) is administered orally, once daily • Steroids were allowed but not required‡

Visit XtandiHCP.com or snap the QR code for more information

• Falls: In the two studies, falls including fall-related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas. • Hypertension: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients.

Drug Interactions • Effect of Other Drugs on XTANDI - Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible.

• Effect of XTANDI on Other Drugs - XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information. †As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC that progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,2 ‡In the PREVAIL trial, 27% of patients in the XTANDI arm and 30% of patients in the placebo arm received glucocorticoids for varying reasons. In the AFFIRM trial (Study 1), 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids. AFFIRM was a phase 3, multicenter, placebocontrolled, randomized trial that enrolled 1199 patients with metastatic CRPC who had previously received docetaxel.1 References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433.

Table 2. Adverse Reactions in Study 2

Table 1. Adverse Reactions in Study 1 XTANDI N = 800 XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information. INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)]. WARNINGS AND PRECAUTIONS Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure. Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDItreated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

XTANDI N = 871

Placebo N = 399

Grade Grade Grade Grade 3-4 1-4 3-4 1-4a (%) (%) (%) (%) General Disorders Asthenic 50.6 9.0 44.4 Conditionsb Peripheral 15.4 1.0 13.3 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 5.3 24.3 Arthralgia 20.5 Musculoskeletal 15.0 Pain Muscular 9.8 Weakness Musculoskeletal 2.6 Stiffness Gastrointestinal Disorders Diarrhea

21.8

9.3 0.8

4.0

2.5

17.3

1.8

1.3

11.5

0.3

1.5

6.8

1.8

0.3

0.0

Grade 1-4a (%)

Grade Grade Grade 3-4 1-4 3-4 (%) (%) (%)

General Disorders Asthenic 46.9 3.4 33.0 Conditionsb Peripheral 11.5 0.2 8.2 Edema Musculoskeletal And Connective Tissue Disorders

2.8 0.4

Back Pain

28.6

2.5

22.4

3.0

Arthralgia

21.4

1.6

16.1

1.1

Gastrointestinal Disorders Constipation

23.2

0.7

17.3

0.4

Diarrhea

16.8

0.3

14.3

0.4

Vascular Disorders 1.1

17.5

0.3

Vascular Disorders Hot Flush

20.3

0.0

10.3

0.0

Hypertension

6.4

2.1

2.8

1.3

Hot Flush

18.0

0.1

7.8

0.0

Hypertension

14.2

7.2

4.1

2.3

Nervous System Disorders

Dizzinessc

11.3

0.3

7.1

0.0

Headache

11.0

0.2

7.0

0.4

7.6

0.1

3.7

0.0

5.7

0.0

1.3

0.1

2.1

0.1

0.4

0.0

0.6

8.5

0.6

10.5

0.0

4.7

1.1

0.1

5.7

0.0

1.3

5.8

1.3

Headache

12.1

0.9

5.5

0.0

Dysgeusia

Dizzinessc Spinal Cord Compression and Cauda Equina Syndrome Paresthesia Mental Impairment Disordersd Hypoesthesia

9.5

0.5

7.5

0.5

7.4

6.6

4.5

3.8

Mental Impairment Disordersd Restless Legs Syndrome

6.6

0.0

4.5

0.0

Respiratory Disorders

4.3

0.3

1.8

0.0

4.0

0.3

1.8

0.0

6.5

0.3

2.4

4.8

1.3

Infections And Infestations Upper Respiratory 10.9 Tract Infectione Lower Respiratory 8.5 Tract And Lung f Infection Psychiatric Disorders 8.8

0.0

6.0

0.5

Anxiety

6.5

0.3

4.0

0.0

11.0

Infections And Infestations Upper Respiratory 16.4 0.0 Tract Infectionf Lower Respiratory Tract And 7.9 1.5 Lung Infectiong Psychiatric Disorders 8.2

Renal And Urinary Disorders Hematuria

8.8

Injury, Poisoning And Procedural Complications

Renal And Urinary Disorders Hematuria

6.9

1.8

4.5

1.0

Pollakiuria

4.8

0.0

2.5

0.0

Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 Non-pathologic 4.0 1.4 0.8 Fractures Skin And Subcutaneous Tissue Disorders

0.0 0.3

Pruritus

3.8

0.0

1.3

0.0

Dry Skin

3.5

0.0

1.3

0.0

0.1

1.3

0.3

Respiratory Disorders 3.3

Dyspneae

Insomnia

Epistaxis

Placebo N = 844

a CTCAE v4 b Includes asthenia and fatigue. c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebotreated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Fall

12.7

1.6

5.3

NonPathological 8.8 2.1 3.0 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 16.4 Appetite

0.7 1.1

0.7

Investigations Weight Decreased

12.4

0.8

8.5

0.2

Reproductive System and Breast Disorders Gynecomastia

3.4

0.0

1.4

0.0

a b c d

CTCAE v4 Includes asthenia and fatigue. Includes dizziness and vertigo. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections In Study 1, 1% of patients treated with

XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included nonpathologic fractures, joint injuries, and hematomas. Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)]. Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)]. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)]. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category X [see Contraindications (4)]. Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during

ASCOPost.com | OCTOBER 15, 2014

MEDXT14535_PREVAIL Brief Summary PI-TAB Colors: Black Trim/live: DO NOT PRINT Bleed: None Trim: 10.5"w × 13.5"h Live: 9.5"w × 12.5"h Output @ 100% Giant Creative Strategy

treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day,and cleft palate and absent palatine bone at 30 mg/kg/ day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)]. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)]. OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day

(0.3 times the human exposure based on AUC). Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: September 2014 14B006-XTA-BRFS Rx Only © 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

076-0516-PM

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disparities in outcomes, suggesting at least some role for differences in access across population subgroups. Furthermore, the incentives drug manufacturers face for pricing new cancer therapies are “perverse,” she maintained. Patients pay relatively little for their care after insurance and copay assistance, undermining their ability to “shop” for effective treatment at reasonable prices. Physicians and hospitals have no comparative effectiveness data for many cancers and available treatment to help guide treatment choices. Insurance coverage is virtually guaranteed for U.S. Food and Drug Administration (FDA)-approved cancer indications. Most cancer treatment remains paid for by Medicare fee for service, “which rewards physicians and hospitals to do more, even when the value of doing more for an individual patient is minimal,” Dr. Conti commented. Indeed, current estimates suggest a sizable proportion of oncology outpatient practice profit comes from the administration of chemotherapy.

Ensuring Access, Quality, Innovation Given the need for reform, the next question is how best to proceed. “What

reform should do is improve access to and quality of cancer care, preserving the incentives for innovation while reining in spending,” she said, proposing several steps that are critical for meeting these objectives. “First, we must measure and identify best cancer care practices across a wide variety of cancer subtypes treated in the outpatient and inpatient settings.” Efforts such as ASCO’s Choosing Wisely initiative are important steps in the right direction, Dr. Conti said. Next is changing drug reimbursement policy. “We can keep the current system as it is, but we need to make this reimbursement more closely match the acquisition costs of these drugs, essentially wringing out the profit that chemotherapy provides in the outpatient setting. Alternatively, we can change the locus of responsibility for purchasing drugs from oncologists and their practices to pharmacy benefit managers, group purchasing organizations, and insurers,” she elaborated. “Either way, these reforms require adopting policies that replace ‘buy and bill’ with reimbursements that reward oncologists for what they do every day for their patients. “We must strive to keep oncology practices ‘whole’ during this transition to make sure access is not continued on page 28

Tough Questions About Health-Care Reform Put Economist in Hot Seat

lthough diverse stakeholders agree that health reform is needed, there is little consensus on the specifics of that reform. Best of ASCO Seattle attendees put a number of pointed questions to health economist Rena Conti, PhD, of the University of Chicago, asking about thorny issues such as cost control, the parties steering reform, and the impact on practices.

Drug Costs Is it time for the FDA to start entertaining the question of “me too” drugs or the additive cost of new therapies? Is it part of the solution to mandate, for example, that new technologies be proved to be superior rather than be proved to just be more costly? The U.S. Food and Drug Administration (FDA) has absolutely no congressional power to assess costs in its evaluation of drugs or devices, and I do not expect that

this Congress is going to award the FDA that responsibility…. In the past, Congress has entertained the possibility of awarding the Centers for Medicare & Medicaid Services (CMS) this responsibility. It has passed. The closest we have come is the implementation of Medicare Part D, where commercial insurers and pharmacy benefit managers were awarded responsibility for negotiating drug prices on behalf of their patients, including Medicare beneficiaries. Given this, what I am arguing for is a practical approach to reform. We are already seeing commercial insurers and some large practices making decisions about cancer drug coverage and reimbursement. Other reform pilots are taking physicians and hospitals out of the drug profiting business altogether. continued on page 28

The ASCO Post | OCTOBER 15, 2014

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Best of ASCO® Health-Care Reform continued from page 27

disrupted for patients,” Dr. Conti said. Ongoing efforts to move away from feefor-service reimbursement and toward episode-based reimbursement are consonant with these goals. Maintaining quality of care will also be key. “You cannot alter the incentives for reimbursement where doctors are responsible for a full episode of care for a patient without making sure that quality incentives—both in terms of the measurement and also in terms of the reporting of these measures— are in place. These metrics must be meaningful. Without them, we could transition from a system that rewards physicians for doing too much toward

Health-Care Questions continued from page 27

Non-U.S. Health-Care Systems A number of drugs confer minimal benefit if at all, but cost up to $15,000 or more a month. Yet the same drugs are not approved 50 miles north of here [in Canada] or in Europe, where there is an organization that decides the benefit drugs can confer, and if this organization does decide these drugs are effective, they are approved oftentimes at 10% or 20% of what it costs us to buy the same drugs here. How do you place that in the context of utilization? I don’t believe we are going to have a National Institute for Health and Care Excellence (NICE)-type or Canadian Health Technology Assessment (HTA)type system any time soon. We have gone through many years of health reform debates. Each one of these health-care debates entertained the possibility of a government agency that would negotiate on behalf of fee for service Medicare beneficiaries. Each time, those types of provisions have failed Congressional approval. I’m not arguing that this type of system may not be effective in mitigating high drug launch prices and price increases. I’m arguing as a realist, that we are not likely going to see this type of reform in the next 10 years unless things radically change in our political system. The other aspect of prices that I think is incredibly important to understand is that many of the drug prices that have captured the American public’s attention are list prices. These are sticker prices, like those seen in a car dealership. Virtually, no one pays those list prices. There are considerable discounts that drug manufacturers give to certain types of purchasers of these drugs under the current U.S. system. These discounts may not be

a system that rewards stinting on access or quality of care for patients with cancer,” Dr. Conti said. “Payers could move to a reimbursement system where physicians and hospitals get paid for treating a given cancer subtype based on some level of evidence,” Dr. Conti added. “Essentially this would mean that reimbursement would no longer be based only on indication-drug pair, but practices could be reimbursed for their choice of treatments based on a menu of treatments related to the evidence supporting that use.” Reform must also ensure that the pharmaceutical industry still has incentive to innovate. “The key is how we get those cures, how we get those breakthroughs,” she said. Possible reforms passed on to payers or patients. That is a problem. There are also patient assistance programs that can be quite generous for certain types of cancer drugs.

Copayment Issues [I disagree about] the large availability of copay assistance. If you put yourself in the shoes of the patient, you cannot afford those drugs, you have no copay assistance available to help, and you are desperate to get needed treatment. I do not doubt that you have patients who are struggling with the amount of money that they need to spend on cancer care, but coinsurance payments for fee for service Medicare beneficiaries are actually pretty low. My argument is a larger one, which is the following: Phar-

could include additional payments to drug manufacturers for major advances in certain cancer subtypes, and/or additional patent life.

Stakeholders’ Roles in Reform “I believe that each stakeholder has a role” in the ongoing health-care reform, Dr. Conti concluded. “Providers must be willing to try innovative ways to responsibly control costs while improving quality; they may have to give up revenue from the drugs in order to go to a different type of system. Payers need to assure the best use of limited resources for the development of innovative benefit designs for patients and also reimbursement models for patients,” she said. “Finally, drug manufacturers must and politicians. But I don’t think it involves doctors enough. Nobody knows more about oncology than we do. The problem here is that we can tell you a lot of what to do, but we’re not consulted on a lot of these things. By “we” I mean myself and my friends and colleagues at the University of Chicago Comprehensive Cancer Center. I am also a member of ASCO, and I am deeply committed to ensuring in this period of transition treating oncologists in the community and in academic medical centers are engaged in reform. When I use the term we, I mean that the ASCO membership needs to get in front of these very tough, but very important discussions, including what do we mean by quality of care and how do we measure it best, how do we want to be reimbursed

Measuring quality of care is hard in practice — particularly for many cancer subtypes where there aren’t widely accepted treatment pathways that are very well validated and accepted. ASCO’s involvement in defining quality of care is critical. —Rena Conti, PhD

ma does provide very generous copayment assistance for many cancer drugs for non-Medicare beneficiaries. Many of these have high-income thresholds. This is a type of discount that allows Pharma to charge high prices for other paying segments of the market.

Input on Costs The problem that I have whenever I hear an economist speak is that they use the word we. And I’m not sure who “we” really are. I know “we” includes economists, insurance company executives, drug companies,

to provide the best care for our patients and keep the lights on in our practices? We must get in front of these issues to argue from a position of strength.

Measuring Quality of Care Who is determining the quality measures, and what tools are they using to measure quality of care? One of the methodologies that CMS is using is very subjective, like giving patients questionnaires asking, “How do you think your doctor [is doing]?” Under health-care reform, there are currently 108 measures that are required

find ways to innovate in the most costeffective way possible to try out novel reimbursement schemes that are linked to value and while continuing to provide patient assistance to ensure patients who are not insured or are underinsured get treated,” she added. n Disclosure: Dr. Conti reported no potential conflicts of interest.

References 1. Polite BN, Conti RM, Shulman LN: Health care in America in 2014: Current and future implications of the Patient Protection and Affordable Care Act. ASCO Annual Meeting. Education Session. Presented May 31, 2014. 2. Bickell NA, Andrulis D, Katz SJ: The winds of change: Cancer disparities in the health care reform era. ASCO Annual Meeting. Education Session. Presented June 2, 2014.

to be collected by outpatient medical practices. Those measures are largely related to patient satisfaction and other types of process measures not related to specialty care. A handful of those measures have something to do with cancer care, but those are mostly about preventive screening, not necessarily about the outcomes of actual cancer treatment. Those quality-of-care measures were adopted by CMS many years ago. The important thing for you to know is that under reform oncology practices are going to be required to start measuring and reporting these outcomes starting next year. Soon payment is going to be attached to your performance on these measures. The decrement in payment is not a very large share of total practice revenue; it’s approximately 1% to 3% of Medicare reimbursement if you fail to meet these quality requirements. I agree with your comment’s sentiment that quality of cancer care is not very well captured by these measures. I suspect that there will be more quality measures identified and tested in the coming years by large practices and commercial insurers. Measuring quality of care is hard in practice—particularly for many cancer subtypes where there aren’t widely accepted treatment pathways that are very well validated and accepted. ASCO’s involvement in defining quality of care is critical. Finally, the tying of quality with payment goes both ways. If you and your practice can demonstrate very significant quality of care over competitors, there is no reason that insurers won’t try to use those quality measures to steer patients toward some groups over others. n

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

ASCOPost.com | OCTOBER 15, 2014

PAGE 29

FDA Update

Lymphatic Mapping Agent Receives Orphan Drug Designation for Head and Neck Cancers

avidea Biopharmaceuticals, Inc, recently announced that technetium 99m tilmanocept (Lymphoseek Injection) has been granted Orphan Drug Designation by the U.S. Food & Drug Administration (FDA) for use in sentinel lymph node detection in patients with cancer of the head and

targeted lymphatic mapping agent used in the evaluation of lymphatic basins that may have cancer involvement in patients with breast cancer, melanoma, and head and neck cancer

patients with oral cavity carcinoma. The agent is currently approved by the FDA for use in lymphatic mapping to assist in the localization of lymph nodes draining a primary tu-

mor in patients with breast cancer or melanoma and for use in guiding sentinel lymph node biopsy in head and neck cancer patients with squamous cell carcinoma of the oral cavity. n

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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

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The ASCO Post | OCTOBER 15, 2014

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Debates and Didactics in Hematology and Oncology Conference Thoracic Oncology

Managing Resistance to Targeted Agents: The Future of NSCLC Therapy By Caroline Helwick

he bane of treating non–small cell lung cancer (NSCLC) patients with druggable mutations has been the development of resistance to targeted agents. New compounds are meeting the challenge of treating resistant disease, according to Fadlo R. Khuri, MD, FACP, Professor and Chair of Hematology and Medical Oncology, and Deputy Director of the Winship Cancer Institute of Emory University, Atlanta. Dr. Khuri is also the Roberto C. Goizueta Distinguished Chair in Cancer Research at Emory. “The bottom line is that this is a new era in lung cancer, not just for research but for treatment,” Dr. Khuri said in an interview with The ASCO Post. At the Debates and Didactics in Hematology and Oncology meeting in Sea Island, Georgia, and in a follow-up interview, Dr. Khuri described the emerging treatment landscape for NSCLC patients with the epidermal growth factor receptor (EGFR) mutation or the ALK fusion oncogene.

Next-Generation EGFR Inhibition The successful targeting of the EGFR mutation with an EGFR inhibitor was initially proven a half-dozen years ago in the IPASS study1 and has been replicated many times over with gefitinib and erlotinib. These early studies indicated that “phenotype is no substitute for genotype,” as patients with EGFR mutations responded to EGFR inhibitors while patients with wild-type EGFR fared better with chemotherapy. The latest research on EGFR inhibitors suggests that targeting may actually be not just mutation-specific, but exonspecific. The second-generation EGFR inhibitor afatinib (Gilotrif) proved its superiority over chemotherapy in the 345-patient LUX-Lung 3 trial.2 Median progression-free survival was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR] = 0.58, P = .001). Analysis of outcomes according to the patient’s specific EGFR mutation revealed that “not all EGFR mutations are created equal,” Dr. Khuri indicated. For those with the common exon 19 deletion and the exon 21 point mutation L858R (n = 308), median progression-free survival was even longer: 13.6 months for afatinib and 6.9 months for chemotherapy (HR = 0.47, P = .001).

At the 2014 ASCO Annual Meeting, researchers evaluated overall survival in the two afatinib registration studies and actually showed an overall survival difference for afatinib in patients with exon 19 deletions.3 Median overall survival was 33.3 months with afatinib vs 21.1 months with pemetrexed (Alimta)/cisplatin (HR = 0.54, P = .0015) in LUX-Lung 3 and 31.4 months vs 18.4 months with gemcitabine/cisplatin (HR = 0.64, P = .0229) in LUX-Lung 6. “Afatinib was not as effective in patients with exon 21 mutations as it was in patients with the exon 19 deletion, where it showed a survival advantage,” he noted. “Why the exon 19 mutation is biologically different from the exon 21 mutation, and why afatinib is more robust in exon 19, we don’t fully understand at this time.” “Afatinib may prove to be a drug that we strongly consider for front-line treatment in the patient with a specific exon 19 mutation,” he predicted. The exon-specific activity of erlotinib and gefitinib is not yet known.

Overcoming the T790M Mutation The next generation of EGFR inhibitors will target the T790M mutation, an acquired exon 20 mutation found in approximately half of the tumors that develop secondary resistance to tyrosine kinase inhibitors.4 These exciting novel compounds are more active, and safer, than the current arsenal. At ASCO 2014, Janne et al reported a response rate of 64% and disease control rate of 94% with AZD9291 as a single agent in this subset.5 “Consistent with the preclinical data, the deepest and most durable responses with this drug are seen in pa-

tients with T790M mutations,” he said. The newer agents are also better tolerated. The regimen of afatinib plus cetuximab, which has also shown activity in patients with resistant disease, is associated with substantially higher rates of diarrhea and rash than any of the novel EGFR inhibitors in development. Rash is observed in fewer than 5% of patients treated with CO1686, though there is a tendency for prolongation of the QTc interval, “which could be of concern” with this compound, he add-

combination (HR = 0.54, P = .0015). “This was an impressive study. We clearly see that patients with EGFR mutations randomized to this combination had a striking difference in progressionfree survival of more than 6 months, and (absent crossovers in the trial) we could eventually see a difference in overall survival,” he said. This appears to be the first adequately powered evaluation of erlotinib/bevacizumab specifically in patients with EGFR mutations.

The fact that we now have two compounds, and several others in the pipeline, for a translocation recognized only 7 years ago in lung cancer is truly amazing. —Fadlo R. Khuri, MD, FACP

ed. This drug also causes hyperglycemia in nearly 50% of patients. In general, these third-generation EGFR inhibitors are “making tremendous strides” in T790M-mutated tumors and could be granted accelerated approval for this subset of patients, he predicted.

Erlotinib Plus Bevacizumab Interestingly, activity was also recently observed for erlotinib plus bevacizumab (Avastin), in a study reported at ASCO 2014 by Japanese investigators.6 JO25567 randomly assigned 150 chemotherapy-naive EGFR mutation–positive patients to erlotinib alone or with bevacizumab, and showed a 6.3-month improvement in progression-free survival with the

Treating NSCLC in 2014 and Beyond ■ In advanced non–small cell lung cancer, emerging compounds are able to target the acquired mutations that convey resistance to treatment. ■ Afatinib appears to be particularly robust in patients with EGFR mutations in exon 19. ■ Third-generation tyrosine kinase inhibitors will be effective against the common T790M mutation. ■ Erlotinib plus bevacizumab appears to be active in patients with EGFR mutations. ■ Next-generation inhibitors of the ALK fusion gene may be even more active than crizotinib. ■ At this time, evidence does not support using these new compounds in early-stage disease; this is being studied in the ALCHEMIST trial.

ALK-EML4 Fusion Gene The ALK fusion gene is present in about 5% of NSCLC cases, and is successfully targeted by crizotinib (Xalkori). Next-generation ALK inhibitors will likely improve upon successes achieved with this drug—specifically, the new agents will be able to overcome resistance due to certain gatekeeper mutations acquired following crizotinib exposure. “The fact that we now have two compounds, and several others in the pipeline, for a translocation recognized only 7 years ago in lung cancer is truly amazing,” Dr. Khuri commented. Crizotinib was associated with a doubling in progression-free survival, vs chemotherapy, in ALK-positive patients in the pivotal second-line trial and was quickly approved for this subset of patients.7 In the first-line setting, the final analysis of PROFILE 1014 showed that crizotinib improved progression-free survival from 7.0 months to 10.9 months (HR = 0.45, P < .0001), and responses were rapid and durable.8 With 68% of patients still in follow-up, median overall survival has not been reached in either arm. The second-generation ALK inhibitor ceritinib (Zykadia) may prove to be even more potent in this setting. The drug is highly active, even in patients previously treated with crizotinib, Dr. Khuri indicated. continued on page 32

The ASCO Post | OCTOBER 15, 2014

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Debates and Didactics in Hematology and Oncology Conference Future of NSCLC Therapy continued from page 30

In the ASCEND-1 trial of 228 ALKpositive patients, median change from baseline was 46% with ceritinib treatment.9 The progression-free survival rate at 12 months was 61.3% in ALK inhibitor–naive patients, 39.1% for all patients, and 28.4% in previously treated patients. “Ceritinib seems, preclinically, to be more potent than crizotinib. Clinically, the median progression-free survival exceeds 12 months [not reached in the study], which is better than originally reported for crizotinib in treatmentnaive patients,” he noted. “From my perspective, this drug looks very active.” Dr. Khuri said he is further encouraged by data for two other novel ALK inhibitors in development: AP26113 and alectinib. AP26113 is active in both ALK-positive and EGFR-mutated patients; it could be beneficial in either subset or in the small group (< 5%) of patients harboring both mutations. In a study reported at ASCO 2014, responses to AP26113 were observed in 75% of all 57 ALK-positive patients and in 69% of those previously treated with crizotinib.10 Alectinib was evaluated in 47 patients, 70% of whom received at least two prior regimens, with responses observed in 60%.11 “These are very impressive response rates in pretreated patients,” Dr. Khuri commented. Under the promise of these newer ALK inhibitors, the future treatment paradigm for advanced-stage ALK-positive NSCLC will include testing for sensitive gatekeeper mutations and treating accordingly, he said.

Dr. Khuri emphasized personalization of care by histology, use of molecular markers in the first-line setting (with EGFR and ALK testing being critical), use of maintenance therapy (switch, or continued pemetrexed or erlotinib), and as trials confirm their benefit, the incorporation of next-generation EGFR and ALK inhibitors.

Adjuvant Use? Not Yet Despite the potential for these new agents in advanced disease, Dr. Khuri cautioned that they are not ready for adjuvant use. “We have very compelling evidence that chemotherapy in the adjuvant setting (for stage IB, IIA, IIB, and III tumors) improves overall survival and increases cure rate,” he said. “We have only inferential data about targeted therapies in that setting, and we can’t be sure they don’t cause harm. While I am not being a treatment nihilist, I think the bar has to be set higher for early-stage disease.” “What we do know,” he continued, “is that if a patient with an EGFR or ALK mutation [has a disease recurrence], we can induce a durable partial remission with the relevant targeted agent. We need further proof that we can impact overall survival before we take these agents into the adjuvant setting.” The benefit of targeted agents in early-stage disease will be evaluated in the ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) group of clinical trials. After surgery, tumor specimens will be screened for EGFR mutations and ALK fusion genes, and patients with abnormalities will be randomly assigned in treatment trials to erlotinib or crizo-

tinib vs placebo, given for up to 2 years after standard therapy. Patients lacking mutations in these genes will be monitored for 5 years. “ALCHEMIST is very important, and it’s why clinicians should not be treating early-stage patients off protocol with targeted agents,” he said. “If in these prospective trials we find an advantage in terms of progression-free survival, then I would be more comfortable using targeted agents for earlystage disease.” n Disclosure: Dr. Khuri reported no potential conflicts of interest.

References 1. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009. 2. Sequist LV, Yang JC, Yamamoto N, et al: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327-3334, 2013. 3. Yang JC, Sequist LV, Schuler MH, et al: Overall survival in patients with advanced non-small cell lung cancer harboring common (Del19/L858%) epidermal growth factor receptor mutations: Pooled analysis of two large open-label phase III studies (LUX-Lung 3 and LUX-Lung 6) comparing afatinib with chemotherapy. ASCO Annual Meeting. Abstract 8004. Presented June 2, 2014. 4. Sequist LV, Waltman BA, Dias-Santagata D, et al: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3:75ra26, 2011. 5. Janne PA, Ramalingam SS, Yang JC, et al: Clinical activity of the mutant-selective

EGFR inhibitor AZD9291 in patients with EGFR inhibitor-resistant non-small cell lung cancer. ASCO Annual Meeting. Abstract 8009. Presented May 31, 2013. 6. Kato T, Seto T, Nishio M, et al: Erlotinib plus bevacizumab versus erlotinib alone as first-line treatment for advanced EGFR mutation-positive nonsquamous non-small cell lung cancer: An open-label randomized trial. ASCO Annual Meeting. Abstract 8005. Presented June 2, 2014. 7. 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. 8. Mok T, Kim D, Wu Y, et al: First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients with advanced ALK-positive non-squamous non-small cell lung cancer: results of a phase III study (PROFILE 1014). ASCO Annual Meeting. Abstract 8002. Presented June 3, 2014. 9. Kim DW, Mehra R, Tan DS, et al: Ceritinib in advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer: Results of the ASCEND-1 trial. ASCO Annual Meeting. Abstract 8003. Presented June 2, 2014. 10. Gettinger SN, Bazhenova L, Salgia R, et al: Updated efficacy and safety of the ALK inhibitor AP26113 in patients with advanced malignancies, including ALK+ non-small cell lung cancer. ASCO Annual Meeting. Abstract 8047. Presented May 31, 2014. 11. Gadgeel S, Ou SH, Chiappori A, et al: A phase I dose escalation study of a new ALK inhibitor, CH542480202, in ALK+ non-small cell lung cancer patients who have failed crizotinib. 15th World Conference on Lung Cancer. Abstract O16.06. Presented October 29, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post D. Ross Camidge, MD, PhD, on REVEL Trial in NSCLC see page 56

Stanley B. Burns, MD, FACS, and His Fascinating Archive of Photos From Medical History see pages 146-151

Ann H. Partridge, MD, and Clifford A. Hudis, MD, FACP, on ASCO Clinical Practice Guideline see page 62

Sigrid Barklund, BA, MS, and Milan J. Anadkat, MD, on Dermatologic Toxicity see page 74

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | OCTOBER 15, 2014

PAGE 33

Announcements

Robert S. Miller, MD, FACP, FASCO, Joins ASCO as Medical Director of Society’s Institute for Quality

obert S. Miller, MD, FACP, FASCO, Assistant Professor of Oncology and Oncology Medical Information Officer at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, has been named Medical Direc-

Robert S. Miller, MD, FACP, FASCO

tor of the Institute for Quality (iQ) of the American Society of Clinical Oncology (ASCO). Dr. Miller is a pioneer in healthrelated information technology and in 21st Century methods of communicating critical medical information to health providers and patients. A long-time ASCO member and volunteer, Dr. Miller will begin his new position on December 3, 2014. Watch for a detailed interview with Dr. Miller in an upcoming issue of The ASCO Post. “We are very excited that Dr. Miller will be joining ASCO as the Medical Director for our Institute for Quality,” said Allen S. Lichter, MD, Chief Executive Officer of ASCO. “Dr. Miller has served ASCO in many integral roles over the years and his leadership and medical knowledge will help guide and revolutionize our continuing effort of improving the quality of cancer care.”

Quality Initiatives The Medical Director will lead a team of more than 30 individuals working with stakeholders across the cancer community to advance iQ’s quality initiatives that have the potential to truly transform the health-care industry. These efforts include The Quality Oncology Practice Initiative (QOPI), QOPI Certification Program (QCP), Practice Guidelines, and CancerLinQ. “Having been a volunteer since 1999, I am deeply committed to ASCO’s mission and am thrilled to serve the Society on a permanent basis,” said Dr. Miller. “I look forward to collaborating with ASCO volunteers, the ASCO Board of Directors, and ASCO staff to establish methods, programs, tools, and other initiatives that improve the care we provide for people living with cancer.” Dr. Miller is board-certified in internal

medicine and medical oncology. Prior to joining Johns Hopkins, he served as the President of Sacramento Center for Hematology and Medical Oncology, Inc, and Assistant Clinical Professor of Medi-

cine at the University of California, Davis. Dr. Miller earned his MD from the Medical College of Virginia School of Medicine, completed a residency in Internal Medicine at the University of California,

San Francisco, a fellowship in Medical Oncology at Stanford University School of Medicine, and received his graduate certificate in biomedical informatics at Oregon Health & Science University. n

The ASCO Post | OCTOBER 15, 2014

PAGE 34

Debates and Didactics in Hematology and Oncology Conference Breast Cancer

Pathologic Complete Response: Understanding the Subtleties By Caroline Helwick

n the neoadjuvant treatment of breast cancer, the importance of achieving a pathologic complete response (pCR) varies substantially by breast cancer subtype. Patients are increasingly interested in this outcome, but it means different things to different patients, according to two breast cancer specialists from Emory University, who discussed the meaning of pCR at the Debates and Didactics in Hematology and Oncology meeting in Sea Island, Georgia.

Likelihood of Achieving a pCR The recent meta-analysis by Cortazar et al illustrates the huge variability in pathologic complete response by breast cancer subtype.1 In general, hormone receptor–positive cancers (luminal A and B) have the least chance of a pCR after neoadjuvant chemotherapy, especially if they are low-grade. HER2positive cancers have a better chance, especially the hormone receptor–negative subset, and approximately onethird of patients with triple-negative

It’s complicated, but pathologic complete response is not predictive of outcome for the majority of breast cancers. —Ruth M. O’Regan, MD

“It’s complicated, but pathologic complete response is not predictive of outcome for the majority of breast cancers,” said Ruth M. O’Regan, MD, Professor of Hematology and Medical Oncology at Emory University and Chief of Hematology and Medical Oncology at the Georgia Cancer Center for Excellence at Grady Memorial Hospital, Atlanta. Amelia B. Zelnak, MD, Assistant Professor of Hematology and Medical Oncology at Emory, added, “As we use more and more neoadjuvant therapy, our patients are really attuned to how the treatment is working. We need to be careful about how we discuss this with them. There are patients who achieve a pCR who still have recurrences, and many others who don’t achieve a pCR and still do well long-term.” Dr. Zelnak noted that the early preoperative trials—especially National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and B-27—showed that patients achieving a pathologic complete response had better long-term outcomes, but these early data were not broken down by HER2 or hormone receptor status, and were conducted before intrinsic subtyping entered the picture. Since that time, the issue of pathologic complete response—who achieves it, what it means—has become infinitely more nuanced.

breast cancer achieve pCR. “The point is, if we really believe that pCR is the gold standard for outcome, we have a lot of patients who, unfortunately, don’t achieve it,” Dr. O’Regan commented. Estrogen receptor–positive cancers are the least responsive to neoadjuvant chemotherapy and need alternative treatments in the preoperative setting. “We are struggling with how to downstage these cancers,” Dr. O’Regan added. She and Dr. Zelnak compared chemotherapy to endocrine neoadjuvant therapy in a pilot study of 46 patients stratified by 21-gene recurrence score.2 Patients with a recurrence score ≥ 25 received docetaxel plus cyclophosphamide, while those with recurrence score ≤ 10 received exemestane; patients with recurrence score ranging from 11 to 24 were randomly assigned between these arms. The only patients to achieve a pCR (22%) were those in the highest recurrence score group who received chemotherapy. Chemotherapy was also associated with a high rate of complete and partial radiologic responses (90%) in the intermediaterisk group; the response rate was lower with exemestane (67%). The fact that two-thirds or more of patients did respond indicates that downstaging is occurring. However, 80% of patients did not achieve a pathologic complete response, she em-

phasized. “If pCR is important in estrogen receptor–positive cancer, these patients need a different approach,” she suggested.

Meta-analysis Important, but Perhaps Misleading Cortazar’s meta-analysis of almost 12,000 patients in a dozen neoadjuvant studies concluded that patients who attain a pathologic complete response have improved event-free survival.1 With the attainment of pCR, defined by ypT0/is ypN0 (ie, absence of invasive cancer in the breast or nodes; ductal carcinoma in situ allowed), events were reduced by 52% (hazard ratio [HR] = 0.48). However, some associations between pCR and long-term outcomes were far stronger than others. Hazard ratios for eventfree survival were greatest for patients with triple-negative cancers (HR = 0.24), of whom 34% achieved a pathologic complete response, and for patients with HER2-positive, hormone receptor–negative disease receiving trastuzumab (Herceptin, HR = 0.25). In estrogen receptor–positive tumors, grade was also important. The pCR rate for low-grade tumors was only 7%,

pilot trial] even though pCR rates are much lower among hormone receptor– positive patients, it still appears that patients who achieve a pCR do better long-term.… It still has some prognostic value among HER2-positive, hormone receptor–positive cancers.”

Pertuzumab and pCR The U.S. Food and Drug Administration (FDA) used the findings from Cortazar’s meta-analysis to support the approval of pertuzumab (Perjeta) in the neoadjuvant setting. The neoadjuvant NeoSphere trial had shown a 46% pathologic complete response rate among patients receiving pertuzumab in addition to docetaxel and trastuzumab,4 and in TRYPHAENA, pertuzumab plus trastuzumab given with chemotherapy produced pCRs in 81% of hormone receptor–negative patients and 47% of hormone receptor–positive ones.5 Approval of the drug was further bolstered by data from the metastatic setting in CLEOPATRA, where pertuzumab added to trastuzumab and docetaxel improved not only response rates and progression-free survival, but also overall survival (HR = 0.66, P = .0008),6 Dr. Zelnak noted.

There are patients who achieve a pCR who still have recurrences, and many others who don’t achieve a pCR and still do well long-term. —Amelia B. Zelnak, MD

whereas it was 16% for grade 3 tumors. The German Breast Group also looked in detail at pCR and diseasefree survival by intrinsic subgroup and showed no impact of pCR in the luminal A group or among luminal B cancers that are HER2-positive.3 The achievement of pCR was predictive in the three other subsets: luminal B HER2-negative, HER2-positive/estrogen receptor–negative, and triple-negative. “Overall, pCR is a surrogate marker for outcome in breast cancer but this varies according to the breast cancer subtype. In particular, pCR is not a good marker in low-grade [estrogen receptor]–positive disease,” Dr. O’Regan emphasized. However, Dr. Zelnak added, “[In our

The adjuvant APHINITY trial should elucidate the association between pathologic complete response and long-term outcomes. “We are optimistic that APHINITY will confirm long-term improvements in outcomes with pertuzumab,” Dr. Zelnak said. “However, we felt more comfortable with this before we saw the data from ALTTO.”

NeoALTTO vs ALTTO “For HER2-positive disease, we think the truth is in the big trials,” Dr. O’Regan said. For this reason, ALTTO was met with disappointment. In NeoALTTO, the addition of lapatinib (Tykerb) to trastuzumab resulted continued on page 36

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Debates and Didactics in Hematology and Oncology Conference Pathologic Complete Responses continued from page 34

in a pathologic complete response rate of 51%, vs 30% with trastuzumab alone and 25% with lapatinib; the highest pCR rate, 61%, was obtained with dual blockade among the hormone receptor–negative subset.7 At 3 years, events were reduced by 62% among patients achieving a pCR vs not (P = .0003), and survival was also significantly improved (P = .005). “The suggestion, again, was that pCR is more predictive of outcome in hormone receptor–negative cancers, and these patients may do better with the combination of two anti-HER2 agents,” Dr. O’Regan observed. “This was very exciting. We were hopeful it would translate into a meaningful difference in the adjuvant setting.” ALTTO, however, failed to confirm the benefit of dual anti-HER2 blockade, which Dr. O’Regan attributed, in part, to the population being at lower risk (40% node-negative, 60% hormone receptor–positive) than those in NeoALTTO or in the pivotal adjuvant trastuzumab trials.8 The fact that the overall 4-year disease-free survival rate approached 90% in all arms indicated these were relatively good-prognosis patients, she added. “NeoALTTO did not translate into differences in the adjuvant setting, for whatever reason, and this begs the question of whether we rushed into using pCR as a surrogate for long-term outcomes.… I think we should have been more reticent about hormone receptor status,” Dr. O’Regan suggested. Dr. Zelnak indicated that the FDA considered “the body of evidence” in the case of pertuzumab, and rather than universally embrace pCR as a surrogate endpoint for long-term outcomes, the FDA is more likely to evaluate drugs on a case-by-case basis.

Heterogeneity of HER2Positive Disease HER2-positive breast cancer demonstrates marked heterogeneity, and this may be influencing pCR rates, Dr. O’Regan indicated. Carey et al recently reported that in hormone receptor–positive tumors, nearly 50% are luminal B, 34% are luminal A, and 17% are the HER2 intrinsic subtype.9 Luminal A tumors do not derive much benefit from chemotherapy, and pCRs in this subgroup are not very predictive of outcomes. “Being onethird of HER2-positive, hormone re-

Pathologic Complete Response in Breast Cancer ■ Attainment of a pathologic complete response (pCR) after neoadjuvant therapy is not predictive of outcome for the majority of breast cancer patients. ■ The likelihood of achieving a pCR varies greatly according to breast cancer subtype. ■ In luminal A cancers, pCR is very low and is not predictive of outcome. ■ In luminal B cancers, pCR is low and seems to be predictive of outcome. ■ In estrogen receptor–negative cancers, pCR is predictive of outcome, but a subset of patients have a favorable outcome without achieving a pCR. ■ In HER2-positive cancers, pCR is probably not as important for the estrogen receptor–positive subset, but in estrogen receptor–negative cancers it may be predictive. ■ About one-third of patients with triple-negative cancer achieve a pCR, and this correlates with outcome in most cases.

ceptor–positive tumors, are the luminal A tumors driving pCR rates down in this group?” Dr. O’Regan asked. The influence of estrogen receptor within HER2-positive tumors has been explored by University of Pittsburgh researchers, who showed that pathologic complete response rates following trastuzumab therapy are highest (52%) in cancers that are hormone receptor–negative, next highest in cancers with weak-to-moderate estrogen receptor expression (33%), and lowest in HER2-positive cancers with the strongest estrogen receptor expression (8%).10 They concluded that the addition of trastuzumab to neoadjuvant chemotherapy significantly increases pCR rates in all HER2-positive tumors, but the benefit of trastuzumab and chemotherapy decreases as estrogen receptor expression increases. “These findings suggest that the triple-positive cancers perhaps need to be treated differently,” she said, “and there may be many who can get by with less treatment.”

carboplatin clearly does add toxicity, and we don’t have evidence of a survival advantage for adding carboplatin in the metastatic setting.”

Triple-Negative Disease

References 1. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 384:164-172, 2014. 2. Zelnack AB, Murali S, Styblo TM, et al: Phase II trial evaluating the use of 21-gene recurrence score to select preoperative therapy in hormone receptor-positive breast cancer. ASCO Annual Meeting. Abstract 562. Presented June 1, 2013. 3. Von Minckwitz G, Untch M, Blohmer JU, et al: Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30:1796-1804, 2012.

Dr. O’Regan and Dr. Zelnak emphasized that pathologic complete response is clearly important in triplenegative disease, and it may also vary according to the subtype within triplenegative disease. (Six subtypes have been described.) An emerging question, according to Dr. Zelnak, is whether carboplatin should be added to the neoadjuvant regimens for triple-negative tumors. In CALGB 40603, the addition of carboplatin to paclitaxel produced a 60% pCR rate, vs 46% without carboplatin,—an increase of 76% with carboplatin on board (P = .0018).11 However, she noted, “in contrast to pertuzumab,

Conclusion In conclusion, Drs. O’Regan and Zelnak emphasized that pathologic complete response is predictive of long-term outcomes only in subsets of early breast cancer, primarily triple-negative and HER2-positive/hormone receptor–negative patients. Especially in patients with low-grade estrogen receptor–positive tumors, it is not predictive. For patients in whom pCR is important, but is not achieved, more aggressive therapy and/ or a clinical trial are warranted. Finally, clinicians and patients should not consider pathologic complete response the be-all and end-all for treatment outcomes. “You can’t really look just at pCR,” Dr. Zelnak said, “as the final indication for how patients will do.” n

Disclosure: Dr. O’Regan is a consultant for and received research support from Novartis and Genentech/Roche. Dr. Zelnak reported no potential conflicts of interest.

4. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25-32, 2012. 5. Schneeweiss A, Chia S, Hickish T, at al: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278-2284, 2013. 6. Swain SM, Kim SB, Cortés J, et al: Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): Overall survival results from a randomised, doubleblind, placebo-controlled, phase 3 study. Lancet Oncol. 14:461-471, 2013. 7. Piccart-Gebhart M, Holmes AP, de Azambuja E, et al: The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-positive breast cancer survival follow-up analysis of the NeoALTTO study (BIG 1-06). 2013 San Antonio Breast Cancer Symposium. Abstract S101. Presented December 11, 2013. 8. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al: First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone, trastuzumab alone, their sequence, or their combination in the adjuvant treatment of HER2-positive early breast cancer. 2014 ASCO Annual Meeting. Abstract LBA4. Presented June 1, 2014. 9. Carey L, Berry DA, Ollila D, et al: Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. ASCO Annual Meeting. Abstract 500. Presented June 2, 2013. 10. Bhargava R, Dabbs DJ, Beriwal S, et al: Semiquantitative hormone receptor level influences response to trastuzumabcontaining neoadjuvant chemotherapy in HER2-positive breast cancer. Mod Pathol 24:367-374, 2011. 11. Sikov WM, Berry DA, Perou CM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant weekly paclitaxel followed by dose-dense AC on pathologic complete response rates in triple-negative breast cancer: CALGB 40603. 2013 San Antonio Breast Cancer Symposium. Abstract S5-01. Presented December 13, 2013.

ASCOPost.com | OCTOBER 15, 2014

PAGE 37

Announcements

Margaret Foti, PhD, MD (hc), Receives Ellen V. Sigal Advocacy Leadership Award CODE: PAL-14-1

argaret Foti, PhD, MD (hc), Chief Executive Officer of the American Association for Cancer Research (AACR), received the Ellen V. Sigal Advocacy Leadership Award from the national advocacy organization Friends of Cancer Research (Friends) at its 18th Annual Cancer Leadership Awards Reception held recently in Washington, DC.

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and solutions that will accelerate the development of effective treatments for patients,” Dr. Foti said. “I am deeply honored to receive this award bearing her name. “I am immensely proud of AACR’s

accomplishments in the battle against cancer over the years, but there is much more work to be done,” she continued. “We will continue to provide support and opportunities for profes-

sional development to basic researchers and physician-scientists at all stages of their careers, so that they can continue to make the advances that lead to more cures.” n

FOR HR+/HER2- ADVANCED BREAST CANCER

Margaret Foti, PhD, MD (hc)

This is the second year Friends of Cancer Research has awarded the Ellen V. Sigal Advocacy Leadership Award, named for the chairperson and founder of Friends to celebrate her lifelong commitment to science, research, and patient advocacy.

Steadfast Advocacy “Friends of Cancer Research is truly honored to recognize Margaret Foti as the second recipient of the Sigal Advocacy Leadership Award,” said Ellen Sigal, PhD, Chairperson and Founder of Friends. “Her dedication to cancer research, trailblazing work as CEO of the AACR, and steadfast advocacy for science and patients is unparalleled and invaluable to all in the community.” The award honors advocates who have made unprecedented contributions to the cancer research community. Dr. Foti serves as Chief Executive Officer of the AACR. During her long tenure, AACR membership has grown from 3,000 to more than 35,000 laboratory, translational, clinical, and population scientists; other health-care professionals; and cancer advocates residing in 97 countries. Under Dr. Foti’s leadership, the organization’s scientific meetings, peer-reviewed journals, and science and public policy work have flourished, furthering progress against cancer through research, education, communication, and collaboration.

Groundbreaking Partnerships “Ellen Sigal is a true visionary, an advocate, a collaborator, and a dear friend. She has made an enormous impact by fostering groundbreaking partnerships in the cancer field to discuss national policies

Palbociclib US Expanded Access Program (EAP) An open-label expanded access program within the United States for palbociclib, an investigational agent, in combination with letrozole as treatment of post-menopausal women with hormonereceptor–positive (HR+), HER2-negative advanced breast cancer. • Palbociclib 125 mg orally once daily for 3 weeks followed by 1 week off • Letrozole 2.5 mg orally once daily on a continuous dosing schedule

Primary Objective

To provide access to palbociclib in the United States to post-menopausal women with HR+/HER2advanced breast cancer who are deemed appropriate for letrozole therapy. • Patients may continue on study treatment until documented disease progression, discontinuation of study treatment for any reason, or until palbociclib becomes commercially available

Key Inclusion Criteria*

• Post-menopausal women with proven diagnosis of advanced adenocarcinoma of the breast (locoregionally recurrent or metastatic disease) • ER-positive and/or PR-positive tumor (as per local laboratory results) • HER2-negative tumor (as per local laboratory results) • Patients must be appropriate candidates for letrozole therapy

Key Exclusion Criteria*

• Patients who have previously participated in a palbociclib trial or who have received prior treatment with any CDK inhibitor are not eligible *Other eligibility criteria apply. Please see www.clinicaltrials.gov for more information. FOR ADDITIONAL INFORMATION

Call: 1-800-420-6755 E-mail: Palbociclib-EAP@parexel.com Visit: www.clinicaltrials.gov (trial number: NCT02142868; protocol number: A5481034) This EAP study is part of the (Cyclin-Dependent Kinase inhibitor in cancer) clinical trial program of Pfizer Oncology. This program is for patients in the United States only. Palbociclib (PD-0332991) is an investigational agent and its safety and efficacy have not been determined. CDK656114-01 May 2014 © 2014 Pfizer Inc. All rights reserved.

The ASCO Post | OCTOBER 15, 2014

PAGE 38

2014 Breast Cancer Symposium How Accurate Is the Pathologic Assessment of the Partial Mastectomy Specimen? By Caroline Helwick

he pathologic evaluation of lumpectomy margins is “fraught with problems and pitfalls,” said Stuart J. Schnitt, MD, Director of Anatomic Pathology at Beth Israel Deaconess Medical Center and Professor of Pathology at Harvard Medical School, Boston, who was part of a multidisciplinary discussion of margin assessment during the 2014 Breast Cancer Symposium.

posium. There are technical and methodologic issues, issues with definition and interpretation, and issues regarding the distribution of tumor in the breast. One of the technical issues is the “pancake phenomenon,” a term that describes how gravity affects the specimen as it sits on the examination table. The typical specimen compresses, or flattens, and this can impact margin assess-

Margin assessment of lumpectomy specimens is very problematic. There are technical and methodologic issues, issues with definition and interpretation, and issues regarding the distribution of tumor in the breast. —Stuart J. Schnitt, MD

“Quite frankly,” he said, “given the numerous limitations of margin assessment after lumpectomy, it’s amazing that we do as well as we do!”

Pathologic Evaluation of Margins Dr. Schnitt cited a few basic assumptions in the assessment of lumpectomy specimens: • Margin evaluation is an exercise in probabilities, not absolutes. • Patients with positive margins are more likely to have residual disease at or near the primary site than those with negative margins. • A positive margin does not guarantee the presence of residual disease, nor does a negative margin preclude the presence of even extensive residual disease. “The goal of margin evaluation is not to ensure that there is no residual tumor in the breast, but to identify patients more likely to have a large residual tumor burden who require further surgery, and, conversely, to identify those unlikely to have a large residual tumor burden and who therefore are suitable candidates for breast-conserving surgery without further excision,” he said.

Limitations of Margin Assessment “Margin assessment of lumpectomy specimens is very problematic,” Dr. Schnitt said to the oncologists at the sym-

ment. The relationship of margins to each other, as it was in vivo, can change once it arrives at the pathology lab, Dr. Schnitt said. Specimen orientation, which is normally accomplished via the placement of short and long sutures by the surgeon, can be another problematic area for the pathologist reading the specimen. So can the application of ink to the specimen and the identification of tissue-marking dye colors on the microscopic slides used to assess margins present challenges. In one study in which eight pathologists examined specimens for color and color distinctness, certain colors— black, green, red, and blue—were accurately identified by most participants, but identifying violet and distinguishing between orange and yellow dyes proved difficult.1 “It was basically the flip of a coin whether the pathologist recognized the margin as orange or yellow. Things like this have serious implications for calling a particular margin positive or negative,” he said.

EXPERT POINT OF VIEW

arold Burstein, MD, Associate Professor of Medicine at Dana-Farber Cancer Institute, Boston, spoke to The ASCO Post about the multidisciplinary discussion of margin assessment during the 2014 Breast Cancer Symposium.

Should Oncologists Be Concerned? “There is a real art to being a good pathologist. There are layers of sophistication that are invisible Harold Burstein, MD to other clinicians,” he said. “Having said that, it is also clear that some of the historic rules about margin assessment were arbitrarily set. The need to achieve a certain margin threshold is the kind of dogmatic rule that probably doesn’t apply anymore.” “Margins are related to recurrence, but the difference between ‘no ink on tumor’ and 1 mm, for example, is very small, and it’s easy to over-interpret these very tiny differences. In the modern era, where we have good imaging, good attention to surgical detail, good attention to radiotherapy and systemic drug therapy—those issues get even smaller,” Dr. Burstein said. “The main thing is,” he said, “good breast cancer care is multidisciplinary. That means having a great pathologist working together with other clinicians.” n Disclosure: Dr. Burstein reported no potential conflicts of interest.

Furthermore, ink can “stray” from its intended mark and render the specimen surface hard to read. And there is no uniform sampling method for lumpectomy specimens, therefore, this process is subject to sampling error, he added. “Sampling ranges from very limited sectioning to total sequential embedding,” Dr. Schnitt said. “And even with total, sequential embedding, only a small proportion of the specimen is examined microscopically.” For example, Dr. Schnitt explained, suppose a 4.2-cm lumpectomy specimen is cut at 3-mm intervals, resulting in 14 slices. Each slice is embedded in paraffin and cut at 5 microns, resulting in 14 sections, 5 microns each. This amounts to 70 microns of tissue examined from a 4.2-cm specimen, which totals only 0.2% of the specimen. “Even when we entirely embed the specimen, we are examining less than 1% of it. Complete histologic ex-

Surgical Margins in Ductal Carcinoma in Situ ■ A retrospective analysis of 253 patients with ductal carcinoma in situ found that locoregional recurrence and survival did not differ according to margin status—close vs negative margins. ■ Locoregional recurrence was documented in 13 patients, including those with negative margins and those with close margins.

amination of this 4.2-cm lumpectomy specimen would require 8,400 slides,” he said.

Issues With Definitions and Measurements There is also no general agreement among surgeons or radiation oncologists as to what constitutes an adequate negative margin. In fact, there is no margin width about which more than 50% of these professionals agree is “adequate” or “negative,” Dr. Schnitt said. All the available data are from retrospective studies; the issue has never been addressed in randomized trials and never will be, he added. The lack of a standard definition of what constitutes an adequate or negative margin has resulted in large variability in reexcision rates following breast-conserving surgery. A 2012 study of 54 surgeons found their reexcision rates for patients with negative margins varied from 0% to 70%.2 Almost half of the reexcisions, in fact, were performed on patients with negative margins (ie, no tumor at the inked tissue edge). Another critical issue, he said, is “How well does any given margin measurement reflect reality?” Dr. Schnitt continued on page 39

ASCOPost.com | OCTOBER 15, 2014

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2014 Breast Cancer Symposium With Breast-Conserving Surgery, Margin Status Not a Factor in Recurrence By Caroline Helwick

n a chart review of 754 early-stage breast cancer patients undergoing breast-conserving surgery, margin status did not impact risk of locoregional recurrence or breast cancer-specific survival, though it did predict for overall survival, as did numerous other factors. Tumor biology remained the most significant determinant of outcome, Jared Forrester, MD, and investigators from the Medical College of Wisconsin in Milwaukee reported.1 The research was presented recently at

the 2014 Breast Cancer Symposium in San Francisco. Margin status was defined as negative when there was ≥ 2 mm between the tumor and the surrounding tissue excised, close when there was < 2 mm, and positive when there was tumor on ink. Margin status was not significantly associated with locoregional recurrence, which was observed in 28 patients. Increased risk was conferred by tumor grade 3 (7.5-fold) and no

radiotherapy (6.7-fold), Dr. Forrester reported. Breast cancer subtype was significantly associated with breast cancerspecific survival and was highest for patients with luminal A tumors. Risk was increased for basal (22.5-fold), luminal B (19.9-fold), and HER2-positive (16.5-fold) tumors, as well as for tumors of unknown subtype (6.7-fold). Margin status was not significant. Overall survival for the population was 92%, and many factors were pre-

Partial Mastectomy Specimen

the treatment recommendation. “If I had not pursued this, I would have said this was a 2-mm margin, which most surgeons and radiation oncologists would agree is fine, considering the patient would be irradiated. In reality, this was a margin of less than 1 mm.” Microscopic foci of residual disease in the breast are frequent, even with clearly negative margins and even with

T1 tumors. In one classic study, 42% of patients with tumors that were < 2 cm and excised with a 2-cm margin were found to have residual disease, with invasive cancer and ductal carcinoma in situ occurring equally.3 Residual disease was also found in 17% of patients with 3-cm margins and in 10% with 4-cm margins— “and these results are for margin widths that are all unacceptably large,” Dr. Schnitt said.

continued from page 38

offered a case in point from his own practice. The specimen showed the distance from tumor to ink to be 2 mm, however, a suspicious area provoked Dr. Schnitt to look further at additional sections obtained from the same tissue block. On these subsequent levels, he found the tumor was actually < 1 mm from the margin, which changed

In Ductal Carcinoma in Situ, Margin Status Need Not Dictate Reexcision By Caroline Helwick

study of 252 patients with ductal carcinoma in situ raises questions regarding the need to reexcise close margins.1 The findings were presented at a poster session during the 2014 Breast Cancer Symposium by Rachel Gentile, BS, of the Medical College of Wisconsin. The researchers evaluated data from 252 patients with ductal carcinoma in situ, who underwent breastconserving surgery between 2003 and 2010. Two-thirds of patients also underwent radiation therapy and about one-half received hormonal therapy. After a median follow-up of 5 years, margin status was not found to be predictive of locoregional recurrence, breast cancer-specific survival, or overall survival, the retrospective

study showed. The researchers defined close margins as < 2 mm (observed in 29%) and negative margins as ≥ 2 mm (achieved in 63%); one patient had a positive margin, and margin status was not determined in 7% of patients. Overall survival at 5 years was 96%. Locoregional recurrence was documented in 13 patients, 5 of whom had close margins, 7 of whom had negative margins and 1 of whom had margins of unknown status. Median time to recurrence was almost 5 years. In the multivariate analysis, locoregional recurrence was significantly more likely among older patients (> 70), who had almost a sevenfold risk. Risk was increased sixfold for patients with progester-

one receptor-negative tumors. In addition, mortality was four times higher in the absence of radiation therapy, but no variables were significantly associated with breast cancer-specific survival. In their poster, the investigators suggested that for patients with ductal carcinoma in situ, “routine re-excision for close margins may not be warranted.” n Disclosure: Ms. Gentile reported no potential conflicts of interest.

Reference 1. Gentile R, Currey AD, Forrester JA, et al: The significance of margin status in patients with DCIUS undergoing breastconserving surgery. 2014 Breast Cancer Symposium. Abstract 98. Presented September 4, 2014.

dictive: margin status, age, race, nodal status, chemotherapy, anti-endocrine therapy, and radiation. n

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

Reference 1. Forrester J, Currey AD, Tuyishi B, et al: The effect of margin status and molecular subtype on women with invasive breast cancer treated with breast-conservation therapy. 2014 Breast Cancer Symposium. Abstract 83. Presented September 4, 2014.

Does Margin Width Really Matter? “So, given the foregoing information, do millimeters really matter in margin assessment?” Dr. Schnitt asked. “In fact, in current clinical practice, margin width must be viewed in the context of other factors that influence the risk of local recurrence, such as breast cancer subtype and the impact of systemic therapy.” Fortunately, multidisciplinary conferences help guide patient care in complex cases. A new understanding of risks imposed by subtype and the efficacy of modern systemic therapy also help to ameliorate pitfalls in the pathologic assessment, though systemic therapy, by itself, does not compensate for inadequate resection, Dr. Schnitt cautioned. n

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

References 1. Williams AS, Hache KD: Recognition and discrimination of tissue-marking dye color by surgical pathologists: Recommendations to avoid errors in margin assessment. Am J Clin Pathol 142:355-361, 2014. 2. McCahill LE, Single RM, Aiello Bowles EJ, et al: Variability in reexcision following breast conservation surgery. JAMA 307:467-475, 2012. 3. Holland R, Veling SH, Mravunac M, et al: Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 56:979-990, 1985.

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Important Safety Information • Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

Myelosuppression—notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

• Bone Marrow Suppression: In the randomized trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigotreated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo.

Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure

• Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care • Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have

600-10-0007-14d

07/14

Printed in USA

• In the ALSYMPCAa exploratory updated analysis,b median overall survival was 14.9 months for Xofigo (95% confidence interval [CI]: 13.9-16.1) vs 11.3 months for placebo (95% CI: 10.4-12.8) [hazard ratio (HR)=0.695; 95% CI: 0.581-0.832]1 • In the ALSYMPCA prespecified interim analysis, median overall survival was 14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2) [P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)]1

30% reduction in the risk of death vs placebo1

ALSYMPCA was a phase 3, randomized, double-blind, controlled trial that evaluated Xofigo plus best standard of care (n=614) vs placebo plus best standard of care (n=307).1

An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1

To learn more, visit www.xofigo-us.com

not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued

reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)

• Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations

References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

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

• Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were

radium Ra 223 dichloride INJECTION

Xofigo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE Because clinical trials are conducted under widely varying conditions, adverse reaction rates Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of symptomatic bone metastases and no known visceral metastatic disease. another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with 2 DOSAGE AND ADMINISTRATION bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) 2.3 Instructions for Use/Handling of Xofigo and best standard of care and 301 patients received placebo and best standard of care General warning once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, organization. vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% Xofigo should be handled by the user in a manner which satisfies both radiation safety and of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, Treatment discontinuations due to adverse events occurred in 17% of patients who received caregivers and patient’s household members) from radiation or contamination from spills of bodily Xofigo and 21% of patients who received placebo. The most common hematologic laboratory fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). accordance with national and local regulations. Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal Xofigo exceeds the incidence for placebo. precautions for handling and administration such as gloves and barrier gowns when handling Table 3: Adverse Reactions in the Randomized Trial blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected System/Organ Class Xofigo (n=600) Placebo (n=301) area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 safety officer should be contacted immediately to initiate the necessary measurements and required % % % % procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamineBlood and lymphatic system disorders tetraacetic acid (EDTA) solution is recommended to remove contamination. Pancytopenia 2 1 0 0 For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times Gastrointestinal disorders after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect Nausea 36 2 35 2 caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly Diarrhea 25 2 15 2 and separately from other clothing. 19 2 14 2 Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. Vomiting The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. General disorders and administration site conditions The external radiation exposure associated with handling of patient doses is expected to be low, Peripheral edema 13 2 10 1 because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is Renal and urinary disorders recommended to minimize the time spent in radiation areas, to maximize the distance to radiation Renal failure and impairment 3 1 1 1 sources, and to use adequate shielding. Any unused product or materials used in connection with Laboratory Abnormalities the preparation or administration are to be treated as radioactive waste and should be disposed of Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which in accordance with local regulations. the incidence for Xofigo exceeds the incidence for placebo. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Table 4: Hematologic Laboratory Abnormalities 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

Hematologic Laboratory Abnormalities

Xofigo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel. Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo. Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. 3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹ CHANNELÂŹ blockers did not affect the safety and efficacy of Xofigo in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo 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 Xofigo. 8.3 Nursing Mothers Xofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, 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 Xofigo in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ RADIUM ÂŹ ISÂŹ neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data. 8.7 Patients with Renal Impairment No dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)]. 8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo. Infertility There are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of Xofigo during clinical studies. There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGO ÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with Xofigo. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGO ÂŹ &OLLOWÂŹ good hygiene practices while receiving Xofigo and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹPOTENTIALÂŹ to use a highly effective method of birth control during treatment and for 6 months following completion of Xofigo treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway Xofigo is a trademark of Bayer Aktiengesellschaft. ÂŠ 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: 05/2013 "3

The ASCO Post | OCTOBER 15, 2014

PAGE 44

2014 Breast Cancer Symposium Testosterone/Anastrozole Implants Relieve Menopausal Symptoms in Breast Cancer Survivors By Caroline Helwick

ubcutaneous implants containing testosterone in combination with a low dose of anastrozole can relieve menopausal symptoms in breast cancer survivors, according to research presented at the 2014 ASCO Breast Cancer Symposium.1

seek her out for relief of menopausal symptoms, she told The ASCO Post. The objective of the approach is to relieve symptoms related to hormone deficiency and/or endocrine therapy. “We are delivering testosterone and anastrozole for symptom relief. By the [internal review board] protocol, we are not treating their breast cancer, however, we believe there is an anticancer effect as well. We have seen no recurrences of cancer in up to 8 years of therapy,” Dr. Glaser said.

Study Details

Rebecca Glaser, MD

“Menopausal symptoms can be quite severe in breast cancer survivors in whom estrogen therapy is contraindicated. These women have been told that nothing can be done about this, and they are miserable. Our approach takes care of these symptoms— the joint pain and muscle aches, fatigue, even memory complaints,” said Rebecca Glaser, MD, a surgeon at Wright State University in Dayton, Ohio. Since 2006, Dr. Glaser has performed more than 1,000 pellet insertions in patients with breast cancer using subcutaneous implants containing testosterone or testosterone plus anastrozole (Fig. 1). Many of her surgical patients continue seeing her for these implants. Oncologists also refer patients to her, and some postmenopausal women without cancer also

The goal of the current study was to prospectively assess the clinical effect of this combination on menopausal symptoms—psychological, somatic, and urogenital complaints—in breast cancer survivors (stage 0–IV). Efficacy of therapy was documented using the validated, self-administered, 11-item Menopause Rating Scale (see sidebar), which patients completed prior to and following therapy. The study enrolled and analyzed 72 breast cancer survivors, most of whom were no longer being treated for cancer. More than 90% of patients were treated with 8 mg anastrozole. The mean dose of testosterone, which is dosed based on weight, was 169 mg released over approximately 100 days. The pellets are completely absorbable and were inserted subcutaneously in the gluteal or inguinal area every 3 months on average. Therapeutic testosterone levels were confirmed without elevation of estradiol in any postmenopausal woman.

Menopause Rating Scale

he Menopause Rating Scale is a questionnaire evaluating the severity of 11 symptom categories related to menopause on a scale from 0 (no symptoms) to 4 (extremely severe). These include such symptoms as hot flashes, heart discomfort, trouble sleeping, depressive feelings, irritability, sexual problems, vaginal dryness, mental and physical exhaustion, joint and muscular pain, and more. Women assign a number next to each of the eleven symptoms identified on the questionnaire. Three subscales of symptoms are identified and scored: psychological, somatic, and urogenital. The total and subscale scores are indicative of the severity of a woman’s symptoms and the impact of such symptoms on quality of life. The scale can also be used to measure the impact of treatments to reduce menopausal symptoms. n

Reduction in Symptoms Attributed to Implant The investigators noted statistically significant improvements in the Menopause Rating Scale total score and all subscales (P < .0001), including the following: • Psychological complaints (depression, irritability/aggression, anxiety) • Somatic complaints (hot flashes/ sweating, heart discomfort, sleep problems, physical exhaustion, impaired memory, joint/muscular pain)

• Urogenital complaints (vaginal dryness, bladder problems/incontinence, sexual problems) In addition, all individual symptoms or conditions, including hot flashes, improved after patients received the testosterone/anastrozole implants (P < .0001) (Fig. 2). Total symptoms scores were reduced (ie, improved) by 81% in the total scale, by 86% on the psychological symptom scale, by 74% on the somatic symptom

Summary of MRS responses Post

Pre Hot flashes Heart discomfort Sleep Depression Irritability Anxiety Physical or mental exhaustion Sexual problems Bladder problems Vaginal dryness Joint and muscular discomfort 100

none

Fig. 1: 6 mm x 3.1 mm, 60 mg testosterone + 4 mg anastrozole combination pellet implant.

mild

50 100 100 Percent

moderate

severe

100

very severe

Fig. 2: Summary of distribution of severity scores on Menopausal Rating Scale (MRS) in each of the 11 categories pre- and post-therapy with testosterone plus anastrozole.

ASCOPost.com | OCTOBER 15, 2014

PAGE 45

2014 Breast Cancer Symposium scale, and by 81% on the urogenital symptom scale. “There have been no adverse drug events in any breast cancer survivor treated with parenteral testosterone/ anastrozole therapy,” Dr. Glaser added. “The only side effect has been a slight increase in facial hair, and we offer laser hair removal for $25 for women bothered by this,” she added.

observed in postmenopausal patients, she added. “Our findings support testosterone’s direct, therapeutic effect via the androgen receptor,” Dr. Glaser offered. “Also, the absence of adverse events and the lack of breast cancer recurrences support the safety of these doses in breast cancer survivors.”

Alliance to Evaluate Approach Dr. Glaser indicated that the Alliance A221102 Cooperative Group trial will evaluate the use of subcutaneous testosterone implants in the adjuvant treatment of postmenopausal women with arthralgias related to aromatase inhibitor use. The study will randomize 224 women to subcutaneous testoster-

one or placebo given every 3 months for 6 months. n

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

Reference 1. Glaser RL, York AE, Dimitrakakis C: Breast Cancer Symposium. Abstract 109. Presented September 4, 2014.

Rationale for the Treatment There is strong rationale for using testosterone to treat symptoms related to hormone deficiency in women, she said. Testosterone is the most abundant biologically active female hormone (20 times that of estrogen), is essential for physical and mental health in women and is breastprotective, according to Dr. Glaser. The women achieved a mean level of testosterone of 354 ng/dl, which may appear high, but testosterone’s effect is dose-dependent and these doses are necessary for the treatment to work, she pointed out. “We have previously demonstrated that pharmacologic doses of exogenous testosterone delivered by the subcutaneous implant are necessary for a physiologic effect, replacing both testosterone and the significant contribution of androgen precursors to testosterone production at the cellular level,” she explained in interview. “These patients are not 20-year-olds, who have high levels of testosterone and more importantly, thousands times higher levels of the androgen precursors DHEA [dehydroepiandrosterone] and androstenedione, which also decline with age,” she continued. “Serum levels are fluctuating and transient. The bottom line is, you have to get enough testosterone to the androgen receptor to create a biological effect or clinical response. Some studies have failed to show efficacy because the doses were too low. The doses used in the study and levels on therapy are justifiable: we showed treatment efficacy—every symptom category improved significantly—as well as tolerability and safety,” she noted. No elevations in estradiol have been

Testosterone Implants in Breast Cancer Survivors ■ Symptoms related to menopausal or endocrine therapy were significantly reduced in breast cancer survivors who received treatment with testosterone plus a low dose of anastrozole.

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

Randomized 1:1

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 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 | OCTOBER 15, 2014

PAGE 46

2014 Breast Cancer Symposium Fertility Preservation Suggested With Triptorelin in Long-Term Study By Caroline Helwick

oung women with early breast cancer may be more likely to resume menses and become pregnant when treated with a luteinizing hormone– releasing hormone (LH-RH) analog (also known as a gonadotropin-releasing hormone [GnRH] analog) along with chemotherapy, according to the final follow-up of PROMISE-GIM6, a phase III multicenter trial reported at the 2014 Breast Cancer Symposium.1 “Data from PROMISE and POEMS [another recent trial] support the use of LH-RH analogs during chemotherapy as a strategy to preserve ovarian function and fertility in breast cancer patients,” said Matteo Lambertini, MD, an oncology fellow working with Dr. Del Mastro at the IRCCS AOU San Martino-IST in Genova, Italy.

Historically Mixed Results Eight randomized trials and eight systematic reviews have evaluated the role of LH-RH analogs as a strategy to preserve ovarian function in breast cancer patients, with mixed results. Data on long-term outcomes is scarce, he said. The current ASCO and European Society for Medical Oncology (ESMO) guidelines consider this approach experimental. Dr. Lambertini suggested that “current guidelines should consider updating recommendations for fertility preservation in this setting, adding LHRH analogs as a widely available option.” While calling the PROMISE study “impressive” in its achievement of longterm outcome data on more than 85% of its population, Hope S. Rugo, MD, Professor of Medicine and Director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, cautioned that the data on fertility preservation remain premature. “[LH-RH] analogs,” she said, “are not a substitute for established methods.”

PROMISE Details Dr. Lambertini presented updated results from PROMISE-GIM6 after 7.3 years of follow-up. The 1-year results showed a highly significant 72% reduction in the risk of treatment-related early menopause in women receiving adjuvant triptorelin (Trelstar), vs chemotherapy alone.2 In the updated analysis, women in the PROMISE-GIM6 study were more than twice as likely to become pregnant

over 7 years when treated with adjuvant triptorelin compared with chemotherapy alone. The fact that disease-free survival was similar confirmed the safety of the combination in cancer patients, Dr. Lambertini said. PROMISE-GIM6 was a multicenter, open-label trial of 281 premenopausal women with early-stage breast cancer who were candidates for neoadjuvant or adjuvant chemotherapy. Eighty percent of subjects had hormone receptor– positive disease. Patients were randomly assigned to chemotherapy alone (n = 133) or chemotherapy plus triptorelin at 3.75 mg every 4 weeks (n = 148) starting at least 1 week prior to chemotherapy and continued for the duration of treatment. After a median follow-up of 7.3 years, these were the key findings: • There were eight pregnancies in the triptorelin arm vs three in the chemotherapy-alone arm. The incidence rate of pregnancy was 0.9 per 100 person-years vs 0.4 per 100 person-years in the respective arms. • The 5-year cumulative incidence of pregnancy was 2.9% in the triptorelin arm and 1.6% in the chemotherapy-alone arm, respectively, yielding a hazard ratio (HR) of 2.56 (P = .142). • The 5-year cumulative incidence estimate of resumption of menses at any time was 72.6% vs 64.0%, respectively (HR = 1.28, P = .071). • The 5-year disease-free survival rate was 80.5% and 83.7%, respectively (HR = 1.17, P = .519). • The 5-year overall survival was 93.3%, with no statistical comparison between the arms due to a low number of events. Dr. Lambertini said that while these findings were nonsignificant trends, they support those from the recent PO-

EMS study, reported at the 2014 ASCO Annual Meeting.3 In POEMS, hormone receptor–negative patients receiving the LH-RH agonist goserelin (Zoladex) had a lower rate of ovarian failure at 2 years (8% vs 22%) and twice the likelihood of pregnancy (adjusted odds ra-

age, followed by diminished ovarian reserve (which is difficult to measure). Type, dose, and schedule of chemotherapy also matter (higher doses are related to greater risk), as does the use of endocrine therapy. Options for preserving fertility

Current guidelines should consider updating recommendations for fertility preservation in this setting, adding LH-RH analogs as a widely available option. —Matteo Lambertini, MD

The use of [LH-RH] agonists during chemotherapy to protect ovarian function remains controversial. —Hope S. Rugo, MD

tio = 2.45) compared with women not receiving this drug. Unlike PROMISE, the study did not include women with hormone receptor–positive disease.

Caution: More Data Needed In her discussion of this paper, Dr. Rugo emphasized that fertility preservation is a factor for many of the 20,000 women of childbearing age diagnosed with breast cancer each year. “This is an important issue for oncologists and patients,” she said. The most important risk factor for ovarian failure, she noted, is increasing

Triptorelin in Young Breast Cancer Patients ■ Young breast cancer patients receiving the LH-RH analog triptorelin showed a trend toward more resumption of menses and achievement of pregnancy at 7 years post-treatment than the control arm in the final analysis of PROMISE-GIM6. ■ The 5-year cumulative incidence of pregnancy was 2.9% in the triptorelin arm and 1.6% in the chemotherapy-alone arm, respectively, yielding a hazard ratio of 2.56 (P = .142). ■ Women with hormone receptor–positive disease received continued ovarian suppression for 2 years, which may have diluted the potential for showing statistically significant differences. ■ At a median follow up of 7.3 years, no differences in disease-free survival between treatment arms were observed (HR = 1.17, 95% CI = 0.72–1.92, P = .519).

include ovarian stimulation, ie, cryopreservation of embryos and oocytes. “Ovarian stimulation is the most proven method of fertility preservation for young women with breast cancer, and with current techniques, this now takes only about 2 weeks, which is a very modest delay for most women starting chemotherapy,” she noted. On the other hand, the use of LH-RH agonists as a means of ovarian suppression for fertility preservation has mostly been studied in small trials, with mixed results and no long-term data. This strategy has also not been met with enthusiasm by some fertility specialists, who point out that it may not be protecting the primordial follicles. Alkylating agents induce amenorrhea by affecting the resting oocyte/primordial follicles, she indicated. In the PROMISE study, the impact of triptorelin is hard to determine, since patients whose ovarian function resumed within 1 year could receive monthly triptorelin for at least 2 years, said Dr. Rugo. Also, 93% received adjuvant endocrine therapy, 23% with tamoxifen alone and almost 70% with tamoxifen or an aromatase inhibitor plus triptorelin. “The investigators did this because continued on page 48

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The ASCO Post | OCTOBER 15, 2014

PAGE 48

2014 Breast Cancer Symposium CTNeoBC Analysis: Response to Neoadjuvant Chemotherapy Varies by Breast Tumor Subtype By Caroline Helwick

omen who achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy rarely have local or regional recurrence of breast cancer, but this largely depends on tumor subtype, which remained an independent predictor of locoregional recurrence when pathologic response was taken into account in the CTNeoBC analysis. These findings—which were derived from the pivotal meta-analysis of pCR studies by Cortazar et al,1 involving almost 12,000 women—were presented at the 2014 Breast Cancer Symposium by Eleftherios (Terry) P. Mamounas, MD, MPH, FACS, Medical Director of the Comprehensive Breast Program at the UF Health Cancer Center in Orlando, Florida. Dr. Mamounas is also Chairman of the Breast Committee of NRG Oncology, Philadelphia.

Controversial Measures “There is limited information on rates and patterns of [locoregional recurrence] in patients treated with neoadjuvant chemotherapy, and this has resulted in controversy on the use of sentinel lymph node biopsy and postoperative radiotherapy,” Dr. Mamounas noted. He said the various associations between pathologic complete response and locoregional recurrence, by tumor subtype, “can potentially help to better

Fertility Preservation continued from page 46

they believed that ovarian suppression was an important part of treating patients with estrogen receptor–positive disease,” she noted. Because of this design, long-term follow-up understandably showed no statistically significant difference in the resumption of menses 7 years later, she said. “I would also be hesitant for patients with higher-risk estrogen receptor–positive breast cancer to preserve their ovaries and ovarian function, since various datasets suggest that ovarian function suppression may be an important part of treatment, as it improves disease-free survival,” she said. “Maybe we don’t want all of the ovarian function to improve right away, following treatment in estrogen receptor–positive patients with high-risk disease.” The National Surgical Adjuvant

identify patients at higher risk for recurrence who may benefit from the addition of radiotherapy, and those at low risk who may not need it.” The data presented found that pathologic complete response and tumor subtype were both strong predictors of locoregional recurrence. These two predictors may be more informative than tumor stage at diagnosis, Dr. Mamounas reported. In an interview with The ASCO Post, Dr. Mamounas said, “This confirms

subtypes, pCR doesn’t matter as much, as locoregional recurrence rates were low for all groups irrespective of pCR.” “We saw that a bad prognostic factor becomes less important if you achieve a pCR,” Dr. Mamounas said.

Study Details While both pathologic complete response and breast cancer subtypes have been shown to independently predict for locoregional recurrence, the combined effect of both these factors on

Particularly in the unfavorable subtypes—triple-negative, HER2positive, and high-grade hormone receptor–positive patients—having positive nodes does not bode well in terms of locoregional recurrence. —Eleftherios (Terry) P. Mamounas, MD, MPH, FACS

what we have known from previous trials about the meaning of [pathologic complete response]. Having a pCR puts the patient at low risk for recurrence, but within that group, you do see differences by subtype. In the worse subtypes, such as triple-negative, women who achieve a pCR have recurrence rates in the single digits, even those with locally advanced disease. For good-prognosis

locoregional recurrence has not been established. By examining predictors of locoregional recurrence after neoadjuvant chemotherapy, the CTNeoBC aimed to elucidate this issue. The main definition of pathologic complete response used was ypT0/is, ypN0 (ie, absence of invasive cancer in the breast and axillary nodes; ductal carcinoma in situ allowed). The end-

Breast and Bowel Project (NSABP) B-30 substudy established that in women with high-risk estrogen receptor–positive disease, amenorrhea for ≥ 6 months predicted for improved overall survival (HR = 0.52, P = .002) and disease-free survival (HR = 0.51, P < .001).4 There are also caveats to the findings from POEMs, which was compromised by the fact that for almost half its enrollees, long-term outcomes could not be determined, she added. Strategies for reducing ovarian failure, she added, are hard to assess, as fertility is not the same as amenorrhea, levels of follicle-stimulating hormone are not predictive, and the desire for pregnancy is highly individualized and changes over time. Furthermore, definitions of ovarian failure vary widely, and modern treatments may be associated with lower rates than are currently estimated from older regimens, she pointed out.

Conclusions In short, Dr. Rugo cautioned, “The use of [LH-RH] agonists during chemotherapy to protect ovarian function remains controversial. Given the lack of apparent risk, however, they could be considered in patients with estrogen receptor–negative disease, with a discussion of the known benefits. They are not a substitute for established methods.” Ongoing trials (eg, SOFT) and future trials (eg, POISE) are expected to provide more answers on this issue. n

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

References 1. Lambertini M, Boni L, Michelotti A, et al: Long-term outcome results of the phase III PROMISE-GIM6 study evaluating the role of LHRH analog during chemotherapy as a strategy to reduce

points were time to first locoregional recurrence in the absence of prior distant recurrence (locoregional recurrence concurrent with distant recurrence was included as a locoregional recurrence event), and cumulative incidence of locoregional recurrence. Risk factors evaluated in the model included age (≥ 50 or < 50 years), tumor subtype, pCR status, baseline stage, and surgery type (lumpectomy or mastectomy). Postoperative radiotherapy was delivered to virtually all lumpectomy patients and to about one-third of mastectomy patients. Trastuzumab (Herceptin) was given to HER2-positive patients neoadjuvantly in 38% of cases and adjuvantly in 45%. The investigators assessed locoregional recurrence rates among 11,995 women with stage I to III breast cancer treated with neoadjuvant chemotherapy. After a median follow-up of 5.4 years, locoregional recurrences occurred in 992 (8.3%) patients. “In patients treated with neoadjuvant chemotherapy, the overall 5-year rates of [locoregional recurrence] were generally low—less than 10%,” Dr. Mamounas noted. Data on all covariates in the multivariable analysis were available for 5,252 patients, of whom 391 had locontinued on page 49

ovarian failure in early breast cancer patients. ASCO Breast Cancer Symposium. Abstract 105. Presented September 4, 2014. 2. Del Mastro L, Boni L, Michelotti A, et al: Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: A randomized trial. JAMA 306:269-276, 2011. 3. Moore HCF, Unger JM, Phillips KA, et al: Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy to reduce ovarian failure in earlystage, hormone receptor-negative breast cancer. ASCO Annual Meeting. Abstract LBA505. Presented May 31, 2014. 4. Swain SM, Jeong JH, Geyer CE Jr, et al: Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med 362:2053-2065. 2010.

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2014 Breast Cancer Symposium CTNeoBC Analysis continued from page 48

coregional recurrences. The median follow-up for this group was 3.5 years.

pCR as Predictor for Recurrence The 5-year cumulative incidence of locoregional recurrence by breast pCR and nodal status post-treatment was 6.2% for women attaining pathologic complete response (ypT0/is, ypN0), 6.7% for those with residual disease in the breast only (ypT1-3, ypN0) and 11.8% for those with positive nodes (ypTany, ypN+). Compared to women with a pCR, those with residual disease in the breast and none in the nodes had a 1.6 times increased risk of locoregional recurrence, whereas those with cancer in the nodes had a 2.7 times higher risk of recurrence (P < .0001). “Particularly in the unfavorable subtypes—triple-negative, HER2positive, and high-grade hormone receptor–positive patients—having positive nodes does not bode well in terms of locoregional recurrence,” he added. These patients may need more aggressive local therapy and radiotherapy. The effect of pathologic complete response on locoregional recurrence was evident in patients treated with either mastectomy or lumpectomy plus breast radiotherapy.

Tumor Subtype as Predictor of Recurrence The rate of locoregional recurrence varied considerably by tumor subtype (P < .001), with the highest

rate (14.8%) observed among patients with hormone receptor–negative/ HER2-positive tumors and the lowest rate (4.2%) among women with grade 1 or 2 hormone receptor–positive/HER2-negative tumors. Locoregional recurrence rates were 12.2% for patients with triple-negative disease, 9.7% for patients with hormone receptor–positive/ HER2-positive tumors, and 9.2% for those with grade 3 hormone receptor–positive/HER2negative tumors. The odds ratios give an idea of the increased risk by subtype. For example, compared to patients with grade 1 or 2 hormone receptor–positive/HER2negative tumors, patients with hor-

Pathologic Complete Response and Locoregional Recurrence ■ Both pCR and tumor subtype are independent predictors of locoregional recurrence. ■ In women with poor-prognosis subtypes, the achievement of pCR has a favorable impact on reducing the risk of locoregional recurrence.

mone receptor–negative/HER2-positive tumors had a five times increased risk for locoregional recurrence. Age, baseline stage (3 vs 1 or 2), and surgery type were not independent predictors of recurrence. However, Dr. Mamounas added that in women undergoing lumpectomy, age “does matter.” Higher risk is incurred in younger women with poor-progno-

EXPERT POINT OF VIEW

t the Breast Cancer Symposium, William M. Sikov, MD, Associate Professor of Medicine at the Warren Alpert Medical School of Brown University, Providence, Rhode Island, gave a talk on the use of pathologic complete response in the clinic and summarized the CTNeoBC findings for The ASCO Post. “The study showed that patients who have more aggressive cancers are more likely to respond to William M. Sikov, MD neoadjuvant chemotherapy, and receive the greatest benefit if they achieve a pCR. On the other hand, if these patients do not respond they tend to have the poorest prognosis,” he said. “This information does guide me in the clinic,” he said. “If patients with high-grade cancers achieve pCRs, not only are we likely improving distant recurrence but also locoregional recurrence. It’s another reason to consider neoadjuvant treatment—in part, to be able to assess response to therapy, which we can’t do in the adjuvant setting. Down the road, this may allow us to tailor our locoregional therapy to fit the patient’s needs.” n Disclosure: Dr. Sikov reported no potential conflicts of interest.

sis subtypes, especially those lacking pathologic complete responses. In this younger age group, locoregional recurrence occurred in 35% of hormone receptor–negative/HER2-positive women who did not achieve a pCR, vs 11% of those with a pCR, he reported. “Age is an independent predictor of [locoregional recurrence] in lumpectomy patients, but not in mastectomy patients,” he said. “They may need more intensive treatment.” He also noted that the study’s findings support the conduct of ongoing clinical trials attempting to individualize the use of radiotherapy and surgery in patients treated with neoadjuvant chemotherapy: NSABP B-51/RTOG 1304 and ALLIANCE 11202. n

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

References 1. Mamounas EP, Cortazar P, Zhang L, et al: Loco-regional recurrence after neoadjuvant chemotherapy: Pooled analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC). Breast Cancer Symposium. Abstract 61. Presented September 4, 2014. 2. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 384:164-172, 2014.

Awards

Aron Goldhirsch, MD, Receives 2014 Gianni Bonadonna Breast Cancer Award

ron Goldhirsch, MD, was presented with the 2014 Gianni Bonadonna Breast Cancer Award and Lecture during the 2014 Breast Cancer Symposium, held recently in San Francisco. Dr. Goldhirsch is Director of the

Aron Goldhirsch, MD

Multidisciplinary Program of Senology and Deputy Scientific Director at the European Institute of Oncology, Milan, Italy. For his award lecture, Dr. Goldhirsch discussed adjuvant therapies developed over the past several decades. Dr. Goldhirsch is also Professor of Medical Oncology at the University of Bern, Switzerland. He is an international leader in the field of breast cancer. His areas of research include new adjuvant treatments for breast cancer, definition of biologic features that predict responsiveness or resistance to anticancer treatments, and quality-of-

life–oriented approaches. Dr. Goldhirsch’s commitment to international cooperation and clinical trials led him to chair the Update Committee of the Early Breast Cancer Trialists’ Collaborative Group, which conducts large-scale meta-analyses of breast cancer treatments. He is also ViceChair of the Breast International Group, a consortium of coop- Dr. Sandra M. Swain holds the 2014 Gianni Bonadonna Award presented to Dr. Aron Goldhirsch during the erative groups around the world 2014 Breast Cancer Symposium. Photo by © ASCO/Todd for conducting clinical trials for Buchanan 2014. breast cancer therapies. ASCO Past President Sandra M. award to Dr. Goldhirsch during the Swain, MD, FACP, presented the 2014 Breast Cancer Symposium. n

For patients with advanced gastric or gastroesophageal (GE) junction adenocarcinoma who have progressed on or after prior fluoropyrimidineor platinum-containing chemotherapy, CYRAMZA is the only FDA-approved antiangiogenic to significantly extend overall survival CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe

events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with ChildPugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

CYRAMZA monotherapy significantly extended overall survival (OS)1

CYRAMZA significantly delayed disease progression1 MAJOR OUTCOME MEASURE

OVERALL SURVIVAL: MEDIAN – MONTHS (95% CI)1 1.0

Placebo

months

(4.4, 5.7)

(2.8, 4.7)

5.2

0.8

OS PROBABILITY

CYRAMZA

0.6

3.8

Hazard Ratio=0.78 (0.60, 0.998); P=0.047

0.4

CYRAMZA Placebo

0.2

0.0 0

238 117

10 11 12 13

14 15 16 17 18 19

0 1

0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk CYRAMZA Placebo

154 66

92 34

49 20

17 7

• The percentage of deaths at the time of analysis was 75% (179 patients) and 85% (99 patients) in the CYRAMZA and placebo arms, respectively1

7 4

3 2

37%

• Median progression-free survival (PFS) with CYRAMZA was 2.1 months (95% CI: 1.5, 2.7) vs 1.3 months (95% CI: 1.3, 1.4) with placebo (hazard ratio 0.48 [95% CI: 0.38, 0.62]; P<0.001)1 — The percentage of events at the time of analysis was 84% (199 patients) and 92% (108 patients), respectively The phase III REGARD trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma who had progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measure was PFS. All patients were Eastern Cooperative Oncology Group Performance Status 0 or 1. Prior to enrollment, 85% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease, and 15% of patients progressed during treatment or within 6 months after the last dose of adjuvant chemotherapy. Patients were randomized 2:1 to CYRAMZA 8 mg/kg every 2 weeks + best supportive care (BSC) (n=238) or placebo + BSC (n=117).1 CI=confidence interval.

INCREASE IN MEDIAN OS

Most Common Adverse Reactions

Use in Specific Populations

• The most commonly reported adverse reactions (all grades; grade 3-4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

• The most common serious adverse events with CYRAMZA in Study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZAtreated patients vs 8.7% of patients who received placebo. • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%). • Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZAtreated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. • As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZAtreated patients with post-baseline serum samples tested positive for anti-ramucirumab antibodies using an enzymelinked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

Drug Interactions • No formal drug interaction studies have been conducted.

• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant. • Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility. Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on next page. RB HCP ISI 21JUL2014 Reference: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

CYRAMZATM (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information. WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. INDICATIONS AND USAGE CYRAMZA as a single-agent is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single-agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of CYRAMZA as a single agent was evaluated in 570 patients, including patients in Study 1 who received CYRAMZA. Study 1 randomized patients (2:1) to receive CYRAMZA 8 mg/kg intravenously every two weeks (n=236) versus placebo every two weeks (n=115) in a double-blind, placebo-controlled trial in previously treated gastric cancer. In Study 1, patients with an ECOG performance status of 2 or greater, bilirubin greater than or equal to 1.5 mg/dL, uncontrolled hypertension, major surgery within 28 days, or receiving chronic anti-platelet therapy other than once daily aspirin were excluded. Patients received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months. In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo. Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo Adverse Reactions N=236 N=115 (MedDRA)a All Grades Grade 3-4 All Grades Grade 3-4 System Organ Class (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a MedDRA Version 15.0. Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo). Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA–treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) of CYRAMZAtreated patients with post baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay TM

CYRAMZA (ramucirumab) injection

PA000IPAM00-BS 9.25x13.25

methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No formal drug interaction studies have been conducted. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single-agent. Geriatric Use Clinical Trials of CYRAMZA as a single agent did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 236 patients who received CYRAMZA in Study 1, 35% were 65 and over, while 9% were 75 and over. Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab. Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab. Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility. Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Recommended Dose and Schedule The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. Do not administer CYRAMZA as an intravenous push or bolus. Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Of increased risk of an arterial thromboembolic event. • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment. Additional information can be found at www.CYRAMZAhcp.com.

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FDA Update

FDA Grants Orphan Drug Designation to Bivalent Vaccine for Neuroblastoma

he U.S. Food and Drug Administration (FDA) has granted orphan drug designation to MabVax Therapeutics’ vaccine for the treatment of relapsed or recurrent high-risk neuroblastoma in remission or with limited residual disease after best available treatment. The bivalent vaccine is intended to elicit a targeted immune response against the

two most common antigens on neuroblastoma cells, GD2 and GD3. Results of a recent phase I published in Clinical Cancer Research demonstrated encouraging outcomes with the vaccine in a small cohort of patients with relapsed neuroblastoma.1 Antibody responses against GD2 and/ or GD3 were observed in 12 of 15 pa-

tients, and disappearance of minimal residual disease was documented in 6 of 10 patients assessable for response. A phase II trial is being planned for 2015. n

gliosides vaccine in combination with β-glucan for high-risk neuroblastoma in second or later remission. Clin Cancer Res 20:1375-1382, 2014.

Reference 1. Kushner BH, Cheung IY, Modak S, et a: Phase I trial of a bivalent gan-

Aldoxorubicin Receives FDA Orphan Drug Designations for Glioblastoma, Small Cell Lung Cancer, and Ovarian Cancer

he U.S. Food and Drug Administration has granted Orphan Drug Designations to aldoxorubicin in three indications: glioblastoma multiforme, small cell lung cancer, and ovarian cancer. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifi-

cally to albumin, allowing greater doses of the chemotherapeutic agent to be administered while reducing its toxic side effects. Aldoxorubicin is currently being studied in a global phase III clinical trial evaluating the efficacy and safety of aldoxorubicin as a second-

line treatment for patients with softtissue sarcoma. CytRx, a biopharmaceutical research and development company, is also evaluating aldoxorubicin in two phase II clinical trials, one in patients with late-stage glioblastoma multiforme and the other in HIV-related Kaposi’s sarcoma.

A global phase IIb trial in patients with relapsed small cell lung cancer is expected to commence later this month, and the company is undertaking a phase Ib combination study of aldoxorubicin plus gemcitabine as a potential precursor to a trial in relapsed ovarian cancer. n

Awards

CancerCare® Awarded $1.5 Million Grant From Susan G. Komen®

ancerCare, a leading national nonprofit organization providing free, professional support services to anyone affected by cancer, has received a $1.5 million grant to assist people diagnosed with breast cancer. The grant will support a CancerCare program in partnership with Susan G. Komen called “Linking A.R.M.S.” Linking A.R.M.S. provides financial assistance for breast cancer patients for hormonal and oral chemotherapy, pain and antinausea medication, child care, trans-

portation, lymphedema care, and durable medical equipment.

Hope to Thousands “We are tremendously grateful for the continued support of Susan G. Komen,” said CancerCare CEO Patricia J. Goldsmith (see interview with Ms. Goldsmith on page 136). “This substantial grant will provide help and hope to thousands of people diagnosed with breast cancer during what may be one of the most overwhelming times in their lives. Costs such

This substantial grant will provide help and hope to thousands of people diagnosed with breast cancer during what may be one of the most overwhelming times in their lives. —Patricia J. Goldsmith

A breast cancer diagnosis is a lifealtering event, and while patients are making difficult decisions about their medical care, day-to-day needs like childcare and transportation can be equally challenging. —Judith A. Salerno, MD, MS

as transportation and child care can oftentimes prevent our clients from receiving proper treatment and, thanks to Susan G. Komen, this will now be less of an obstacle for thousands of individuals.” “A breast cancer diagnosis is a life-altering event, and while patients are making difficult decisions about their medical care, day-to-day needs like childcare and transportation can be equally challenging. Last year alone, CancerCare provided direct financial assistance to 1,356 breast cancer patients undergoing

treatment. We’re pleased to again award funding to this important program to allow them to continue this work,” said President and CEO of Susan G. Komen, Judith A. Salerno, MD, MS.

For Additional Information Those interested in learning more or applying for financial assistance can visit www.cancercare.org/financial or call 800-813-HOPE (4673). To learn more, visit www.cancercare.org or call 800-813-HOPE (4673). n

The ASCO Post | OCTOBER 15, 2014

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AACR Special Conference on Pancreatic Cancer Gastrointestinal Oncology

Early Study Finds BRCA-Mutated Pancreatic Cancer Responds to PARP Inhibition Trio By Caroline Helwick

wo-thirds of patients with advanced pancreatic adenocarcinoma who harbored BRCA mutations responded to the combination of veliparib, cisplatin, and gemcitabine in a phase IB trial that is paving the way for future studies of novel poly(ADPribose) polymerases (PARP) inhibitors in this challenging tumor type. “BRCA-mutated [pancreatic adenocarcinoma] is a small but distinct subgroup seen mostly in Ashkenazi Jewish patients, those with familial [pancreatic

first-degree relative with the disease). PALB2, a partner and localizer to BRCA2 mutations, occurs in a smaller fraction (1%–3%) of cases of advanced pancreatic adenocarcinoma, but it is still important. The PALB2 protein stabilizes the BRCA2 protein and anchors it to the nucleus, allowing it to carry out its DNA repair function. More recently, PALB2 has been shown to associate with the BRCA1 protein as well, providing a linkage between BRCA1 and BRCA2 in homologous recombination

The triplet combination [veliparib/ cisplatin/gemcitabine] showed high activity in BRCA-related pancreatic adenocarcinoma. —Eileen M. O’Reilly, MD

creatic adenocarcinoma associated with BRCA1 or BRCA2 mutations,” she said. “DNA damage control may be a novel target and a therapeutic opportunity.”

Study of Veliparib Veliparib is a potent oral irreversible small molecule inhibitor of PARP 1 and 2. It is being evaluated in three nonrandomized trials in combination with cisplatin-based therapy in previously treated and also untreated patients with known BRCA or PALB2 mutations, or a very strong personal or family history of pancreatic, breast, and ovarian cancer that suggests these mutations may be present. Data have been analyzed for the phase IB lead-in dose-finalization study of this triplet combination, and Dr. O’Reilly presented the findings at the conference.1

Study Details adenocarcinoma], and patients with breast or ovarian cancer in the family. BRCA mutation may be a predictive biomarker for benefit to DNA-damaging drugs,” said Eileen M. O’Reilly, MD, Associate Director of Clinical Research at the Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York. At the American Association for Cancer Research (AACR) Special Conference on Pancreatic Cancer held recently in New Orleans, Dr. O’Reilly described the potentially new therapeutic direction for this subgroup of patients.

BRCA in Pancreatic Cancer BRCA mutations, especially BRCA2, convey an increased risk of developing pancreatic adenocarcinoma. Risk is estimated to be 2.2-fold in persons with BRCA1 mutations and 3.4- to 10-fold in those with BRCA2 mutations. While BRCA mutations are rare in the general population of patients with pancreatic adenocarcinoma—5% to 8%—their frequency rises to as high as 16% in patients of Ashkenazi Jewish heritage and perhaps to 19% in persons with familial pancreatic adenocarcinoma (ie, at least one

repair of double-stranded DNA breaks. DNA repair, however, can be compromised through PARP inhibition, and this might be harnessed therapeutically in pancreatic adenocarcinoma, Dr. O’Reilly said. PARP inhibition leads to transformation of single-strand breaks into doublestrand breaks that are cytotoxic in cells and renders them unable to be repaired

The study evaluated 17 patients with locally advanced or metastatic pancreatic adenocarcinoma, 9 of whom had a BRCA mutation and 10 who were BRCA wild-type. Four dose levels of veliparib were evaluated, in combination with cisplatin and gemcitabine. “The triplet combination showed high activity in BRCA-related pancreatic adenocarcinoma,” Dr. O’Reilly said. “The majority of patients are still alive.”

BRCA-Mutated Pancreas Cancer ■ In patients with locally advanced or metastatic pancreatic adenocarcinoma, BRCA mutations occur in a small percentage of patients overall, but in as many as one in six patients with familial disease or Ashkenazi Jewish heritage. ■ PARP inhibition with veliparib, in combination with cisplatin and gemcitabine, yielded responses in 66% of these patients. ■ A number of PARP inhibitors are now being evaluated in this tumor type.

through homologous repair. BRCAdeficient pancreatic cell lines are sensitive to cisplatin, mitomycin, and PARP inhibitors, and patients with BRCA mutations are sensitive to DNA-damaging agents, earlier studies have shown. “This effect of synthetic lethality provides the therapeutic rationale for the development of PARP inhibitors for pan-

In the BRCA-mutated subgroup, six patients responded, for an objective response rate of 66%, and three patients achieved stable disease, yielding a disease control rate exceeding 88%. Responses were observed in both BRCA1and BRCA2-mutated patients. “We saw a very high level of activity, with six partial responses, many of

which were sustained and several are still ongoing,” she said. The duration on study for all but one of the responders was at least 9 months. The exception was a patient who was recently treated for breast cancer, which might have dampened her response to the regimen, the investigators believe. In contrast, no significant activity was observed in non-BRCA-mutated patients. There were no responses, and the duration on treatment was less than 3 months. Two dose-limiting toxicities were observed: neutropenia (65% grade 3/4) and thrombocytopenia (59% grade 3/4), mostly with 80 mg daily continuous dosing. “Otherwise, the drug was fairly well tolerated,” she said.

Future Directions The first prospective randomized trial of this combination is underway in BRCA/PALB2-mutated patients with stage III/IV disease. The recommended phase II dose will be 80 mg veliparib twice daily on days 1 to 12 every 3 weeks, with fixed doses of cisplatin (25 mg/m2) and gemcitabine (600 mg/m2). Other PARP inhibitor studies in pancreatic adenocarcinoma are evaluating olaparib, rucaparib, and BMN673. In addition, a prospective registry of patients with BRCA-mutated pancreatic adenocarcinoma has been developed to better understand the molecular phenotype of BRCA-mutated disease vs several control cohorts. The registry is expected to provide insights into predisposing factors in high-risk persons. The investigators also hope to gain insight into other issues, such as the mechanisms of response and resistance to PARP inhibition and platinum, through the correlative science program. n

Disclosure: Dr. O’Reilly reported a financial relationship with Celgene.

Reference 1. O’Reilly EM: BRCA-mutated pancreas adenocarcinoma: Emerging therapeutic implications. AACR Special Conference on Pancreatic Cancer. Abstract IA28. Presented May 21, 2014.

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Journal Spotlight Thoracic Oncology

Significant Improvement in Overall Survival With Second-Line Addition of Ramucirumab to Docetaxel in Stage IV NSCLC By Matthew Stenger

n the phase III REVEL trial reported in Lancet, Edward B. Garon, MD, of the David Geffen School of Medicine at UCLA/Translational Research in Oncology–US Network, Los Angeles, and colleagues found that the addition of the antiangiogenic vascular endothelial growth factor receptor (VEGFR)-2 inhibitor ramucirumab (Cyramza) to docetaxel produced a statistically significant improvement in overall survival as secondline treatment in patients with non–small cell lung cancer (NSCLC) who had disease progression on or after platinumbased therapy.1 The findings indicate a role of VEGFR-2 inhibition in this setting. Ramucirumab is a human IgG1 monoclonal antibody that binds to the VEGFR-2 extracellular domain with high affinity and thus prevents binding of VEGF ligands and receptor activation.

(ever for 82% and 77%), histology (nonsquamous in 74% and 72%, squamous in 25% and 27%), EGFR status (mutant in 2 % and 3%, unknown in 65% and 66%), best response to platinum-based chemotherapy (response or stable disease in 67% in both), previous maintenance treatment (21% and 23%), previous taxane (24% in both), previous bevacizumab (14% and 15%), and time since previous therapy (< 9 months in 64% and 60%).

Improved Overall Survival After a median follow-up of 9.5 months in the ramucirumab group and 8.8 months in the control group, median overall survival was 10.5 months (interquartile range = 5.1–21.2

Toxicity The most common clinical adverse events of any grade in the ramucirumab group were fatigue (55% vs 49% in the

[I]n patients with advanced nonsmall-cell lung cancer with disease progression during or after first-line platinum-based therapy, ramucirumab plus docetaxel can significantly prolong survival compared with docetaxel….

Study Details This double-blind trial included 1,253 patients with squamous or nonsquamous stage IV NSCLC from academic medical centers and community clinics in 26 countries on six continents. Patients were randomly assigned between December 2010 and January 2013 to receive docetaxel at 75 mg/m2 and either ramucirumab at 10 mg/kg (n = 628) or placebo (n = 625) on day 1 of 21-day cycles until disease progression, unacceptable toxicity, withdrawal, or death. Patients had to have shown disease progression during or after a single platinum-based chemotherapy regimen, with or without bevacizumab (Avastin) or maintenance therapy. Randomization was stratified by sex, region, performance status, and previous maintenance therapy. The primary endpoint was overall survival in the intent-totreat population. The ramucirumab and control groups were generally balanced for age (median, 62 and 61 years), sex (67% and 66% male), race (84% and 80% white, 12% and 14% Asian), Eastern Cooperative Oncology Group performance status (0 in 33% and 32%, 1 in 67% and 68%), measurable disease (96% in both), smoking history

benefit of ramucirumab on overall survival, including among patients with nonsquamous disease (11.1 vs 9.7 months, HR = 0.83, 95% confidence interval [CI] = 0.71–0.97), those with squamous disease (9.5 vs 8.2 months, HR = 0.88, 95% CI = 0.69-1.13), those with response to first-line platinum treatment (11.2 vs 10.3 months, HR = 0.84, 95% CI = 0.71-0.99), and those without response to first-line platinum treatment (8.3 vs 6.3 months, HR = 0.86, 95% CI = 0.68–1.08).

—Edward B. Garon, MD, and colleagues

months) vs 9.1 months (interquartile range = 4.2–18.0 months), yielding a hazard ratio (HR) of 0.86 (P = .023). Treatment after study discontinuation was received by 51% of patients in the ramucirumab group and 55% of the control group. Median progression-free survival was 4.5 vs 3.0 months (HR = 0.76, P < .0001). Investigator-assessed objective response occurred in 23% vs 14% of patients (odds ratio [OR] = 1.89, P < .0001) and the disease control rate was 64% vs 53% (odds ratio [OR] = 1.60, P < .0001), with the ramucirumab benefit being similar in nonsquamous and squamous cell disease subgroups. The trial was not powered for subgroup analysis. However, subgroup analysis showed consistent numeric

Role of Ramucirumab in Lung Cancer ■ The addition of ramucirumab to docetaxel in second-line treatment significantly improved overall survival and progression-free survival. ■ Toxicities were generally manageable with appropriate dose reductions and supportive care.

control group) and diarrhea (32% vs 27%). The most common grade ≥ 3 clinical adverse events occurring in > 5% of either group were fatigue (14% vs 10%), hypertension (6% vs 2%) and dyspnea (4% vs 8%). The most common grade ≥ 3 hematologic adverse events were neutropenia (49% vs 40%, grade 4 in 37% vs 28%), febrile neutropenia (16% vs 10%), and leukopenia (14% vs 12%). An increased incidence of neutropenia and febrile neutropenia in patients from East Asia (Taiwan and South Korea) led to a reduction in docetaxel dose to 60 mg in 27% of East Asian patients, with the reduction being associated with a reduction in the neutropenia rate compared with that observed in other regions. Overall, granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was used in 42% vs 37% of patients and 13% vs 8% were admitted to hospital for febrile neutropenia. Anemia of any grade occurred in 21% vs 28% of patients (grade ≥ 3 in 3% vs 6%. Transfusion was required in 10% vs 12%. Patients in the ramucirumab group had more bleeding or hemorrhage

events of any grade (29% vs 15%, grade ≥ 3 in 2% vs 2%), including significantly more epistaxis (19% vs 6%, grade ≥ 3 in < 1% vs < 1%). Other bleeding events included pulmonary hemorrhage (8% vs 7%, grade ≥ 3 in 1% vs 1%), hemoptysis (6% vs 5%, grade ≥ 3 in 1% vs 1%), and gastrointestinal hemorrhage (3% vs 2%, grade ≥ 3 in 1% vs < 1%). “Although the incidence of bleeding was higher in the ramucirumab arm, it was almost exclusively secondary to events such as epistaxis, while more concerning events such as pulmonary and gastrointestinal hemorrhages were not increased,” Dr. Garon commented to The ASCO Post. Serious adverse events occurred in 43% vs 42% of patients. Adverse events led to dose adjustment in 33% of ramucirumab patients and 23% of control patients, with the most common reasons being neutropenia (12% vs 9%), fatigue (9% vs 6%), and febrile neutropenia (7% vs 5%). Death due to adverse events occurred in 5% vs 6% of patients.

Quality of Life Data on global quality of life, measured using the Lung Cancer Symptom Scale, were available at baseline for 77% of patients in the ramucirumab group and 79% in the control group and for 47% and 49% at 30-day follow-up. There was no difference between groups in time to deterioration of quality of life (stratified HR = 1.00, P = .99). The investigators concluded: Our study shows that, in patients with advanced non-small-cell lung cancer with disease progression during or after firstline platinum-based therapy, ramucirumab plus docetaxel can significantly prolong survival compared with docetaxel, providing evidence for the role of a VEGFRtargeted therapy and offering patients with non-squamous and squamous recurrent disease a potential option for treatment. n Disclosure: The study was funded by Eli Lilly. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Garon EB, Ciuleanu T-E, Arrieta O, et al: Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): A multicentre, double-blind, randomised phase 3 trial. Lancet 384:665-673, 2014.

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Perspective

REVEL: Winning a Questionable Race By D. Ross Camidge, MD, PhD

he investigators and sponsors of the phase III REVEL trial should be congratulated and probably commiserated. In this large study, reported by Garon and colleagues in The Lancet and reviewed in this issue of The ASCO Post, 1,253 patients with advanced non–small cell lung cancer (NSCLC) were randomized to either the standard second-line chemotherapy of docetaxel or docetaxel in combination with ramucirumab—an antibody directed against VEGFR2.1

Study Details REVEL was a well-conducted, impressive effort involving patients accrued from 26 countries across 6 continents over barely 2 years. The primary endpoint of improving median overall survival was met (10.5 vs 9.1 months, hazard ratio [HR] = 0.86, P = .023), as were the key secondary endpoints of improving both median progression-free survival (4.5 vs 3 months, HR = 0.76, P < .0001) and the objective response rate (23 vs 14%, P < .0001). There was a minor increase in toxicity from the addition of ramucirumab, but the serious adverse event and treatment-related death rates were essentially identical between the two arms of the study. Yet, despite this being an exemplary, unequivocally positive phase III trial advancing overall survival from docetaxel monotherapy in the secondline NSCLC setting for the first time since docetaxel was licensed nearly 15 years ago, the reception to REVEL at the 2014 ASCO Annual Meeting was lukewarm. Why?

4.5 months) and overall survival (12.3 vs 10.3 months).2 Since then, a first-line phase III combination study of bevacizumab with cisplatin and gemcitabine (AVAiL) showed prolonged progression-free survival but failed to show an overall survival advantage (the primary endpoint of the study). Further, a series of phase III studies adding in various small-molecule inhibitors of angiogenic kinases to different lines of chemotherapy have also all failed to show overall survival advantages.3-6

Challenges in Identifying Biomarkers One of the problems in terms of advancing this field has been the lack of progress in identifying robust predictive biomarkers of benefit from antiangiogenics. Certainly, squamous histology was identified early on as a potential predictive marker of toxicity for bevacizumab; it is therefore noteworthy that, in

Despite [REVEL] being an exemplary, unequivocally positive phase III trial advancing overall survival from docetaxel monotherapy in the second-line NSCLC setting for the first time since docetaxel was licensed nearly 15 years ago, the reception to REVEL at the 2014 ASCO Annual Meeting was lukewarm. Why? —D. Ross Camidge, MD, PhD

The ECOG 4599 Peak To some extent, the development of antiangiogenics in NSCLC peaked with the ECOG 4599 study, which showed that bevacizumab (Avastin), an antibody directed against VEGF— the predominant ligand of VEGFR2— added significantly to standard first-line carboplatin and paclitaxel in nonsquamous, but otherwise unselected, advanced NSCLC. ECOG 4599 showed that bevacizumab improved both median progression-free survival (6.2 vs Dr. Camidge is Associate Director for Clinical Research, University of Colorado Cancer Center, Denver.

after progression on an initial bevacizumab-containing regimen has now been proven to be beneficial in metastatic colorectal cancer, whether using ramucirumab would be any different than using or continuing bevacizumab in the second-line setting in NSCLC becomes a major question.7 Arguments in favor of VEGFR2 being a more effective target than VEGF note that trials of ramucirumab vs placebo (REGARD) and of paclitaxel plus or minus ramucirumab (RAINBOW) both showed that ramucirumab prolonged overall survival in second-line advanced gastric cancer, whereas a study of platinum/fluorouracil–based chemotherapy plus or minus bevacizumab in first-line advanced gastric cancer (AVAGAST) did not.8-10 Intriguingly, all of the chemotherapy combination trials positive for overall survival with either bevacizumab or ramucirumab in lung and gastric cancer have used taxane-based regimens. Consequently, whether REVEL and RAIN-

contrast to the majority of bevacizumab studies, all lung cancer histologies were included in the REVEL study, with no suggestion of a differential effect by histology. However, it is uncertain whether this represents a true biologic differentiation between the two drugs or the difference in the vascular fragility (potentially of both tumor and host) in the lung cancer population present in a first-line study—as opposed to those who have survived first-line chemotherapy to enter a second-line study. Indeed, since continuation of bevacizumab into the second-line setting

BOW were better set for success than AVAGAST and AVAiL just because of their design has to be considered.

Ramucirumab: The Overall Benefit A head-to-head comparison of a taxane combined with ramucirumab vs a taxane combined with bevacizumab in the bevacizumab-eligible population would be the most satisfying scientific way to address whether ramucirumab in REVEL represents a true new drug indication in NSCLC or just a new indication for an overall class. However, since the

overall benefit compared to placebo is so modest in REVEL, it is hard to imagine that the size of any significant differential benefit between antiangiogenics would ever be clinically meaningful. Even if the efficacy of ramucirumab in REVEL truly represents a new drug effect, when targeted therapy combined with accurate predictive biomarkers has generated amazing results in EGFR mutant and ALK-rearranged NSCLC, the reaction by those at the 2014 ASCO Annual Meeting may reflect the fact that progression-free survival and overall survival advantages of less than 2 months are just not exciting enough for thoracic oncologists anymore. In fact, Maurice Pérol, MD, of the Léon-Bérard Cancer Centre, Lyon, France, the presenter of REVEL at the ASCO Annual Meeting, made the point that the very absence of a predictive biomarker for ramucirumab might be an advantage, emphasizing its value in those lung cancer patients without an actionable genetic abnormality. Yet, patients with EGFR mutations, ALK rearrangements, or other actionable markers would almost certainly have been contained within the REVEL dataset. Therefore, unfortunately, this logic doesn’t hold up. In the absence of information on specific drivers, it is not possible to even say that driver-negative patients are deriving the same degree of benefit (vs a greater or lesser degree of benefit) compared to the overall unselected population within the trial.

Consider the Cost Perhaps, in the era of economic meltdowns and health-care restructuring, the study’s tentative reception simply reflects anticipatory “sticker shock” from what those extra few weeks are likely to cost. In REVEL, ramucirumab was given at 10 mg/kg every 21 days. In April of 2014, following its licensing by the U.S. Food and Drug Administration for second-line advanced gastric cancer, ramucirumab at 8 mg/kg every 14 days, was priced at $7,140 per infusion, approximately 20% more than bevacizumab costs.11,12 While breakthroughs should certainly be heralded and everyone has to pay the bills somehow, it is hard not to fantasize about a world where ramucirumab in NSCLC was continued on page 60

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

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

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There was a 53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (hazard ratio [HR]=0.47; 95% confidence interval [CI], 0.35-0.62; P<0.0001). There were 78 deaths and 122 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

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

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

Percentage surviving

80 60 40 20 0

7 8 OS (months)

ZELBORAF (n=337)

Dacarbazine (n=338)

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

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

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

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

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

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

75%

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

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

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | OCTOBER 15, 2014

PAGE 60

Perspective

D. Ross Camidge, MD, PhD continued from page 56

launched as not just another marginally effective anti-angiogenic, but also as the cheapest one in its class by far—bringing a little incremental benefit more comfortably within reach of everyone and every health system. In that world,

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

References 1. Garon EB, Ciuleanu T-E, Arrieta O, et Safety:7" al: Ramucirumab plus docetaxel versus pla-

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

ADRs

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

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

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

37 33 45 23 24 9 8 19 5 14

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

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

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

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

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

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

cebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL). Lancet 384: 665-673, 2014. 2. Sandler A, Gray R, Perry MC, et al: Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006.

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

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

3. Reck M, von Pawel J, Zatloukal P, et al: BO17704 Study Group. Overall survival with cisplatin–gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: Results from a randomized phase III trial (AVAiL). Ann Oncol 21:1804-1809, 2010. 4. Herbst RS, Sun Y, Eberhardt WE, et al: Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): A double-blind, randomized, phase 3 trial. Lancet Oncol 11:619-626, 2010. 5. Paz-Ares LG, Biesma B, Heigener D, et al: Phase III, randomized, doubleblind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol 30:3084-3092, 2012. 6. Scagliotti G, Vynnychenko I, Ichinose Y, et al: An international, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small cell lung cancer. J Clin Oncol 30:2829-2836, 2011. 7. Bennouna J, Sastre J, Arnold D, et al: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomised phase 3 trial. Lancet Oncol 14:29-37, 2013. 8. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastrooesophageal junction adenocarcinoma (REGARD). Lancet 383:31-39, 2014. 9. Wilke H, Van Cutsem E, Oh SC, et al: RAINBOW: A global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy. J Clin Oncol 32 (suppl 3): Abstract LBA7, 2014. 10. Ohtsu A, Shah MA, Van Cutsem E, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer. J Clin Oncol 29:3968-3976, 2011. 11. The cost of cancer breakthroughs. Economist. June 4, 2014. Available at www.businessinsider.com/the-cost-ofcancer-breakthroughs-2014-6. 12. Díaz-Rubio E, Pietrantonio F, de Braud F: Continuing single-agent bevacizumab as maintenance therapy after induction XELOX (or FOLFOX) plus bevacizumab in first-line treatment of metastatic colorectal cancer. Oncologist 17:1426-1428, 2012.

Safety:10"

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

the results of REVEL really would have made us sit up and take notice. n

ASCOPost.com | OCTOBER 15, 2014

PAGE 61

Announcements

Society Announces Candidates for 2015 ASCO Election

ourteen distinguished ASCO members have been selected by the ASCO Nominating Committee as candidates for open leadership positions within the

Society for the 2015 ASCO Election. Biographical information and interviews with each candidate, as well as instructions for casting a proxy ballot, will be made

PRESIDENT-ELECT CANDIDATES (ONE SEAT) Daniel F. Hayes, MD, FASCO University of Michigan Comprehensive Cancer Center

available to members at www.asco.org/ election when proxy voting opens on Wednesday, October 29. The proxy voting will close on Wednesday, November 26.

Election results will be announced by mid-December 2014; elected candidates will assume office at the 2015 ASCO Annual Meeting in June. n

2015 ASCO Candidates

Patrick J. Loehrer, Sr, MD, FASCO Indiana University Simon Cancer Center

TREASURER CANDIDATES (ONE SEAT) Stephen S. Grubbs, MD Medical Oncology Hematology Consults, PA Craig R. Nichols, MD Virginia Mason Medical Center, Testicular Cancer Commons Daniel F. Hayes, MD, FASCO

BOARD OF DIRECTORS— COMMUNITY ONCOLOGIST CANDIDATES (ONE SEAT)

Patrick J. Loehrer, Sr, MD, FASCO

Johannes C. Nunnink, MD, FASCO Vermont Center for Cancer Medicine Ray D. Page, DO, PhD, FACOI The Center for Cancer and Blood Disorders

BOARD OF DIRECTORS— SURGICAL ONCOLOGIST CANDIDATES (ONE SEAT)

Stephen S. Grubbs, MD

Craig R. Nichols, MD

Johannes C. Nunnink, MD, FASCO

Ray D. Page, DO, PhD, FACOI

Michael A. Choti, MD, MBA, FACS

Stephen B. Edge, MD, FACS, FASCO

Blase N. Polite, MD, MPP

Jedd D. Wolchok, MD, PhD

Lisa A. Carey, MD

S. Percy Ivy, MD

Michael A. Choti, MD, MBA, FACS University of Texas, Southwestern Medical Center Stephen B. Edge, MD, FACS, FASCO Baptist Memorial Health Care, Baptist Cancer Center

BOARD OF DIRECTORS— UNDESIGNATED SPECIALTY CANDIDATES (ONE SEAT) Blase N. Polite, MD, MPP University of Chicago, The Center for Clinical Cancer Genetics and Global Health Jedd D. Wolchok, MD, PhD Memorial Sloan Kettering Cancer Center and Ludwig Cancer Research

NOMINATING COMMITTEE— UNDESIGNATED SPECIALTY CANDIDATES (TWO SEATS) Lisa A. Carey, MD University of North Carolina, Breast Center S. Percy Ivy, MD National Cancer Institute, Cancer Therapy Evaluation Program Primo N. Lara, Jr., MD University of California, Davis Comprehensive Cancer Center Emile E. Voest, MD, PhD University Medical Center Utrecht, Netherlands

Primo N. Lara, Jr., MD

Emile E. Voest, MD, PhD

The ASCO Post | OCTOBER 15, 2014

PAGE 62

Journal Spotlight Breast Cancer

ASCO Clinical Practice Guideline: Chemotherapy and Targeted Therapy in Advanced HER2-Negative or HER2 Status–Unknown Breast Cancer By Matthew Stenger

he American Society of Clinical Oncology has released a new clinical practice guideline on chemotherapy and targeted therapy for women with advanced HER2-negative or HER2 status–unknown breast cancer. The guideline is published in the Journal of Clinical Oncology.1 In formulating the consensus guideline, an expert panel undertook a systematic review of randomized evidence from 1993 through the present to address pressing questions in the field. Data from 79 studies form the evidentiary basis of the guideline, including 20 systematic reviews or meta-analyses, 30 studies of first-line treatment options, and 29 studies of second-line or subsequent treatment. The expert panel was co-chaired by Ann H. Partridge, MD, of Dana-Farber Cancer Institute, Boston, and Ian E. Smith, MD, of Royal Marsden Hospital, London. A summary of guideline questions and recommendations follows.

Treatment Indications What are the indications for chemotherapy vs endocrine therapy in estrogen receptor–positive first-relapse metastatic breast cancer? Endocrine therapy should be standard first-line treatment in hormone receptor [HR]-positive advanced/metastatic disease, except for immediately life-threatening disease or if there is concern over endocrine resistance. The main benefit is less toxicity and better quality of life (potential benefit = high); the potential harm is that metastatic dis-

Optimal First-Line Regimen Is there an optimal first-line chemotherapy or targeted therapy regimen? Sequential single-agent chemotherapy rather than combination therapy should be offered, but combination regimens may be considered for immediately life-threatening disease. The benefit is less toxicity and better quality of life (potential benefit = high). The potential harm is for rapidly progressing, life-threatening disease to escape con-

No single agent has demonstrated superiority in advanced breast cancer. Among those appropriate for first-line chemotherapy, evidence of efficacy is strongest for taxanes and anthracyclines. —Ann H. Partridge, MD, and colleagues

trol in the absence of response (potential harm = high), but risk of this is low. Quality of evidence = high; strength of recommendation = strong. With regard to targeted agents, the role of bevacizumab (Avastin) is controversial. Bevacizumab should be considered with single-agent chemotherapy only when there is immediately life-threatening disease or severe symptoms, given improved response rates observed with the combination. It is recognized that there is no currently approved indication for bevacizumab in the United States because the weight of evidence indicates no significant surviv-

New ASCO Clinical Practice Guideline in Breast Cancer ■ Endocrine therapy is recommended first-line treatment in hormone receptor–positive disease. ■ Sequential single-agent chemotherapy is recommended over combination regimens.

ease could progress rapidly and prove fatal in the absence of response, but risk of this is low. Quality of evidence = intermediate; strength of recommendation = strong. (Qualifying statement: The basis for the recommendation is the relative likelihood of response to chemotherapy vs endocrine therapy and not the rapidity of response, for which there are no good data.)

= moderate. (Qualifying statement: Bevacizumab added to single-agent chemotherapy improves response and progression-free survival but not overall survival.) No single agent has demonstrated superiority in advanced breast cancer. Among those appropriate for first-line chemotherapy, evidence of efficacy is strongest for taxanes and anthracyclines. Other options include capecitabine, gemcitabine, platinum-

al benefit. Other targeted agents should not be used in addition to or instead of chemotherapy outside of a clinical trial. The benefit associated with targeted agents is improved disease control (potential benefit = moderate). The potential harms are unique toxicity, increased costs, and barriers to access (potential harm = high). Quality of evidence = high; strength of recommendation

based compounds, vinorelbine, and ixabepilone (Ixempra). Treatment selection should be based on previous therapy, differential toxicity, comorbid conditions, and patient preferences. Drugs for which clinical resistance has already been shown should not be reused. The benefit of single-agent therapy is a patient-tailored approach with potential improvements in disease control and quality of life (potential benefit = high). The harm is the potential use of a less active agent (potential harm = low). Quality of evidence supporting activity of a number of single agents = high, but there is insufficient evidence to support superiority of any single agent; strength of the recommendation = strong. Chemotherapy should be continued until progression of disease, because it modestly improves overall survival and substantially improves progression-free survival, but this has to be balanced against toxicity and quality of life. Short breaks, flexibility in scheduling, or a switch to endocrine therapy (in patients with HR-positive disease) may be considered in some patients. The benefits of continuing chemotherapy until disease progression are more time before progression and modestly improved survival (potential benefit = high). The harm is more-prolonged toxicity (potential harm = moderate).

Quality of evidence = high; strength of recommendation = strong. (Qualifying statement: Achieving balance in continuing treatment to maintain disease control and coping with progressive toxicity is difficult and is influenced by many factors, including drug used—eg, long-term use of capecitabine is relatively easy, whereas use of docetaxel is limited by cumulative toxicity; the strategy requires a continuing dialogue between doctor and patient.)

Tailored Therapy Should first-line treatment vary by hormone receptor status, tumor subtypes, or clinical characteristics? Chemotherapy regimens currently should not be specifically tailored to different breast cancer subtypes (eg, triple-negative, lobular), due to absence of evidence proving differential efficacies. In addition, in vitro chemoresistance assays should not be used to select treatment. The benefits of this nontailored approach are not omitting potentially efficacious treatment and cost-saving on in vitro assays (potential benefit = high). Strength of recommendation = moderate. (Qualifying statement: This recommendation will need to be modified if ongoing or future research suggests benefits of tailoring.)

Subsequent Therapy Is there an optimal second- or later-line chemotherapy or targeted therapy regimen? Second- and later-line therapy may be of clinical benefit and should be offered as determined by previous treatments, toxicity, coexisting medical conditions, and patient choice. No clear evidence exists for the superiority of any regimen. Active agents include those active in first-line treatment. The benefit of drug therapy after the first-line setting is further chance of disease control and symptomatic improvement (potential benefit = high). The harm is toxicity (potential harm = high). Strength of recommendation = strong. (Qualifying statement: The most convincing data are for eribulin [Halaven] based on survival superiority against best standard treatment in a recent large randomized controlled trial, but there is a lack of good comparative data among the various agents.)

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PAGE 63

Perspective

Guidelines and Care: What Comes Next? By Clifford A. Hudis, MD, FACP

he goal of clinical, translational, and basic research is, in the end, the betterment of life on earth. Advances in basic and clinical science ultimately should lead to information that, in turn, enables clinicians to make better treatment decisions for individual patients in order to improve their lives. However, there are barriers to success that we have to overcome. For example, not all treatments are available in all locales, and a critical issue is simply the dissemination of knowledge and results. Relatedly, many skilled clinicians lack the time to carefully consider and weigh every available clinical trial result, instead depending on experts to interpret and contextualize the results of studies. This is, of course, a never-ending process.

The ASCO Clinical Practice Guidelines Process The ASCO Clinical Practice Guidelines process addresses the issue of knowledge dissemination. An international expert panel reviews the relevant available evidence (consisting of phase I to phase III clinical trials as well as historical practice patterns), weighs the evidence, and through a rigorous and transparent process attempts to arrive at the best answers to common clinical challenges. In many cases there really are no “best” answers, and sometimes there is no real evidence at all. But, with regard to breast cancer, one of most prevalent Dr. Hudis is Chief, Breast Medicine Service, Memorial Sloan Kettering Cancer Center; Professor of Medicine, Weill Cornell Medical College;, and Immediate Past-President, American Society of Clinical Oncology.

Stopping Drug Therapy At what point should anticancer therapy be discontinued? Palliative care should be offered throughout the continuum of care. Since there are diminishing returns with later lines of chemotherapy, best supportive care without further chemotherapy should also be offered as an option. Benefits of palliative care include a patient-centered approach emphasizing quality of life (potential benefit = high). The main harm is fear of abandonment

and frequent life-threatening malignancies in the world, we actually do have significant amounts of high-quality data to consider. In the current example—the guideline on chemotherapy and targeted therapy in advanced HER2negative or HER2 status–unknown breast cancer—the expert panel had 79 studies and 20 systematic reviews or meta-analyses to consider, as well as 29 studies specific to second-line treatment or beyond.1 These data were published since 1993 and repre-

easy-to-read tabular fashion in the Journal of Clinical Oncology1 and are further summarized here in The ASCO Post. For readers who need more, the source documents are described in the Journal of Clinical Oncology paper with detailed references. From a practical perspective, the guidelines mirror those of other groups, such as the International Consensus Conference for Advanced Breast Cancer and the National Comprehensive Cancer Network, as well as some of the recommendations

[T]he guideline provides… clinicians with a starting point for decision-making and also covers the vast majority of initial treatment decisions. It is a framework for wise clinicians to begin their thought processes for individual patients and also enables the conduct of ‘next step’ clinical trials by identifying gaps in our knowledge. —Clifford A. Hudis, MD, FACP

sent the standard-setting or practicechanging studies conducted in the modern era of breast cancer therapy. Because an earlier panel focused on HER2-positive disease, this effort addressed the remainder of metastatic breast cancer, both hormone-sensitive and -insensitive HER2-“negative” (really “normal”) disease. Reflecting the era in which it was generated, the evidence also included trials in which HER2 status was not known. The results are presented in an

ASCO recently made to the Choosing Wisely Campaign.2-4 It should be reassuring that independent groups of experts have, more or less, come to similar conclusions regarding the management of advanced or metastatic breast cancer. At the same time, the complementarity of the approaches is helpful in this area of practice, since each of these efforts provides a different perspective on some of the treatment issues yet arrives at more or less identical conclusions.

and giving up hope, which can be addressed by effective communication and appropriate end-of-life planning (potential harm = moderate). Quality of evidence = intermediate; strength of recommendation = strong. (Qualifying statement: Response to second and subsequent lines of chemotherapy is strongly influenced by response to earlier treatment; patients with no response to up to two initial lines of treatment are less likely to respond to a third or subsequent line.) Clinicians should encourage all

eligible patients to enroll onto clinical trials, including the option of phase II and even targeted phase I trials before all standard lines of therapy have been used, in the absence of immediately life-threatening disease. The benefits are that more patients will be directed to clinical studies providing treatment benefits and that the medical community will benefit from more research to improve treatments. The potential harm is that patients will receive inferior treatment. There is no strong evidence to suggest this approach might

Why the Need for Guidelines? Some clinicians have asked why we need guidelines—sometimes because they come from an era where individual physicians were thought to be capable of making the best possible treatment decisions for individual patients, and sometimes because they believe that somatic mutation and other molecular analysis will replace broader clinical guidelines on the way to increasingly individualized treatment. To the first group of skeptics, we could point out that there will always be a need for clinical judgment and thoughtfulness in the application of any guideline. Patients, as we are all taught, don’t necessarily “read the textbook,” and breast cancer in particular has notable clinical variations that are not always reflected in clinical trial experience. That said, the guideline provides all clinicians with a starting point for decision-making and also likely covers the vast majority of initial treatment decisions. It is a framework for wise clinicians to begin their thought processes for individual patients and also enables the conduct of “next step” clinical trials by identifying gaps in our knowledge. For example, the current guideline can’t address the role of surgical resection of oligo-progression (that is, disease progression in the face of effective therapy that is limited to just one site). To the more modern skeptics who believe that sequencing contains the answers to treatment, we can note that this may be increasingly true in some situations in the near future, but even then the proliferation of targets and continued on page 66

impair outcome. Strength of recommendation = strong. n Disclosure: For full disclosures of the guideline panel members, visit jco.ascopubs.org.

Reference 1. Partridge AH, Rumble RB, Carey LA, et al: Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2–negative (or unknown) advanced breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. September 2, 2014 (early release online).

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. ®

22.4-month Median PFS With ARZERRA Plus Chlorambucil 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

HR=hazard ratio; CI=confidence interval. 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

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 | OCTOBER 15, 2014

PAGE 66

Perspective

Clifford A. Hudis, MD, FACP continued from page 63

effective drugs will increase the need for guidelines to assist busy clinicians! Across all of modern society, it is generally the case that the standardization of practices improves quality

and lowers cost by limiting unnecessary variation. In medicine, we have a special obligation to temper that truth with the fact that individual patients require individualized care and thought. The purpose of this guideline is to facilitate that discussion,

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

and I believe it will help considerably. At the same time, we look forward to the next step in our use of science and bioinformatics to help improve the care given to individual patients by skilled and thoughtful physicians: CancerLinQ. n

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

References 1. Partridge AH, Rumble B, Carey LA, et al: Chemotherapy and targeted therapy for women with human epidermal growth

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)

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Perspective

factor receptor 2–negative (or unknown) advanced breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. September 2, 2014 (early release online). 2. Cardoso F, Costa A, Norton L, et al: ESO-ESMO 2nd international con-

sensus guidelines for advanced breast cancer (ABC2). Ann Oncol. September 18, 2014 (early release online). 3. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Breast cancer, version 3.2014.

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

Leukopenia

Herpes simplexb

Lower respiratory tract infection

Adverse Reactions

Available at www.nccn.org/professionals/physician_gls/PDF/breast.pdf. Accessed September 20, 2014. 4. Schnipper LE, Lyman GH, Blayney D, et al: American Society of Clinical Oncology 2013 top five list in oncology. J Clin Oncol 31:4362-4370, 2013.

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

Diarrhea

Anemia

Fatigue

Bronchitis

Nausea

Upper respiratory tract infection

Rashb

Leukopenia

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

15 0

Grade ≥3 %

25 25

All Grades %

Upper abdominal pain

Grade ≥3 %

All Grades %

Grade ≥3 %

Chlorambucil (N = 227)

All Grades %

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

Grade ≥3 %

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.

All Grades %

Pyrexia

Arthralgia a

Fludarabine- and Alemtuzumabrefractory (N = 59)

Cough

Dyspnea

ARZERRA Plus Chlorambucil (N = 217)

For more information on CancerLinQ, visit www.asco.org/ quality-guidelines/cancerlinq.

Edema peripheral

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)

The ASCO Post | OCTOBER 15, 2014

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Announcements

Call for Ideas for Ovarian Cancer Translational Research ‘Dream Team’ Grant

he American Association for Cancer Research (AACR) is accepting submissions of ideas for the Stand Up To Cancer–Ovarian Cancer Research Fund– Ovarian Cancer National Alliance–National Ovarian Cancer Coalition (SU2COCRF-OCNA-NOCC) Translational

Research Dream Team Grant that will offer up to $6 million in research funding. The Translational Research Dream Team grant provides 3 years of funding for research projects that must include therapeutic interventions for ovarian cancer and deliver near-term patient

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.

benefit through investigation by a multidisciplinary, multi-institutional team of experts. Proposals for the grant must describe plans indicating how the group will use a transformative and synergistic approach, and how the work will be translated into the clinic. To maximize creativ-

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)]

ity, innovation, and collaboration, the projects should span multiple disciplines and use modern scientific tools to attack research questions in a coordinated effort.

Advisory Committee A Joint Scientific Advisory Committee appointed by the involved organizations will conduct a unique, interactive, rapid, and rigorous evaluation of the applications via a multistep scientific review process. The committee is comprised of senior laboratory researchers and physician-scientists, as well as advocates. The committee is chaired by Arnold J. Levine, PhD, Professor at the Institute for Advanced Study in Princeton, and at the Cancer Institute of New Jersey in New Brunswick. William G. Nelson, MD, PhD, Director of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, and Jeff Boyd, PhD, Senior Vice President at the Fox Chase Cancer Center in Philadelphia and Chair of OCRF’s Scientific Advisory Committee, will serve as Vice Chairs.

Arnold J. Levine, PhD

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.

William G. Nelson, MD, PhD

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. AZA441R0 August 2014

Jeff Boyd, PhD

Letters of Intent for the SU2COCRF-OCNA-NOCC Translational Research Dream Team Grant are due by November 7, 2014. For more information visit http://www.aacr.org/ Pages/Home.aspx. n

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PAGE 69

Director’s Corner Gynecologic Oncology

Attaining the Goal of Preventing Ovarian Cancer A Conversation With David Fishman, MD

©The Mount Sinai Hospital

By Jo Cavallo

David Fishman, MD

ifteen years ago, David Fishman, MD, launched the National Ovarian Cancer Early Detection Program as part of the National Cancer Institute’s Early Detection Research Network. The goal of the research effort was to develop methods to accurately detect ovarian cancer while it was still confined to the ovary and potentially curable. In 2013, Dr. Fishman renamed the program the Mount Sinai Ovarian Cancer Risk Assessment Program to reflect advances, especially in genetic screening, that can be utilized to combat this usually fatal cancer. “We are not able to detect early-stage ovarian cancer, but we can identify people at risk,” said Dr. Fishman. This year, about 22,000 women in the United States will be diagnosed with ovarian cancer, and 14,270 will die from the disease.1 Until more effective therapies are discovered to improve survival, determining effective preventive strategies in high-risk women may be a more attainable goal. The ASCO Post talked with Dr. Fishman, Director of the Mount Sinai Ovarian Cancer Risk Assessment Program and Professor and Fellowship Director in the Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Medicine at the Icahn School of Medicine at Mount Sinai in New York, about the advances in accurately evaluating risk for ovarian cancer, the importance of screening both women and men for inheritable syndromes that can lead to a variety of cancers, and the hope for more effective preventive strategies.

Assessing Ovarian Cancer Risk What are the known risk factors for developing ovarian cancer? The majority of women who develop ovarian cancer do not have any identifiable risk factors. Only about 20% of women who develop ovarian cancer have known risk factors, which include a personal or

family history of malignancies associated with an increased risk of ovarian cancer, such as breast cancer, or recognized inherited cancer syndromes, such BRCA1 and BRCA2 mutations, Lynch syndrome, and Cowden syndrome gene mutations. As we become more sophisticated in genetics and in the analysis of genetic linkage of gene mutations, I’m afraid we are going to have even more individuals at increased risk of developing ovarian cancer than we currently know. It is unfortunate that we really don’t even know if ovarian cancer starts in the ovary. It may start in a fallopian tube, so there are a lot of unknowns about what puts a woman at risk for this disease.

About the Program What are the components of the Ovarian Cancer Risk Assessment Program? Advances in our understanding of genetics and the linkage of gene mutations to disease have allowed us to more accurately identify people at risk for ovarian cancer. In the past, we just knew about the link between BRCA1 and BRCA2 mutations and Lynch syndrome and the development of breast and ovarian cancers. Now, we know that there are over 21 mutations associated with an increased risk of these diseases. As we discover more gene mutations the numbers of those at risk will rise. Our program has two arms. One is a very strong basic science component to understand the biology of ovarian cancer and the process of metastasis. The other arm is a clinical component based on classic genetics in which a team of board-certified genetic counselors and geneticists validate gene mutations associated with risk and perform formal pedigree analysis to identify women at risk for ovarian cancer as well as family members at risk for not just ovarian cancer but for other cancers as well. With this program, any individual who is currently healthy but at increased risk for ovarian cancer can seek more intensive cancer surveillance and preventive bilateral salpingo-oophorectomy surgery if appropriate. We haven’t given up on finding a cure, but, to me, preventing ovarian cancer from ever taking place will be a much better strategy than treating it after it occurs. Who is eligible for the program? Risk can be perceived or real, and since 80% of women who develop ovarian cancer have no known identifiable risk factors, I would never turn away any woman who wants to be assessed for the disease. We often see women who have no iden-

tifiable risk factors but want to utilize our multidisciplinary team of experts to become educated about their potential risk factors, early surveillance strategies, and what they can do to prevent the cancer.

Early Detection What are you investigating in new methods for the early detection of ovarian cancer? Right now we are using nonresearch tools in patient care. By using tests that are currently commercially available we have the ability to identify those individuals that have known genetic mutations predisposing them to ovarian cancer. For younger women desiring to maintain fertility, we can prescribe birth control pills, which can decrease the risk of ovarian cancer by 50%. For women who have completed their childbearing years, we can offer a prophylactic oophorectomy. We are investigating the effectiveness of transvaginal contrast enhanced ultrasound in detecting preclinical stages of ovarian cancer, but the technology is still not sensitive enough to pick up aberrant, precancerous cells the way a Pap smear can detect dysplasia. So even though we

While I believe the future in more effective treatment is going to be in advances in biologics and combinations of drugs that target the specific unique pathways of how cancer spreads, we do not have anything like that now. What do you envision for more effective strategies against ovarian cancers? I would love to see a competent immune system that could defend the body against errant cells that become malignant. I think it is the concept of immune regulation that will be the future in cancer care. Advances in genetic screening will also improve cancer outcomes. We are in the infancy of identifying genes that are associated with the development of cancers, and I think that the sophistication required to stay on top of this evolving technology is going to mandate implementation of a new specialty of board-certified cancer geneticists to interpret the data. This type of specialization does not exist today, but I believe it will in the near future. We know that all cancers have a genetic basis, but not all cancers are inheritable. General population-based screening

We know that all cancers have a genetic basis, but not all cancers are inheritable. General population-based screening and risk assessment, in which we evaluate an individual’s genetic profile and identify who is at risk for a specific cancer and then intervene before there is a cancer, is going to become a reality. —David Fishman, MD

have pioneered some advances with intravenous contrast, the issue with transvaginal sonography remains that by the time we see a lesion it is often late-stage cancer. We are also researching how ovarian cancer avoids immune surveillance and how to turn on the immune system to defend the body against the cancer. We are focusing on select microRNAs that can activate the immune system to identify malignant cells vs healthy cells, but this work is in its infancy. Ultimately, we would like to prevent cancer, because we do not have drugs that can cure patients. I would love to see 90% survival in this disease, but it is detected too late and survival rates are terrible. Women who are diagnosed with advanced disease have a 5-year survival rate at best approaching 45%. Our newer chemotherapies have had some impact but not nearly enough.

and risk assessment, in which we evaluate an individual’s genetic profile and identify who is at risk for a specific cancer and then intervene before there is a cancer, is going to become a reality. The sophistication we see coming in precision diagnostics and in our understanding of the immune system will result in cancers becoming preventable, and the key will be in immunization and having the immune system turned on to protect us against cancer. n

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

Reference 1. American Cancer Society: What are the key statistics about ovarian cancer? Available at www.cancer.org/cancer/ovariancancer/ detailedguide/ovarian-cancer-key-statistics. Accessed September 19, 2014.

The ASCO Post | OCTOBER 15, 2014

PAGE 70

Announcements

NCI’s Center for Global Health Announces First Major Research Grants to Support Portable Technologies

he National Cancer Institute (NCI) Center for Global Health announced grants that will support the development and validation of low-cost, portable technologies. These technologies have the potential to improve early detection, diagnosis, and noninvasive or minimally invasive treatment of several cancer types with a particularly high prevalence in low- and middle-income countries, noted Ted Trimble, MD, Director of the Center for Global Health. The researchers who received grants under the Center’s first major funding program will be incorporated in studies in India (oral cancers), Brazil (cervical cancer), Colombia (cervical neoplasia, or abnormal cell growth), South Africa (human papillomavirus [HPV] and cervical carcinoma), and the Philippines (cervical dysplasia).

As part of this program, the Center for Global Health has also partnered with the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health for one of the grants.

Jonathan Celli, PhD

Tayyaba Hasan, PhD

Kathleen Schmeler, MD

Rebecca Richards-Kortum, PhD

Louise Kuhn, PhD

Robert Murphy, MD

Jean Anderson, MD

Grant Recipients The grantees are: • Jonathan Celli, PhD, and Tayyaba Hasan, PhD, Massachusetts General Hospital, Boston: Low-cost enabling Miriam Cremer, MD technology for image-guided photodynamic therapy of oral leukoplakia. • Kathleen Schmeler, MD, MD Anderson Cancer Center, and Rebecca Richards-Kortum, PhD, Rice • University, Houston: High-resolution microendoscopy for cervical cancer diagnosis. • • Miriam Cremer, MD, MageeWomen’s Research Institute and Foundation, Pittsburgh: Adaptation and testing of the Cryo-

Pen cryotherapy device for treating cervical neoplasia for use in lowincome settings. Louise Kuhn, PhD, Columbia University, New York: Adapting the Cepheid GeneXpert test to detect HPV. Robert Murphy, MD, Northwestern University, Evanston, Illinois: Low-cost test for hepatitis C virus to identify patients at risk for developing hepatocellular carcinoma.

• Jean Anderson, MD, Johns Hopkins University, Baltimore: Assessing the performance, safety, and efficacy of a new cryotherapy device using liquid CO2. • Dr. Susan Love Research Foundation, Santa Monica, California: Low-cost, portable computer-aided detection and diagnostic tools for noninvasive screening of breast cancer. n

Statement from ASH President Linda J. Burns, MD, on Release of Sunshine Act Data

he Centers for Medicare & Medicaid Services (CMS) has released a large set of data about the payments physicians and teaching hospitals received from pharmaceutical and medical device companies from August 1 to December 31, 2013. This public disclosure, mandated under a provision of the Affordable Care Act known as the Physician Payments Sunshine Act, aims to improve transparency re-

garding the financial relationships of manufacturers, physicians, and teaching hospitals. The American Society of Hematology (ASH) supports greater transparency to improve the quality of health care. However, data are only beneficial if they are complete and accurate. Data released [in the report] are incomplete and may also contain errors, as some physicians may not have been able to

dispute and correct their records during a designated review period and approximately one-third of data to be released today will not be made public until next year. The release of these incomplete data without appropriate disclosures and/or explanatory statements as to their limitations and potential misinterpretations may result in inaccurate and misleading information about physicians and teaching hospitals.

While transparency about industryphysician relationships is critically important, industry support of medicine should not be cast in a negative light. Research and development sponsored by the biomedical/pharmaceutical industry plays an important role in biomedical research and has paved the way for significant scientific discoveries that have benefitted millions of patients. n

ASCOPost.com | OCTOBER 15, 2014

PAGE 71

Announcements

Women at Higher Risk for Breast Cancer to Benefit From Hereditary Risk Assessment Program in Tucson Center

pproximately 12% of women in the United States will develop breast cancer, according to the American Cancer Society. That’s more than 30,000 in Tucson alone, 2,500 of whom are esti-

mated to have a genetic risk factor for cancer. In response to this growing concern, The Breast Center at Carondelet St. Mary’s Hospital in Tucson is collaborating with genetic services specialist

InformedDNA to provide a hereditary risk assessment and genetic counseling program. Available now to patients of The Breast Center, the program helps identify those women at higher risk for

ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4) in Full Prescribing Information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing Information.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] K-Ras Mutation-negative, EGFR-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information] • in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.] Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Infusion Reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary Toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin: In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

cancer, before diagnosis, and helps individuals make informed decisions about their medical care. The Breast Center at St. Mary’s is ofcontinued on page 72

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. K-Ras Testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information]. Perform the assessment for K-Ras mutation 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 Erbitux. Epidermal Growth Factor Receptor (EGFR) Expression and Response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of 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 below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 15 3 2 0 Infusion Reactionb Infection 13 1 9 1 16 0 5 0 Chillsa Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, highc 38 1 24 1 Aspartate Transaminase, highc Alkaline Phosphatase, highc 33 <1 24 0 Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

The ASCO Post | OCTOBER 15, 2014

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Announcements Risk Assessment Program continued from page 71

fering women genetic risk assessments before diagnosis, at the time they receive a screening mammogram. Patients do not pay more for the risk assessment at The Breast Center, whether the patient is insured (the copay does not increase) or uninsured and paying out of pocket.

“The gold standard of care for a person at high risk for cancer is having genetics experts on an integrated care team, especially if he or she is considering genetic testing. InformedDNA’s national network of genetics specialists delivers services via phone and online, making it easier and faster for facilities like The Breast Center at Carondelet St. Mary’s

to provide the best care possible,” said David Nixon, CEO at InformedDNA. “InformedDNA’s Hereditary Risk Assessment Program is a powerful tool that allows us to identify and help high-risk patients,” said Gerlinde Tynan, MD, Breast Surgeon and Medical Director of The Breast Center at Carondelet St. Mary’s and the Breast Health Program

Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux (cetuximab) provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 2 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89). Table 2:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab Platinum-based plus Platinum-based Therapy with Therapy with 5-FU 5-FU Alone (n=219) (n=215) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona Infections and Infestations 44 11 27 8 Infectionb Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous Tissue Disorders 70 9 2 0 Acneiform Rashc Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. Chemotherapy = cisplatin + 5-ﬂuorouracil or carboplatin + 5-ﬂuorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm. Colorectal Cancer Study 4: EU-Approved Cetuximab in Combination with FOLFIRI — Study 4 used EU-approved cetuximab. U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 3 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224). Table 3:

Erb0813PBS_693US13PBS02201_7x9wip3.indd 2

at Carondelet St. Mary’s Hospital. “We want to identify patients who may be at higher risk before they develop cancer. Knowing the risk empowers patients to take steps that may help them avoid cancer altogether. We’re really excited about this program. It’s a great example of Carondelet’s commitment to providing the safest and best care possible.”n

Table 3: (Continued)

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFR-expressing, Metastatic Colorectal Cancera EU-Approved Cetuximab plus FOLFIRI FOLFIRI Alone (n=317) (n=350) Grades Grades Grades Body System Grades b 1–4 3 and 4 1–4 3 and 4 Preferred Term % of Patients Skin and Subcutaneous Tissue Disorders 86 18 13 <1 Acne-like Rashd Rash 44 9 4 0 Dermatitis Acneiform 26 5 <1 0 Dry Skin 22 0 4 0 Acne 14 2 0 0 Pruritus 14 0 3 0 Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1 Skin Fissures 19 2 1 0 a Adverse reactions occurring in at least 10% of Erbitux (cetuximab) combination arm with a frequency at least 5% greater than that seen in the FOLFIRI arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. d Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”. Erbitux Monotherapy — Table 4 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions]. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1–51). Table 4:

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFR-expressing, Metastatic Colorectal Cancer Treated with Erbitux Monotherapya Erbitux plus BSC BSC alone (n=118) (n=124) Grades Grades Grades Body System Grades b 3 and 4 1–4 3 and 4 Preferred Term 1–4 % of Patients Dermatology/Skin Rash/Desquamation 95 16 21 1 Dry Skin 57 0 15 0 Pruritus 47 2 11 0 Other-Dermatology 35 0 7 2 Nail Changes 31 0 4 0 Constitutional Symptoms Fatigue 91 31 79 29 Fever 25 3 16 0 18 3 0 0 Infusion Reactionsc Rigors, Chills 16 1 3 0 Pain Pain-Other 59 18 37 10 Headache 38 2 11 0 Bone Pain 15 4 8 2 Pulmonary Dyspnea 49 16 44 13 Cough 30 2 19 2 Gastrointestinal Nausea 64 6 50 6 Constipation 53 3 38 3 Diarrhea 42 2 23 2 Vomiting 40 5 26 5 Stomatitis 32 1 10 0 Other-Gastrointestinal 22 12 16 5 Dehydration 13 5 3 0 Mouth Dryness 12 0 6 0 Taste Disturbance 10 0 5 0 Infection Infection without neutropenia 38 11 19 5 Musculoskeletal Arthralgia 14 3 6 0 Neurology Neuropathy-sensory 45 1 38 2 Insomnia 27 0 13 0 Confusion 18 6 10 2 Anxiety 14 1 5 1 Depression 14 0 5 0 a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related. Erbitux in Combination with Irinotecan — The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

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Announcements

Ohio State Opens First Fully Integrated Cancer Emergency Department

or patients with cancer who already have compromised immune systems, what may seem like a minor medical issue—ie, fever, dehydration, viral infection—can rapidly escalate into an emergency situation requiring care from a medical team familiar with managing

the side effects of cancer treatment. “Cancer patients develop a number of conditions that we want to be very well prepared for, to stabilize them and receive them in the hospital. We want to know about them in advance so we can give them the absolute best care—

The incidence 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 Erbitux (cetuximab) 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 Erbitux. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Aseptic meningitis • Mucosal inflammation DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of 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, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, 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 cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use: The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

and fast,” said Thomas Terndrup, MD, Chair of the Department of Emergency Medicine at The Ohio State University Wexner Medical Center, Columbus. Because the needs of cancer patients are often so complex, The Ohio State University Comprehensive Cancer

Geriatric Use: Of the 1662 patients who received Erbitux (cetuximab) with irinotecan, FOLFIRI or Erbitux monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Rev August 2013 693US13PBS02201

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Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James) and Wexner Medical Center Emergency Department, have worked in close partnership to develop a clinical care model that combines the expertise of emergency medicine physicians and subspecialized oncologists working together in a cancer-specific emergency department to manage the emergency care needs of oncology patients.

Cancer-Specific Care “We’ve assembled a truly unique team that works together to establish protocols for delivering cancer-specific emergency care most effectively, and, in a way that allows us to clearly communicate that to the patients and their caregivers throughout the treatment process to reduce anxiety and stress in an already stressful situation,” Dr. Terndrup said. The oncology team, for example, will communicate with the cancer emergency treatment team in advance of the patient’s arrival in the James Emergency Department via the medical center’s electronic health record system. This ensures the staff on-site triaging the emergent patient understand the patient’s complete history and influencing factors before they arrive. Clinical care guidelines have also been developed through a collaboration of oncologists at the OSUCCC-James and Wexner Medical Center emergency medicine physicians to guide emergent situations that occur in the cancer patient population—ie, severe dehydration, fever, or high calcium levels—so that both teams involved in the patient’s emergency care are following best-inpractice protocols to address that patient’s unique needs. This unit, which includes 15 treatment stations, was designed specifically to address the unique needs of cancer patients and their family members. “Emergency departments can be noisy and chaotic at times. The cancer treatment areas at the OSUCCC-James have been designed to reduce that intensity for cancer patients by offering enhanced privacy, including private bathrooms, natural light, and quiet space for family-physician conversations,” Dr. Terndrup said. “Private treatment rooms also allow us to isolate cancer patients in a negative air flow space. This was done to reduce exposure to infectious diseases in a population that is often at higher risk due to the nature of their disease and treatment.” n

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Dermatologic Events in Oncology Life-Threatening Dermatologic Toxicity By Sigrid Barklund, BA, MS, and Milan J. Anadkat, MD

variety of life-threatening dermatologic adverse events may occur in association with cancer drug therapies. Here, we discuss the recognition and management of three types of such toxicities: type I hypersensitivity/anaphylaxis, Stevens-Johnson syndrome/ toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms.

Type I Hypersensitivity/ Anaphylaxis Type I, IgE-mediated, allergic reactions are the most common hypersensitivity reactions to chemotherapeutic agents, develop within minutes of exposure to the causative agent, and can be life-threatening. These reactions are characterized by cutaneous signs such as urticaria, angioedema, pruritus, and flushing. In more severe cases, anaphylaxis can occur, where systemic manifestations such as hypotension, tachycardia, bronchospasm, and abdominal pain are present in conjunction with cutaneous signs. Anticancer drugs such as platinum compounds, intravenous etoposide, teniposide (Vumon), procarbazine (Matulane), and asparginase (Elspar) are associated with type I hypersensitivity reactions.1 The risk of a type I hypersensitivity reaction typically increases with increasing exposure to a drug. Taxanes are associated with anaphylactoid reactions, which clinically resemble type I IgE-mediated reactions, but are caused by direct nonspecific degranulation of mast cells or basophils.2 In the acute setting, discontinua-

Fig. 1: Hemorrhagic mucositis and cutaneous target lesions characteristic of Stevens-Johnson syndrome and/or toxic epidermal necrolysis.

tion of the offending drug is necessary. Symptoms can be treated with systemic corticosteroids and antihistamines. In the case of anaphylaxis, subcutaneous epinephrine is used. It is helpful to confirm the presence of a hypersensitivity reaction by obtaining a tryptase level within a few hours of the reaction.3 Type I hypersensitivity reactions do not necessarily preclude the continuation of therapy with a causative drug. If

cific anticancer drug is difficult given the frequent use of multiple anticancer agents, coadministration with known trigger drugs, and underreporting in the literature.6 These disorders typically occur 1 to 4 weeks after drug exposure. There is often a prodrome of fever and malaise before the appearance of the characteristic rash and subsequent exfoliation. When less than 10% of body surface area is in-

Type I hypersensitivity reactions do not necessarily preclude the continuation of therapy with a causative drug. If the benefits of continued therapy outweigh the risks, three options exist: premedication, desensitization, or use of a different therapeutic agent. —Sigrid Barklund, BA, MS, and Milan J. Anadkat, MD

the benefits of continued therapy outweigh the risks, three options exist: premedication (acetaminophen, diphenhydramine, and/or corticosteroids), desensitization, or use of a different therapeutic agent.

Stevens-Johnson Syndrome/ Toxic Epidermal Necrolysis Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are potentially life-threatening mucocutaneous blistering disorders characterized by erosions on at least two mucosal surfaces and cutaneous lesions with central dusky necrosis and a rim of erythema (Fig. 1).4,5 Drug exposure is the most common cause of SJS and TEN. The most common culprits are sulfonamide antibiotics, anticonvulsants, nonsteroidal antiinflammatory drugs, and allopurinol, many of which are commonly used in conjunction with chemotherapeutic agents. Although a variety of chemotherapeutic agents are reported in the literature to be associated with StevensJohnson syndrome or toxic epidermal necrolysis, attributing causality to a spe-

volved, the reaction is termed StevensJohnson syndrome, whereas when greater than 30% of body surface area is involved, it is called toxic epidermal necrolysis. For reactions of intermediate severity, the term SJS/TEN overlap syndrome is used.7 Treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis requires discontinuation of the offending agent. Skin-directed therapy is important to encourage wound healing, minimize water loss, and decrease the risk of infection. As SJS and TEN are hypercatabolic states similar to large burns, parenteral fluid, electrolyte, and nutrient resuscitation may be necessary.8,9 Treatment should occur in an ICU or burn unit familiar with managing SJS and TEN. Short-term treatment with corticosteroids (< 5 days) is still controversial but has been shown to be beneficial for early presentations of TEN; longer courses or initiation later in the disease course are associated with an increased risk of infection.10,11 Treatment with granulocyte colony-stimulating factor (G-CSF, Neupogen) may be indicated

for TEN-associated neutropenia.12-15 High-dose intravenous immunoglobulin (2 gm/kg) is most widely used for the treatment of toxic epidermal necrolysis, although the exact mechanism of benefit is unclear.16-21

Drug Rash With Eosinophilia and Systemic Symptoms Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare and potentially life-threatening syndrome characterized by a combination of morbilliform rash, facial or acral edema, fever, lymphadenopathy, eosinophilia, and internal organ involvement.22 Mortality is as high as 10%, usually due to visceral involvement, most commonly fulminant hepatitis.23-27 The onset of the DRESS syndrome typically occurs 2 to 6 weeks after exposure to the causative drug.26,28 The cutaneous signs of DRESS are often nonspecific, but typically manifest as generalized morbilliform erythema and associated edema of the face and upper extremities. The cutaneous signs are accompanied by systemic signs of fever, lymphadenopathy, and visceral involvement. The mechanism of this disorder is unknown, but it is thought to be due to altered metabolism of certain drugs, notably anticonvulsants and allopurinol, and decreased clearance of toxic metabolites. Reactivation of herpesvirus infection (especially HHV-6) in conjunction with a drug hypersensitivity reaction is specific for DRESS.29-33 There are no accepted treatment regimens for DRESS syndrome, though high-dose systemic steroids are frequently used when visceral involvement is severe.34-37 Discontinuation of the causative agent is vital. Treatment of the rash includes topical steroids for milder cases and hospitalization for fluid, electrolyte, and nutrition support in more severe cases. Cutaneous and systemic symptoms can persist for weeks to months after discontinuation of the offending agent, though most patients make a full recovery. Patients should be followed after resolution to monitor for delayed-onset autoimmune disease, most notably hypothyroidism, diabetes mellitus, and cardiomyopathy.38,39 n Disclosure: Ms. Barklund and Dr. Anadkat reported no potential conflicts of interest.

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Dermatologic Events in Oncology References 1. Shepherd GM: Hypersensitivity reactions to chemotherapeutic drugs. Clin Rev Allergy Immunol 24:253-262, 2003. 2. Andakat MJ: Life-threatening (Serious) Dermatologic Adverse Events, in Dermatologic Principles and Practice in Oncology: Conditions of the Skin, Hair, and Nails in Cancer Patients, pp 310-318. Hoboken, NJ; John Wiley & Sons; 2014. 3. Lee C, Gianos M, Klaustermeyer WB: Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents. Ann Allergy Asthma Immunol 102:179-187, 2009. 4. Stevens AM, Johnson FC: A new eruptive fever associated with stomatitis and ophthalmia. Am J Dis Child 24:526533, 1922. 5. Lyell A: Toxic epidermal necrolysis: An eruption resembling scalding of the skin. Brit J Dermatol 68:355-361, 1956. 6. Rosen AC, Balagula T, Raisch DW, et al: Life-threatening dermatologic adverse events in oncology. Anticancer Drugs 25:225-234, 2014. 7. Bastuji-Garin S, Rzany B, Stern RS, et al: Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129:92-96, 1933. 8. Windle EM: Immune modulating nutrition support for a patient with severe toxic epidermal necrolysis. J Hum Nutr Diet 18:311-314, 2005. 9. Coss-Bu JA, Jefferson LS, Levy MI, et al: Nutrition requirements in patients with toxic epidermal necrolysis. Nutr Clin Pract 12:81-84, 1997. 10. Kim PS, Goldfarb IW, Gaisford JC, et al: Stevens-Johnson syndrome and toxic epidermal necrolysis: A pathophysiologic review with recommendations for a treatment protocol. J Burn Care Rehab 4:91100, 1983. 11. Patterson R, Miller M, Kaplan M, et al: Effectiveness of early therapy with corticosteroids in Stevens-Johnson syndrome: Experience with 41 cases and a hypothesis regarding pathogenesis. Ann Allergy 73:2734, 1994. 12. de Sica-Chapman A, Williams G, Soni N, et al: Granulocyte colony-stimu-

lating factor in toxic epidermal necrolysis (TEN) and Chelsea & Westminster TEN management protocol. Br J Dermatol 162:860-865, 2010. 13. Kalyoncu M, Cimsit G, Cakir M, et al: Toxic epidermal necrolysis treated with intravenous immunoglobulin and granulocyte colony-stimulating factor. Indian Pediatr 41:392-395, 2004. 14. Jarrett P, Rademaker M, Havill J, et al: Toxic epidermal necrolysis treated with cyclosporin and granulocyte colony stimulating factor. Clin Exper Dermatol 22:146147, 1997. 15. Goulden V, Goodfield MJ: Recombinant granulocyte colony-stimulating factor in the management of toxic epidermal necrolysis. Br J Dermatol 135:305-306, 1996. 16. Viard L, Wehrli P, Bullani R, et al: Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490-493, 1998. 17. Stella M, Cassano P, Bollero D, et al: Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulins: Our experience. Dermatology 203:45-49, 2001. 18. Metry DW, Jung P, Levy ML: Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis. Pediatrics 112:14301436, 2003. 19. Morici MV, Galen WK, Shetty AK, et al: Intravenous immunoglobulin therapy for children with Stevens-Johnson syndrome. J Rheumatol 27:2494-2497, 2000. 20. Prins C, Vittorio C, Padilla RS, et al: Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: A retrospective, multicenter study. Dermatology 207:96-99, 2003. 21. Paquet P, Jacob E, Damas P, et al: Treatment of drug-induced toxic epidermal necrolysis (Lyellâ&#x20AC;&#x2122;s syndrome) with intravenous immunoglobulins. Burns 27:652-655, 2001. 22. Kardaun SH, Sidoroff A, ValeyrieAllanore L, et al: Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol

156:609-611, 2007. 23. Cacoub P, Musette P, Descamps V, et al: The DRESS syndrome: A literature review. Am J Med 124:588-597, 2011. 24. Chen YC, Chiu HC, Chu CY: Drug reaction with eosinophilia and systemic symptoms: A retrospective study of 60 cases. Arch Dermatol 146:1373-1379, 2010. 25. Bocquet H, Bagot M, Roujeau JC: Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutaneous Med Surg 15:250-257, 1996. 26. Peyriere, H, Dereure, O, Breton, H, et al: Network of the French Pharmacovigilance Centers. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol 155:422428, 2006. 27. Walsh SA, Creamer D: Drug reaction with eosinophilia and systemic symptoms (DRESS): A clinical update and review of current thinking. Clin Exper Dermatol 36:6-11, 2011. 28. Kano Y, Shiobara T: The variable clinical picture of drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms in relation to the eliciting drug. Immunol Allergy Clin N Am 29:481-501, 2009. 29. Tohyama M, Yahata Y, Yasukawa M, et al: Severe hypersensitivity syndrome due to sulfasalazine associated with reactivation of human herpesvirus 6. Arch Dermatol 134:1113-1117, 1998. 30. Descamps V, Valence A, Edlinger C, et al: Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms. Arch Dermatol 137:301-304, 2001. 31. Tohyama M, Hashimoto K: Drug hypersensitivity syndrome and human herpesvirus 6 reactivation. Arch Dermatol 138:268-269, 2002. 32. Carrigan DR, Knox K: Human herpesvirus 6: Diagnosis of active infection. Am Clin Lab 19:12, 2000. 33. Suzuki Y, Inagi R, Aono T, et al: Human herpesvirus 6 infection as a risk factor for the development of severe drug-

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GUEST EDITOR

Mario E. Lacouture, MD

ermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan Kettering Cancer Center, New York. He is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments.

induced hypersensitivity syndrome. Arch Dermatol 134:1108-1112, 1998. 34. Tas S, Simonart T: Management of drug eruption with eosinophilia and systemic symptoms (DRESS syndrome): An update. Dermatology 206:353-356, 2003. 35. Chopra, S, Levell NJ, Cowley G, et al: Systemic corticosteroids in the phenytoin hypersensitivity syndrome. Br J Dermatol 134:1109-1112, 1996. 36. Vittorio CC, Muglia JJ: Anticonvulsant hypersensitivity syndrome. Arch Intern Med 155:2285-2290, 1995. 37. Eshki M, Allanore L, Musette P, et al: Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: A cause of unpredictable multiorgan failure. Arch Dermatol 145:6772, 2009. 38. Chen YC, Chang CY, Cho YT, et al: Long-term sequelae of drug reaction with eosinophilia and systemic symptoms: A retrospective cohort study from Taiwan. J Am Acad Dermatol 68:459-465, 2013. 39. Ushigome Y, Kano Y, Ishida T, et al: Short- and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution. J Am Acad Dermatol 68:721-728, 2013.

THERE’S A

NATURAL KILLER INSIDE EVERYONE WITH THE POTENTIAL TO TAKE ON

MULTIPLE MYELOMA

Despite recent advances, multiple myeloma remains a largely incurable disease, with fewer than half of patients surviving five years after diagnosis.1

Natural killer cells are part of the body’s first line of defense against cancer, but myeloma cells evade and suppress a patient’s natural immune response, making further medical advances challenging.2-11 We need a new approach. Bristol-Myers Squibb is deeply committed to furthering the science behind Immuno-Oncology. Leading the way in Immuno-Oncology research, Bristol-Myers Squibb is investigating the potential of the SLAMF7, KIR, and CD137 pathways to activate the body’s own natural killer cells to target myeloma cells. REFERENCES: 1. SEER Stat Fact Sheets: Myeloma, 2004-2010. http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed July 17, 2014; 2. Godfrey J and Benson DM Jr. The role of natural killer cells in immunity against multiple myeloma. Leuk Lymphoma. 2012;53:1666-1676; 3. Cheng M, Chen Y, Xiao W et al. NK cell-based immunotherapy for malignant diseases. Cell Molec Immunol. 2013;10:230-252; 4. Bernal M, Garrido P, Jiménez P et al. Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma : implications for tumor evasion of T and NK cells. Human Immunol. 2009;70:854-857; 5. Jinushi M, Vanneman M, Munshi NC et al. MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA. 2008;105:1285-1290; 6. Carbone E, Neri P, Mesuraca M et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005;105:251-258; 7. von Lilienfeld-Toal M, Frank S, Leyendecker C et al. Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked. Cancer Immunol Immunother. 2010;59:829-839; 8. Cook G, Campbell JDM, Carr CE et al. Transforming growth factor beta from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes. J Leukoc Biol. 1999;66:981-988; 9. Yu J, Wei M, Becknell B et al. Pro- and anti-inflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity. 2006;24:575-590; 10. Nielsen H, Nielsen HJ, Tvede N et al. Immune dysfunction in multiple myeloma. Reduced natural killer cell activity and increased levels of soluble interleukin-2 receptors. APMIS. 1991;99:340-346; 11. Tinhofer I, Marschitz I, Henn T et al. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood. 2000;95:610-618.

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Expert’s Corner

Despite Growing Awareness, the Global Crisis of Untreated Cancer Pain Persists A Conversation With Virginia LeBaron, PhD, APRN By Ronald Piana

Virginia LeBaron, PhD, APRN

ach day, millions of patients with cancer around the world suffer unrelieved pain because they are denied morphine, the gold standard of cancer pain control. The World Health Organization has called access to morphine a human rights issue. Not surprisingly, the crisis in unrelieved cancer pain is a tale of two worlds: most suffering due to a lack of morphine is felt in the world’s poorer regions. Challenges related to opioid availability affect many low- and middle-income countries, such as India, which has an astounding one-seventh of the world’s population. Despite having a robust pharmaceutical industry and being the world’s largest producer of medical grade opium, the majority of India’s cancer patients die in pain. To better understand this issue, The ASCO Post recently spoke with Virginia LeBaron, PhD, APRN, Postdoctoral Research Fellow at DanaFarber Cancer Institute. Dr. LeBaron has done extensive research into barriers to pain control in resource-challenged areas, most recently in India, where she led a study looking at barriers to opioid availability and cancer pain management.1,2

pain as well as we could. I later went on to graduate school and became a nurse practitioner, focusing specifically on oncology palliative care. I worked with excellent mentors and learned how to properly assess and manage pain. While working as an oncology nurse practitioner, I had a series of fortuitous connections that put me in touch with a non-governmental organization, called The International Network for Cancer Treatment and Research (INCTR). In 2004, this group was looking for a palliative care nurse to assist with a project in Nepal. I volunteered and it was on that first trip when I truly witnessed what cancer was like without pain control. I will never forget a visit to a pediatric hospital ward, seeing children with advanced cancer who were in agony because they had no opioids; only acetaminophen was available to treat their severe cancer pain. That experience affected me deeply. I returned home determined to figure out how we could improve that terrible situation of untreated

site, which was a 300-bed government cancer hospital. I interacted and spent time with nurses, physicians, social workers, pharmacists, and patients and their family members to learn about how they approached and understood cancer pain management. My second key data source included 54 semistructured interviews that were more formal audio-recorded conversations to further explore cancer pain management. And my third source was derived from examining various hospital documents related to pain management. The goal of the study was to explore cancer pain management in a resourceconstrained setting, particularly from the nurse’s perspective in order to understand how limited access to opioids affected their practice. All research projects have certain limitations; barriers related to language and translation were a primary limitation, although I utilized a translator who was fluent in the local language in the field during my entire project. Some may also won-

Cancer is a complex global problem, but there’s a simple solution to alleviating much suffering: access to morphine. —Virginia LeBaron, PhD, APRN

cancer pain. There are lots of problems in the world without clear solutions, but in this situation, we have morphine, an inexpensive medication that would relieve this unnecessary suffering. Back in the States, my unanswered questions about barriers to pain control led me to return to school for my doctorate degree in oncology nursing, and ultimately to India as a Fulbright Fellow to conduct my dissertation research.

Barriers to Pain Management

Cultural Immersion

Please tell the readers a bit about your background and what led to your interest in barriers to pain management. My clinical and research background is in oncology palliative care and my interest in barriers to pain management has evolved from my collective experiences as a clinician, nurse faculty member, and as a researcher. I began my oncology nursing career as a chemotherapy infusion nurse, caring for very sick patients with advanced cancer. Early on, I struggled with whether we were really managing their

Please describe the goals and design of your study and any of its limitations. The design of my research project was an ethnography, which is a qualitative research method that has its roots in anthropology and involves intensive cultural immersion to try to most comprehensively understand a certain phenomenon. I lived in India for 9 months collecting data for my project. Ethnography generally involves three key data sources. First, participant observation is necessary, and for that I spent hundreds of hours in the field

der about generalizability, but I would suggest, based on published results from similar projects and in conversations with other global health experts that the key findings from my research are applicable beyond India, particularly to government hospitals in other low- and middle-income countries.

Perceptions and Biases According to your work, what are the greatest barriers to morphine access in India? This is a complex problem. A combination of factors impede access to morphine for cancer pain in many lowand middle-income countries, such as India. The barriers broadly fall into the categories of policy, education, regulatory issues, and cultural considerations and biases. For example, in the hospital where I did my research, general ward nurses did not administer morphine; it was not something they were trained to do. And I also found that when nurses did advocate for their patients, many physicians were reluctant to or-

der morphine, even if it was available. There was also at tmes a cultural belief that pain was an inevitable and untreatable byproduct of cancer; witnessing cancer patients in severe pain seemed to reinforce this mindset. I was in a city of 8 million people, and the 300-bed hospital where I conducted my research was the only institution that had relatively reliable access to adequate amounts of morphine. But even there, morphine stock-outs still occurred. And more broadly, many developing countries lack national health policies that address pain and palliative care. In many low- and middle-income countries, regulations are very unbalanced and focus more on preventing the illicit use of opioids at the expense of ensuring that these essential medications are available to patients who desperately need them.

Important Misperceptions False perceptions about morphine use among the lay pubic and regulatory agencies have been identified as an impediment to its use. Did you and your colleagues find this perception barrier among health-care professionals? Yes. Unfortunately, there are serious misperceptions about morphine, not just in India, but also throughout much of the world. A large part of this relates to disproportionate fears of addiction when morphine is used to treat pain. There’s also a misperception by many that once opioids are introduced into care, it means the patient is imminently dying, when, in fact, studies show that early, effective, and appropriate pain management intervention not only enhances quality of life, but can improve survival outcomes as well.

Narcotic Drugs and Psychotropic Substances Act What are the first critical steps in breaking down the barriers to access to morphine in India? This past February, India took a major step forward when the parliament approved amendments to the Narcotic Drugs and Psychotropic Substances Act, which eliminated archaic rules that obligated hospitals and pharmacies to obtain four or five licenses, each from a different government agency, every time they needed to purchase pain continued on page 79

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Clinical Trials

Exceptional Responders to Cancer Therapy Study Begins

he National Cancer Institute (NCI) recently launched “The Exceptional Responders Initiative,” a study to investigate the molecular factors of tumors associated with exceptional treatment responses of patients with cancer to drug therapies. Scientists will attempt to identify the molecular features of tumors that predict whether or not a particular drug or class of drugs will be beneficial. Investigators will examine tumor specimens from patients in clinical trials who achieved an exceptional response relative to other trial participants, or other patients who achieved an exceptional and unexpected response to a non-investigational therapy.

Why Do Some Patients Benefit? This initiative was initially considered 2 years ago when, through the use of advanced DNA sequencing methods, the molecular basis for the prolonged remission of bladder cancer in a patient following treatment with a molecularly targeted drug in a clinical trial was determined. Researchers thought it might be possible to understand the mechanism of drug response for a relatively small number of patients in early-phase clinical trials who benefit dramatically from therapy. In the past, trials in which up to only 10% of patients had significant and prolonged responses were considered unsuccessful because it was not possible to understand why some patients benefitted from treatment and others did not. In treating patients with cancer, unexpected and prolonged remissions following standard therapy can be observed; the reasons why certain patients experience these remissions have been unclear. If molecular markers could

be developed that predict positive responses to certain therapies, even in a small subset of patients, it might be possible to more effectively choose treatment programs for individual patients.

Evaluating the Exceptional Responders In this study, some of the tissue and clinical data from exceptional responders will be obtained from NCI-supported trials as well as potentially other clinical trials. The remaining samples and data will come from standard therapy settings, such as community practice, where there are reliable outcome data,

relevant mutations in tumor specimens from patients who experienced an exceptional response to a drug in a clinical trial, even though that drug failed to meet the trial’s endpoint for clinical benefit,” said Louis Staudt, PhD, MD, Director of the NCI Center for Cancer Genomics, a coleader of this study.

agnosis, NCI, and the other co–lead investigator for the study. “The ability to identify molecular markers that are able to predict a clinical response in these subsets of patients will provide us with the tools to further advance our ability to conduct studies consistent with the principles of precision medicine.”

Putting the Data Into Practice

Building on the Data

Ultimately, clinicians would like to use this information to identify patients who may potentially respond to agents with the same or similar mechanism of action. It may be difficult to determine if abnormalities found in exceptional

This exploratory study will also examine the feasibility of conducting a larger exceptional responder study (especially given what is expected to be a limited amount of tissue that can be collected over the study period of 3 to 4 years). The output of this initiative might include a list of plausible mutations, possible mutations, or simply all the mutations found in the exceptional responder cases. Researchers hope other investigators will seek to build on the data generated by this study by testing hypotheses on specimens from a trial that used a particular drug, or by comparing their own dataset with the shared data. Placing the full genomic annotation of 100 cases of exceptional responders in the public domain should aid all clinicians and researchers looking for patterns in drug response.

The increasing ability of molecular technologies to stratify tumor types by prognosis or response to treatment will result in many common cancers being separated into specific subtypes that may respond to drugs in very different ways. —Barbara A. Conley, MD

and from pharmaceutical industry trials or other sources. Consequently, letters of solicitation are being sent to cancer centers and other clinicians nationwide to ask them to assist in this effort. DNA and RNA from tissue samples will be isolated at the Biospecimen Core Resource at Nationwide Children’s Hospital, Columbus, Ohio. Those isolates will then be shipped to a DNA sequencing and analysis center at Baylor University, Houston. “The feasibility of this approach is supported by reports in the literature of

responders are functionally significant and whether the abnormalities actually drive tumor growth. Additionally, relevant mutations may be present in less than 5% of tumors, making them difficult to identify. “The increasing ability of molecular technologies to stratify tumor types by prognosis or response to treatment will result in many common cancers being separated into specific subtypes that may respond to drugs in very different ways,” noted Barbara A. Conley, MD, Division of Cancer Treatment and Di-

How Can You Help? Questions from investigators, physicians, and hospitals looking to contribute tumor samples can be sent by email to the Exceptional Responder’s email box at NCIExceptionalResponders@ mail.nih.gov. For more details about the Exceptional Responders initiative, please go to the Q&A at http://www.cancer. gov/newscenter/newsfromnci/2014/ ExceptionalRespondersQandA. n

The Value of Federally Funded Cancer Research ASCO has created a badge to raise awareness of the importance of federally funded biomedical research that improves the lives of people worldwide. The plenary presentations at ASCO’s Annual Meeting all were the result of federally funded research. To call attention to the value of federal funds, The ASCO Post has printed this badge alongside reports on data resulting from federally funded research.

Virginia LeBaron, PhD, APRN continued from page 78

medications. Another critical step is to develop educational programs that address cultural barriers related to using opioids to manage pain, and to ensure that basic palliative care instruction is integrated into nursing and medical school curricula. Equally important is to ensure that

morphine is available throughout India, as there are many rural areas where access to pain relief is completely absent. Many patients and family members struggle to travel to city hospitals, such as the one where I conducted my research. We, as a health-care community, must find a way to decrease the disparity of access to pain relief and palliative care services that impacts

so many patients in need around the world. This is especially critical as the global cancer burden disproportionately affects low- and middle-income countries. Cancer is a complex global problem, but there’s a simple solution to alleviating much of its suffering: access to morphine. n Disclosure: Dr. LeBaron reported no potential conflicts of interest.

References 1. LeBaron V, Beck S, Black F, et al: Nurse moral distress and cancer pain management: An ethnography of oncology nurses in India. Cancer Nurs 37:331-344, 2014. 2. LeBaron V, Beck S, Black F, et al: An ethnographic study of barriers to cancer pain management and opioid availability in India. Oncologist 19:515-522, 2014.

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The ASCO Post | OCTOBER 15, 2014

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In the Clinic Melanoma

First Approval of PD-1 Inhibitor: Pembrolizumab in Unresectable or Metastatic Melanoma By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n September 4, 2014, pembrolizumab (Keytruda) was granted accelerated approval for the treatment of patients with unresectable or metastatic melanoma with disease progression following treatment with ipilimumab (Yervoy) and, in BRAF V600 mutation– positive patients after treatment with a BRAF inhibitor.1 Pembrolizumab is the first programmed death receptor-1 (PD1) inhibitor to be approved for use in the United States. As a condition of accelerated approval, Merck is required to conduct a multicenter, randomized trial establishing the superiority of pembrolizumab over standard therapy. Two ongoing confirmatory trials are assessing pembrolizumab in either ipilimumab-refractory (Trial P002) or ipilimumab-naive (Trial P006) patients with unresectable or metastatic melanoma, both with the coprimary endpoints of progression-free survival and overall survival.

Supporting Study Approval was based on overall re-

sponse rate and duration of response in a multicenter phase I study in 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab and with prior BRAF inhibitor treatment in those with BRAF V600–mutant dis-

OF NOTE Pembrolizumab carries warnings/ precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, hypophysitis, nephritis, and hyperthyroidism/hypothyroidism.

ease.2,3 Patients were randomly assigned to receive intravenous pembrolizumab at 2 mg/kg (n = 89) or 10 mg/kg (n = 84) every 3 weeks until disease progression or unacceptable toxicity. To be enrolled in the study, patients could not have autoimmune disease,

any medical condition that required immunosuppression, or a history of severe immune-mediated adverse reactions to ipilimumab. Patients had a median age of 61 years (64% < 65 years), 60% were male, 97% were white, 66% and 34% had Eastern Cooperative Oncology Group performance status of 0 and 1, 17% had BRAF V600–mutant disease, 39% had elevated lactate dehydrogenase, 82% had M1c disease, 9% had brain metastases, and 73% had received at least two prior therapies for advanced or metastatic disease. The objective response rate was 24% (95% confidence interval = 15%–34%) in patients receiving 2 mg/kg (the approved dose), with 1 complete response and 20 partial responses being observed. Among the 21 patients with a response,

tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.

How It Is Given The recommended dose of pembrolizumab is 2 mg/kg via intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. Treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, symptomatic hypophysitis, grade 2 nephritis, grade 3 hyperthyroidism, AST or ALT > 3 to 5 times or total bilirubin > 1.5 to 3 times upper limit of normal, and any other severe or grade 3 treatment-related

Pembrolizumab in Melanoma ■ Pembrolizumab (Keytruda) was granted accelerated approval in unresectable or metastatic melanoma with disease progression after treatment with ipilimumab or a BRAF inhibitor. ■ Pembrolizumab is given at 2 mg/kg via intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

3 (14%) had disease progression at 2.8, 2.9, and 8.2 months after initial response. The remaining 18 patients (86%) had ongoing responses with durations of 1.4+ to 8.5+ months, including 8 with ongoing responses of ≥ 6 months. One additional patient developed two new asymptomatic lesions at the first tumor assessment while exhibiting a 75% decrease in overall tumor burden. With continuation of treatment, this reduction in tumor burden was durable for more than 5 months. Responses were observed in patients with and without BRAF V600–mutant disease. A similar response rate was observed in the 10-mg/kg group.

How It Works Pembrolizumab is an anti–PD-1 monoclonal antibody. It binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2 ligands, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. Binding of PD-L1 and PD-L2 to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands is observed in some

adverse reaction. Treatment can be resumed when adverse reactions recover to grade 0 or 1. Pembrolizumab should be permanently discontinued for any life-threatening adverse reaction, grade 3 or 4 pneumonitis, grade 3 or 4 nephritis, AST or ALT > 5 times or total bilirubin > 3 times upper limit of normal, AST or ALT increases of ≥ 50% in patients with liver metastasis who began treatment with grade 2 increased AST or ALT, grade 3 or 4 infusion-related reactions, inability to reduce corticosteroid dose to ≤ 10 mg/d prednisone or equivalent within 12 weeks, persistent grade 2 or 3 adverse reactions that do not recover to grade 0 or 1 within 12 weeks of last dose, and any recurrent severe or grade 3 treatment-related adverse reaction. No dose adjustment is needed for patients with renal impairment. No dose adjustment is needed for patients with mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment

Safety Profile The most common clinical adverse events of any grade in patients receiving

OF NOTE Pembrolizumab binds to the PD-1 receptor and blocks its interaction with its ligands, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response.

pembrolizumab 2 mg/kg were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), and decreased appetite (26%). The most common grade 3 events were fatigue (7%), anemia (5%), and dyspnea (2%). The most common laboratory abnormalities of any grade were anemia (55%), hyperglycemia (40%), hyponatremia (35%), and hypoalbuminuria (34%), and the most common grade 3 or 4 events were hyponatremia (9%), anemia (8%), hyperglycemia (2%), and increased AST (2%). The most frequent (≥ 2%) serious adverse events were renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. Treatment was discontinued due to adverse events in 6% of patients. Pembrolizumab carries warnings/ precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, hypophysitis, nephritis, and hyperthyroidism and hypothyroidism, and embryofetal toxicity. Corticosteroid treatment of immune-mediated reactions should be based on severity. Hepatic, renal, and thyroid function should be routinely monitored. n References 1. U.S. Food and Drug Administration: Pembrolizumab. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm412861.htm. 2. Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet. July 14, 2014 (early release online). 3. KEYTRUDA® (pembrolizumab) for injection prescribing information, Merck Sharp & Dohme Corp., September 2014. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf.

ASCOPost.com | OCTOBER 15, 2014

PAGE 83

Announcements Genitourinary Oncology

Advanced Robotic Technology Used to Remove Kidney Tumor in First-Time Outpatient Procedure

eck Medical Center of the University of Southern California (USC) has become the first medical center in the world to use a new robotic technology in an outpatient procedure for a patient with kidney cancer. Urologic surgeons at the USC Insti-

Gill said. Although this surgery was on a kidney, the surgery may also be an option for cancer of the prostate, liver, pancreas, and other organs, he noted. Most kidney tumors are discovered

when they are small and the patient is not experiencing symptoms. Although traditional surgery is an effective remB:7.875 in edy, the risk of complications from in such surgery can beT:7.625 daunting. Of 12 S:7.125 in

patients in the United Kingdom who participated in a 2011 proof-of-concept study of high-intensity focused ultrasound for kidney tumors, seven were cancer-free after 24 months. n

Inderbir Gill, MD

tute of Urology, part of Keck Medicine of USC, used a U.S. Food and Drug Administration (FDA)-cleared laparoscopic device, the high-intensity focused ultrasound (HIFU) surgical ablation system for ablating intra-abdominal tumors. The system enables surgeons to penetrate the abdominal cavity with keyhole cuts to eliminate tumors of 4 cm or less.

Same-Day Surgery Inderbir Gill, MD, Founding Executive Director, USC Institute of Urology, and Chairman and Professor, Catherine and Joseph Aresty Department of Urology at the Keck School of Medicine of USC, performed the surgery on a 62-year-old Van Nuys resident, who went home the same day, 3 to 4 days earlier than patients typically experience with kidney cancer surgery. “Using a focused beam of ultrasound directly on the tumor and minimally invasive surgery, we destroyed the tumor without surgically removing it from the body,” Dr. Gill said. “The most important aspects of this technology are the reduced trauma to the patient and the ability to save the kidney, without the tumor, for a healthier lifestyle post-surgery. This surgery offers fewer chances for infection and post-operative complications. Our goal is to save as much of the good kidney as possible and help patients return to a normal lifestyle quickly.”

This is no routine cancer hospital. At the new James, the third-largest cancer hospital in America, we understand that each person’s cancer is unique. Here, the world’s brightest researchers, oncologists and other specialists work together, focused solely on discovering, developing and delivering the most effective treatment for all types of cancer. To successfully detect and treat each cancer, sub-specialized cancer physicians must work side-by-side with cancer researchers, understand the disease at the molecular level and determine which treatments will stop it. The new James brings together the newest technology and these teams of experts in an amazing structure designed for one purpose...our patients.

Procedure an Option for Tumors 4 cm or Smaller High-intensity focused ultrasound surgery is an option for patients whose tumors are 4 cm or less which accounts for about 10% of all kidney tumors, Dr.

Opening December 2014. To learn more visit cancer.osu.edu.

The ASCO Post | OCTOBER 15, 2014

PAGE 84

Journal Spotlight Gastrointestinal Oncology

Lower- vs Higher-Than-Expected Long-Term Colorectal Cancer Mortality After Removal of Lower- vs Higher-Risk Adenomas By Matthew Stenger

ew data are available on long-term risk of colorectal cancer mortality after adenoma removal. In a Norwegian study reported in The New England Journal of Medicine, Magnus Løberg, MD, of the Department of Health Management and Health Economics, University of Oslo, and colleagues found that patients who had low-risk adenomas removed had lower colorectal cancer mortality risk and those who had high-risk adenomas removed had higher colorectal cancer mortality risk compared with the general population over 7.7 years of follow-up.1 The findings suggest that frequent colonoscopic surveillance may be unnecessary after removal of low-risk adenomas.

for 44.0%, 10 to 14 years for 27.6%, and 15 to 19 years for 11.5%. The number of adenomas per occurrence was one for 88.9% and two or more for 11.1%, and adenoma location was distal in 47.4%, proximal in 13.7%, and multiple or unspecified in 39.0%. A total of 23,449 (51.3%) had removal of low-risk adenomas and 22,306 (48.8%) had removal of high-risk adenomas, including at least two adenomas (22.8%), villous or tubulovillous growth pattern adenomas (28.8%), and adenomas with high-grade dysplasia (15.3%). Review of detailed pathology reports for 442 patients showed that 8.2% of 220 patients with adenomas classified as high-risk had low-risk ad-

Study Details In the study, the linked Cancer Registry and Cause of Death Registry of Norway were used to estimate colorectal cancer mortality among patients who underwent removal of colorectal adenomas between 1993 and 2007 and who were followed through 2011. Incidence-based standardized mortality ratios (SMRs) were generated using colorectal cancer mortality rates for the Norwegian general population. Polyp size and exact number were not available from the cancer registry. Highrisk adenomas were defined as multiple adenomas or adenomas with a villous component or high-grade dysplasia. Current Norwegian guidelines recommended colonoscopy after 10 years for patients with high-risk adenomas (eg, those with high-grade dysplasia, a villous component, or size ≥ 10 mm) and after 5 years for patients with at least three adenomas, with no surveillance recommended for those with lowrisk adenomas.

Patients and Risk Characterization A total of 40,826 patients who had undergone removal of colorectal adenomas were identified. In the cohort: 50.8% of patients were male; age at first adenoma removal was 40 to 49 years for 9.3%, 50 to 59 years for 22.9%, 60 to 69 years for 28.0%, 70 to 79 years for 26.7%, and ≥ 80 years for 13.2%. The period of first adenoma removal was 1993 to 1999 for 34.7% and 2000 to 2007 for 65.3%. Duration of follow-up was 0 to 4 years for 16.9%, 5 to 9 years

Adenoma Removal and Colorectal Cancer Mortality ■ Overall, there was no difference in risk of colorectal cancer mortality in patients with adenoma removal vs the general population. ■ Patients with removal of high-risk adenomas had a 16% increase and those with removal of low-risk adenomas had a 25% decrease in risk of colorectal cancer mortality.

deaths, SMR = 0.75, 95% CI = 0.63– 0.88). Colorectal cancer mortality was also increased in the adenoma cohort vs the general population among patients with first adenoma removal in 1993 to 1999 (SMR = 1.17, 95% CI = 1.03– 1.33), those with at least two adenomas per occurrence (SMR = 1.19, 95% CI = 1.00–1.43), those with villous/tubu-

Our finding that the removal of lowrisk adenomas reduces the risk of death from colorectal cancer over a period of 8 years to a level below the risk in the general population is consistent with the hypothesis that surveillance every 5 years after removal of low-risk adenomas may confer little benefit over less intensive surveillance strategies. —Magnus Løberg, MD, and colleagues

enomas and that 30.2% of those with adenomas characterized as low-risk had high-risk adenomas.

Colorectal Cancer Mortality Rates Median follow-up was 7.7 years (maximum, 19.0 years). Overall, 1,273 patients (387 per 100,000 person-years) were diagnosed with colorectal cancer; 383 (115/100,000 person-years) died of colorectal cancer compared with 398 expected colorectal cancer deaths in the general population (SMR = 0.96, 95% confidence interval [CI] = 0.87–1.06). Compared with colorectal cancer mortality in the general population, colorectal cancer mortality was significantly increased among patients with high-risk adenomas removed (242 observed deaths vs 209 expected deaths, SMR = 1.16, 95% CI = 1.02–1.31) and significantly decreased among patients with low-risk adenomas removed (141 observed deaths vs 189 expected

lovillous growth pattern (SMR = 1.26, 95% CI = 1.08–1.47), and those with high-grade dysplasia (SMR = 1.40, 95% CI = 1.15–1.72). Colorectal cancer mortality was decreased among men (SMR = 0.86, 95% CI = 0.74–1.00; SMR = 1.06, 95% CI = 0.93–1.22, for women), those with first adenoma removal in 2000 to 2007 (SMR = 0.76, 95% CI = 0.65–0.89), those with one adenoma per occurrence (SMR = 0.89, 95% CI = 0.79–1.00), those with tubulous growth pattern (SMR = 0.83, 95% CI = 0.73-0.94), and those with low-grade dysplasia (SMR = 0.87, 95% CI = 0.78–0.98).

Multivariate Analysis The investigators performed a multivariate analysis of colorectal cancer mortality including age, sex, number of adenoma occurrences, period of adenoma removal, adenoma location, number of adenomas, grade of dysplasia, and growth pattern. In this analy-

sis, first adenoma removal in the 2000s (hazard ratio [HR] = 0.63, P < .001, vs 1990s) was associated with significantly reduced mortality. Factors associated with increased mortality included two or more adenomas per occurrence (HR = 1.31, P = .02, vs 1 per occurrence), villous/tubulovillous growth pattern (HR = 1.40, P = .002, vs tubulous growth pattern), high-grade dysplasia (HR = 1.45, P = .002, vs low-grade dysplasia), and increasing age at first adenoma removal (HRs = 2.43 for 50–59 years, 3.85 for 60–69 years, 7.38 for 70–79 years, and 17.74 for ≥ 80 year age groups, all P ≤ .01, vs 40–49 year group). The investigators concluded: After a median of 7.7 years of follow-up, colorectal-cancer mortality was lower among patients who had had low-risk adenomas removed and moderately higher among those who had had highrisk adenomas removed, as compared with the general population…. Our finding that the removal of low-risk adenomas reduces the risk of death from colorectal cancer over a period of 8 years to a level below the risk in the general population is consistent with the hypothesis that surveillance every 5 years after removal of low-risk adenomas may confer little benefit over less intensive surveillance strategies. Furthermore, complications associated with colonoscopy are not trivial and might offset the benefit of surveillance….

Dr. Løberg and Mette Kalager, MD, PhD, also of the University of Oslo, contributed equally to The New England Journal of Medicine article. n

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

Reference 1. Løberg M, Kalager M, Holme Ø, et al: Long-term colorectal-cancer mortality after adenoma removal. N Engl J Med 371:799807, 2014.

ASCOPost.com | OCTOBER 15, 2014

PAGE 85

Perspective

Colonoscopic Polypectomy and Predicting Cancer Risk: A Work in Progress By Srinadh Komanduri, MD, and Al B. Benson III, MD, FACP, FASCO

olon cancer screening using colonoscopy has significantly decreased the incidence and mortality of colorectal cancer in the United States. In the National Polyp Study (NPS), colorectal cancer was prevented by removal of adenomatous polyps.1 A more recent study looking at long-term follow-up from the NPS demonstrated a 53% reduction in colon cancer mortality with colonoscopy and polypectomy.2 Current screening guidelines recommend identification of those with inherited cancer syndromes with distinct screening/management recommendations, and for all others options including fecal occult blood testing yearly, flexible sigmoidoscopy, computed tomography colonography, barium enema, and colonoscopy beginning at age 50. Those individuals with low-risk adenomas (one or two adenomas < 10 mm) are advised to undergo surveillance colonoscopy every 5 to 10 years, whereas those with high-risk adenomas (high-grade dysplasia, villous adenoma, tubular adenoma ≥ 10 mm, or more than three adenomas) are evaluated every 3 to 5 years.

Study Details As summarized in this issue of The ASCO Post, Løberg and colleagues report their data from over 40,000 patients in Norway from a large database study assessing the long-term risk of colorectal cancer after adenoma removal.3 Colorectal cancer mortality was estimated in this cohort using the linked Cancer Registry and Death Registry of Norway. The study demonstrated a lower risk of colorectal cancer mortality with “low-risk” adenomas than with those considered “high risk.” Higher risk was defined Dr. Komanduri is Director, Interventional Endoscopy, Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, and Dr. Benson is Professor of Medicine, Division of Hematology-Oncology, Department of Medicine, and Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago.

as having multiple adenomas or adenomas with villous histology and/ or high-grade dysplasia. While this definition does not take into account polyp size, it still allows for a reasonable level of risk stratification. The median follow-up was 7.7 years. Colonoscopy every 10 years remains the gold standard strategy for colorectal cancer screening, although there are other options as mentioned above.4 These latter options are not as effective for cancer screening and do not allow for therapeutic intervention if a polyp is identified. More recently,

enomas, as it appears they have very low risk of interval malignancy. The data may further drive gastroenterologists to ensure high-risk adenomas are completely resected or undergo moreadvanced endoscopic mucosal resection to ensure this is the case. The implications of extending surveillance intervals for low-risk patients not only would result in significant cost savings but would potentially increase patient compliance for follow-up. There are some potential limitations of this data set. We need to keep in mind there is an environ-

[T]hese data may have a significant effect on resource allocation in gastroenterology. That being said, the current study does not demonstrate that aggressive colonoscopic surveillance is justified, but rather suggests that there may be a role for risk stratification based on adenoma detection. —Sri Komanduri, MD, and Al B. Benson III, MD, FACP, FASCO

stool DNA analysis (fecal immunochemical test) has demonstrated promise with improved accuracy, but further data are still needed to validate this option for colorectal cancer screening.

Implications and Limitations The major goal and impact of screening is identification and removal of adenomatous polyps. It is clear that patients who develop adenomas remain at risk for future development of polyps and as such warrant colonoscopic surveillance after polyp removal. With this knowledge, the Norwegian study has significant impact on our understanding of colon polyps and cancer development. The data could significantly alter surveillance intervals for patients with low-risk ad-

mental and racial component in colon carcinogenesis. It is quite possible that these and other factors may be different in the Eastern world compared to the United States, for example, and could influence the age at which screening should commence and the interval between screening assessment. Furthermore, while 7.7 years median follow-up is significant, the data would be that much more meaningful with observation beyond 10 years. Moreover, Norwegian guidelines do not recommend surveillance colonoscopy for adenomas before 10 years. This is significantly different from the 3 to 5 year follow up performed in the United States. Dr. David Lieberman’s editorial accompanying the report by Løberg and

colleagues also emphasizes that the quality of colonoscopy is an important factor, particularly for high-risk patients, since it is known that missed lesions on initial colonoscopy can account for development of future colorectal cancers, as can incomplete removal of polyps.5 In summary, the work by Løberg and colleagues is an excellent cohort study and advances our understanding of the progression of colon carcinogenesis. It is possible these data may have a significant effect on resource allocation in gastroenterology. That being said, the current study does not demonstrate that aggressive colonoscopic surveillance is justified, but rather suggests that there may be a role for risk stratification based on adenoma detection. As such, care should be taken when extrapolating the data to all populations across the world. Further prospective studies are needed to validate surveillance intervals and strategies for high- and low- risk adenomas. In the meantime, patients and clinicians should routinely discuss the quality of the colonoscopy, the determination of high- vs low-risk adenomas, and the risks vs benefits of a future surveillance strategy. n

Disclosure: Drs. Komanduri and Benson reported no potential conflicts of interest.

References 1. Winawer SJ, Zauber AG, Ho MN, et al: Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 329:1977-1981, 1993. 2. Zauber AG, Winawer SJ, O’Brien MJ, et al: Colonoscopic polypectomy and long-term prevention of colorectalcancer deaths. N Engl J Med 366:687696, 2012. 3. Løberg M, Kalager M, Holme O, et al: Long-term colorectal-cancer mortality after adenoma removal. N Engl J Med 371:799-807, 2014. 4. Lieberman DA, Williams JL, Holub JL, et al: Colonoscopy utilization and outcomes 2000 to 2011. Gastrointest Endosc 80:133-143, 2014. 5. Lieberman DA: Colon-polyp surveillance—Do patients benefit? N Engl J Med 371:860-861, 2014.

For patients with bone metastases from solid tumors

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

8.2

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

months longer vs zoledronic acid1

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

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

months

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

XGEVA VA® 120 mg Q4W (n = 2,862) VA

19.5

months

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

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

2 YEARS

P < 0.001

†

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

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

†

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

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

Learn more at XGEVA.com

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

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

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

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

www.XGEVA.com

S:9.5”

Brief Summary: Consult package insert for complete Prescribing Information

DOUS14CDNY4736_XGEVA_Tabloid_BS_V10_8pt_r13.indd 1

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

Xgeva n = 2841 %

Zoledronic Acid n = 2836 %

31 20

32 19

18 32

9 20

21 15

18 15

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

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

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

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

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Journal Spotlight Gastrointestinal Oncology

Early Study Reports Modified Vitamin D Has Potential in Treatment for Pancreatic Cancer

esearchers at the Salk Institute have reported on a synthetic derivative of vitamin D able to collapse the barrier of cells shielding pancreatic tumors, making this challenging cancer more susceptible to therapeutic drugs. The discovery has led to human trials for pancreatic cancer, even in advance of the publication of the study recently in Cell.1 These findings may also have implications for other difficult-to-treat tumors, such as lung, kidney, and liver cancer. “While the success of this drug in humans with pancreatic cancer is still unclear, the findings in animal studies were strong, raising hope that ongoing clinical trials will give people with this terrible disease hope for a truly new type of therapy,” said Ronald M. Evans, PhD, Director of Salk’s Gene Expression Laboratory and Senior Author of the recent paper.

Resistance to Therapy An Ongoing Challenge “For pancreatic cancer, the 5-year survival rate is the lowest of all cancers,” said Dr. Evans, Holder of Salk’s March of Dimes Chair and a Howard Hughes Medical Institute Investigator. “Part of the problem is that the science of pancreatic cancer and its renowned resistance to therapy has not been understood and that’s why the work that we’re doing is so important.” Dr. Evans and his colleagues knew that the ability of the pancreatic tumor to communicate with the tumor microenvironment was key to its growth. This “living shield” around a tumor not

only helps the cancer grow, but blocks the access of immune cells and chemotherapeutic drugs, making the cancer particularly hard to treat.

an activated state, spurring new cell growth. In the case of cancer, however, the stellate cells near a tumor are constantly turned on in response to signals from the tumor. This chronic activation Exploring the Tumor of the stellate cells provides the tumor Microenvironment cells with extra growth factors and In collaboration with researchers therefore helps them proliferate, but around the country involved in an in- also forms a wall-like barrier around the terdisciplinary initiative supported by tumor that protects it from chemotherStand Up to Cancer, Dr. Evans wanted apeutics and other anticancer drugs. to determine how to restore the tumor In 2013, Evans’ group discovered microenvironment to its normal state that stellate cells in the liver could be and weaken the wall around the tumor. inactivated by a chemically modified “There was evidence that the activa- form of vitamin D. They wondered tion of the microenvironment was the- whether the same could hold true in oretically reversible, but nobody knew the pancreas, despite the fact the vitaexactly what was responsible for the ac- min D receptor was not thought to be

While the success of this drug in humans with pancreatic cancer is still unclear, the findings in animal studies were strong, raising hope that ongoing clinical trials will give people with this terrible disease hope for a truly new type of therapy. —Ronald M. Evans, PhD

tivation, making it hard to turn off,” said Mara Sherman, PhD, a Salk Postdoctoral Research Fellow and first author. Drs. Sherman, Evans, and their collaborators focused their attention on one component of this wall: pancreatic stellate cells, which usually respond to small injuries by briefly switching to

present in pancreatic tissue. When the group of researchers examined the differences between activated and inactivated stellate cells in the pancreas, they found that activated stellate cells near a tumor had high levels of the vitamin D receptor. And when the researchers then added modified vitamin D to activated stellate cells the cells quickly reverted back to a healthy, inactivated state, stopping production of signals that spur growth and inflammation. “This was a big surprise because vitamin D has been tried multiple times as a therapy for pancreatic cancer and never worked,” said Dr. Evans. It turned out that activated stellate cells rapidly break down normal vitamin D, preventing the vitamin from binding to the receptor, Dr. Evans explained. But systematic analysis of vitamin D analogues allowed the team to discover a modified form of vitamin D that is more stable, resilient, and effective in vitro.

Novel Vitamin D–Like Compound Fig. 1: In the pancreatic tumor microenvironment, non-cancerous stromal cells (blue) impede the delivery and efficacy of chemotherapy. Image courtesy of the Salk Institute for Biological Studies.

To see whether this new vitamin D–like compound could halt the growth of a tumor, Dr. Evans and

his team next studied its effectiveness in mice. The researchers found that combining the drug with existing chemotherapeutics gave a 50% increase in life span compared to chemotherapy alone. “It’s really remarkable considering that vitamin D itself is not attacking the cancer cells,” said Michael Downes, PhD, a senior staff scientist at Salk and co–corresponding author of the new work. “It’s changing the environment to a more favorable setting needed for the chemotherapy drugs to work.” Studies have shown that people deficient in vitamin D are more likely to develop pancreatic cancer. Based on the new results, Dr. Evans thinks that healthy levels of vitamin D may help keep vitamin D receptor signaling in stellate cells normal and squash a cancer’s growth, at least until a tumor itself forces the stellate cells to “turn on.” “Recently, other research groups have explored the idea of destroying the microenvironment altogether to weaken a tumor,” said Dr. Downes. “Our approach is very different. Instead of destroying, we simply want to reprogram the tumor microenvironment to a healthy state. This has the dual effects of delivering more drugs to the tumor as well as replenishing the tissue with normal stellate cells.”

Next Steps Dr. Evans’ group has teamed up with clinicians at the University of Pennsylvania to launch a clinical trial testing the effectiveness of using their vitamin D–like drug in cancer patients before pancreatic surgery. “Previous trials with vitamin D failed because they didn’t understand the need for a special form of vitamin D and that for pancreatic cancer it must be used in combination with chemotoxic drugs,” Dr. Evans said. “So, by rethinking the problem, we have been able to open up a new route to the treatment of pancreatic cancer and, looking forward, hopefully other diseases as well.” n Reference 1. Sherman MH, Yu RT, Ding N, et al: Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhanses pancreatic cancer therapy. Cell 159:80-93, 2014.

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Journal Spotlight Hematology

Time to Treatment Failure Similar With Rituximab Retreatment vs Maintenance in Low–Tumor Burden Follicular Lymphoma By Matthew Stenger

aintenance rituximab (Rituxan) has been shown to improve progression-free survival vs observation in low–tumor burden follicular lymphoma. In the Eastern Cooperative Oncology Group (ECOG) E4402 Trial (RESORT), reported in the Journal of Clinical Oncology, Brad S. Kahl, MD, of the University of Wisconsin School of Medicine and Public Health, Madison, and colleagues

primary endpoint was time to treatment failure. The retreatment and maintenance groups were generally balanced for age (median, 60 and 59 years), sex (53% and 55% female), race (94% and 95% white), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 84% and 88%), bone marrow involvement (43% and 50%), elevated

RESORT indicates that if opting for single-agent rituximab as initial therapy for low–tumor burden [follicular lymphoma], a strategy of retreatment at disease progression is recommended over a strategy of continuous maintenance therapy. —Brad S. Kahl, MD, and colleagues

found no significant difference in time to treatment failure with a strategy of rituximab retreatment at progression vs rituximab maintenance in patients with previously untreated low–tumor burden follicular lymphoma.1 The maintenance strategy was associated with longer time to first cytotoxic chemotherapy, and the retreatment strategy required less use of rituximab.

Study Details In the trial, 408 patients with previously untreated low–tumor burden follicular lymphoma received four weekly doses of rituximab at 375 mg/m2. Those with a complete or partial response at week 13 (n = 289) were randomly assigned to rituximab maintenance (n = 146) or retreatment (n = 143). Rituximab maintenance consisted of a single dose of rituximab every 3 months until treatment failure. Any progressive disease between scheduled maintenance rituximab doses constituted treatment failure. Rituximab retreatment consisted of retreatment at each disease progression until treatment failure. Treatment failure was defined as no response to retreatment rituximab, time to progression < 26 weeks, initiation of alternative therapy, or inability to complete planned therapy. Patients were evaluated every 13 weeks and underwent repeat computed tomography scans every 26 weeks. The

lactate dehydrogenase (13% and 15%), elevated β2-microglobulin (46% and 38%), stage (III in 55% and 46%, IV in 44% and 53%), Follicular Lymphoma International Prognostic Index (FLIPI) score (low in 15% and 16%, intermediate in 45% in both, high in 40% and 39%), histology grade (1 in 71% and 66%, 2 in 23% and 29%, 3a in 2% and 1%), and time from diagnosis < 1 year (92% and 90%). Overall, the complete response/unconfirmed complete response rate during initial rituximab treatment was 11.8%, with no difference between the random-

with a partial response who were assigned to maintenance rituximab, 51% converted to complete response/unconfirmed complete response during maintenance therapy.

Time to Treatment Failure After a median follow-up of 4.5 years, there were 80 treatment failures in the retreatment group and 78 in the maintenance group. Median time to treatment failure was 3.9 vs 4.3 years (P = .54), with 61% vs 64% of patients remaining free of treatment failure at 3 years (P = .33). There was no difference in risk for treatment failure according to retreatment vs maintenance on multivariate analysis (hazard ratio [HR] = 1.07, P = .68). On multivariate analysis, the only significant predictor of treatment failure was intermediate vs low FLIPI score (HR = 1.71, P = .04). Reasons for treatment failure included rituximab resistance in 26% of the retreatment group vs 21% of the maintenance group, need for initiation of alternative treatment in 10% vs 1%, and inability to complete planned therapy in 16% vs 30%. Among those who could not complete planned therapy, reasons were toxicity, death, or other disease in 5% vs 13% and withdrawal for reasons other than toxicity (eg, patient tired of study commitment) in 11% vs 17%. In a sensitivity analysis censoring patient withdrawals for nonmedical reasons, the estimated treatment failure–free survival was 65% vs 73% at

Rituximab Retreatment vs Maintenance in Follicular Lymphoma ■ There was no significant difference in time to treatment failure as defined in the study for retreatment vs maintenance rituximab. ■ The maintenance strategy was associated with prolonged time to first cytotoxic chemotherapy.

ized groups. The investigators noted that this rate was lower than expected likely due to missing repeat bone marrow assessments. Of 120 patients with partial response who were assigned to rituximab retreatment, 41% converted to complete response/unconfirmed complete response with either no further treatment (24%) or with retreatment at progression (17%). Of 113 patients

3 years (P = .16) and 50% vs 53% at 5 years.

Other Outcomes As expected, more patients in the maintenance group were progression-free at 3 years (50% vs 78%). In the retreatment group, median duration of response was 34.4 months to induction treatment, 18.5 months in 34 of 56 patents responding to first retreatment, and 12 months in

8 of 12 with response to second retreatment. No response was observed in four patients receiving third retreatment. There were few deaths, and overall survival did not differ between groups (94% vs 94% at 5 years). Rates of freedom from cytotoxic chemotherapy were 84% vs 95% (P = .03) at 3 years and 80% vs 92% at 5 years. Including the four induction doses, the median number of rituximab doses was four (range, 4–16) in the retreatment group and 18 (range, 5–35) in the maintenance group. There were no differences in health-related quality of life or anxiety between the two groups.

Toxicity Grade ≥ 3 adverse events were infrequent in both groups. Four grade 3 events occurred in retreatment patients, and 10 occurred in maintenance patients; two grade 4 events occurred in retreatment patients, and one grade 5 event occurred in a maintenance patient. The investigators concluded:

There was a small advantage for [maintenance rituximab] in time to first cytotoxic therapy, but significantly more rituximab was required to achieve this benefit. This trial has implications for both research and practice. With regard to research, it would be highly interesting to determine if a [retreatment] strategy could produce outcomes comparable to those of a [maintenance] strategy, when applied after rituximab plus chemotherapy in high–tumor burden [follicular lymphoma]. Given the widespread use of [maintenance rituximab], the resource use implications are large. With regard to practice, RESORT indicates that if opting for single-agent rituximab as initial therapy for low–tumor burden [follicular lymphoma], a strategy of retreatment at disease progression is recommended over a strategy of continuous maintenance therapy. n

Disclosure: The study was supported by grants from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Kahl BS, Hong F, Williams ME, et al: Rituximab extended schedule or retreatment trial for low–tumor burden follicular lymphoma: Eastern Cooperative Oncology Group Protocol E4402. J Clin Oncol. August 25, 2014 (early release online).

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Perspective

ECOG E4402/RESORT Trial: When ‘Black and White’ Results Are Actually Gray By Richard I. Fisher, MD

Study Design Raises Questions Many of the controversial issues with this study relate to how the actual study design and choice of endpoints influence the conclusions the reader can make today. Rituximab maintenance was scheduled to continue indefinitely until treatment failure occurred. It is now relatively well established that continuing rituximab maintenance for an indefinite duration is not desirable and has been associated with increased infectious complications. Thus, most current studies limit the length of maintenance therapy to 2 years. The endpoints of the study are also problematic. What was the definition of treatment failure? Patients whose lymph nodes went from 1 cm to 2 cm had progressive disease by definition but clearly did not always need additional therapy. This problem is also exaggerated by the use of computed tomography scans every 6 months for the duration of the study. This approach will undoubtedly detect these types of small progressions that do not require therapy, leaving questions about the use of time to treatment failure as an appropriate endpoint. It is stated, but not widely appreciated, that patients on retreatment could be treated multiple times before being called a treatment failure. The difference between this strategy and maintenance can certainly blur in specific patients.

What Determines Treatment Failure? Most problematic, however, is the study definition that “inability to com-

TRIM:7.875” plete planned therapy for any reason” SAFETY:7” is part of the definition of treatment failure. Since maintenance went on forever, a patient who remained in

remission and decided to stop maintenance, say after 2 to 5 years, was called a treatment failure. In fact, ev-

continued on page 92

Now enrolling for alectinib

NCT 02075840 BO28984

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

Randomize 1:1

he results of the ECOG E4402/ RESORT trial recently reported by Kahl and colleagues,1 and reviewed in this issue of The ASCO Post, provide interesting new information on the use of maintenance rituximab (Rituxan) vs retreatment with rituximab at progression in patients with low–tumor burden indolent lymphoma initially treated with single-agent rituximab. The authors conclude that the retreatment strategy provides comparable results while using less rituximab.

BLEED:8.375”

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

Primary Endpoint:

Alectinib1

Crizotinib

Secondary Endpoints:

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

• Objective response rate, investigator-assessed,

by RECIST 1.1

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

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

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Advanced, recurrent, or metastatic ALK-positive NSCLC

• Prior malignancy in past 3 years

• Life expectancy ≥12 weeks

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

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

metastatic disease • Measurable disease by RECIST 1.1

a prior therapy

• Baseline QTc >470 ms or symptomatic

bradycardia <45 beats per minute • Concomitant strong cytochrome P4503A

inhibitors/inducers or QT-prolonging medications

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

Dr. Fisher is President and CEO, Fox Chase Cancer Center – Temple Health, and Senior Associate Dean, Temple University School of Medicine. © 2014 Genentech USA, Inc. All rights reserved. BIO0002445101 Printed in USA.

The ASCO Post | OCTOBER 15, 2014

PAGE 92

Perspective

Richard I. Fisher, MD

[W]hat conclusions can be reached with some certainty? First, a retreatment strategy does appear to provide comparable disease control using less rituximab…. However, maintenance rituximab does produce a major prolongation of progression-free survival and freedom from cytotoxic therapy. For some patients, this also may be a viable option.

continued from page 91

ery patient on the maintenance arm who remains in remission will either continue maintenance forever or ultimately be labeled a treatment failure when they decide they have had enough maintenance therapy and stop the proposed schedule. The concept that everyone on maintenance will ultimately become a treatment failure while those on retreatment may stay in remission is certainly problematic. The authors have tried to answer this question by censoring the patients who chose to stop treatment voluntarily on the maintenance arm from the primary analysis. When they do that, the curves for time to treatment failure separate some, with 65% in the retreatment arm and 73% in the maintenance arm free of treatment failure at 3 years (P = .16 in article’s appendix). Finally, although there was no protocol-based definition of when to institute chemotherapy, there was a

—Richard I. Fisher, MD

significant difference in time to next chemotherapy favoring the maintenance arm (P = .03). This should also impact the cost analysis, which focused on the doses of rituximab administered but not the increased cost of chemotherapy caused by its earlier and therefore perhaps more frequent usage in

the retreatment arm. Recall also that the cost of rituximab is estimated to decrease by 25% to 35% as biosimilar molecules enter the market. Thus, what conclusions can be reached with some certainty? First, a retreatment strategy does appear to provide comparable disease control

using less rituximab based on the definitions employed in this study. For some patients, this is clearly a viable option. However, maintenance rituximab does produce a major prolongation of progression-free survival and freedom from cytotoxic therapy. For some patients, this also may be a viable option. In the end, a knowledgeable physician and an informed patient will need to explore their particular treatment goals. Why should we be surprised? Absolute statements about how to treat follicular lymphoma have never been easy to achieve. n

Disclosure: Dr. Fisher reorted no potential conflicts of interest.

More on Time to Treatment Failure With Rituximab Retreatment vs Maintenance in Low–Tumor Burden Follicular Lymphoma Watch the next issue of The ASCO Post for a commentary from Bertrand Coiffier, MD, and Gilles Salles, MD, for their perspective on the RESORT trial reported in the Journal of Clinical Oncology and discussed in this issue.

Don’t Miss These Important Reports in This Issue of The ASCO Post Elizabeth R. Gerstner, MD, on Newly Diagnosed Glioblastoma see page 109

George D. Demetri, MD, on Sarcoma in 2014 see page 117

William Breitbart, MD, and Yesne Alici, MD, on Depression in Patients With Cancer see page 112

Samia Al-Amoudi, MB, ChB, on Breaking the Silence About Breast Cancer in the Arab World see page 130

Paula K. Rauch, MD, on Helping Patients Talk to Their Children About Cancer see page 144 Charles J. Ryan, MD, and Michael B. Cook, PhD, on Male Pattern Baldness and Increased Risk of Aggressive Prostate Cancer see page 188

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | OCTOBER 15, 2014

PAGE 93

Survivorship

Cancer Survivors Face Lasting Financial Struggles Long After Treatment Ends, New Study Reports

he majority (62%) of America’s middle-income cancer survivors say they were not financially prepared for cancer diagnosis and treatment, according to a new study released by the Washington National Institute for Wellness Solutions (IWS). The study, “Insights from Survivors: Managing the Personal, Emotional, and Financial Impact of Cancer,” surveyed 400 Americans.

Study Details The study population included individuals who were 25 to 65 years at the time of diagnosis and had received radiation or chemotherapy in the past 10 years. Two-thirds of respondents (65%), all with an annual household income between $35,000 and $100,000, did not have sufficient household income to cover treatment-related expenses and incurred debt. After treatment, 30% reported debt of $10,000 or more; 15% reported debt of $20,000 or more; 11% of those younger than 50, or who were diagnosed with Stage III or IV cancer, incurred more than $40,000 in debt. More than half of survivors (57%) felt that at least one aspect of their treatment cost more than they expected. They were also surprised by the extent of the direct and indirect expenses not covered by medical insurance.

Funding Treatment

However, nearly 9 in 10 (85%) cancancer, but even so, the study finds that More than half of the respondents many personal, financial, and emotion- cer survivors look back on their experi(55%) withdrew from personal sav- al needs go unmet. One in four (25%) ence and recognize that at least one asings or investment accounts to finance wished they could have talked more pect of life has actually improved. And, treatment. Credit cards were used by to other survivors through support across all ages, genders, and cancer stagnearly half of the respondents (46%). groups. Among the support services the es, nearly one-half of survivors (45%) Although nearly half (46%) of all cancer survivors recommended are: ranked living a healthy lifestyle a top patients in the United States are workServices of the American Cancer priority following treatment, up from ing age (younger than 65), younger Society (ACS), including ACS Hope one-fourth (28%) before diagnosis. survivors were markedly less prepared. Club, ACS Reach to Recovery program “This study provides valuable insight Survivors younger than 50 were three and ACS Hope Lodge; Look Good Feel from cancer survivors about all stages times more likely to borrow money from friends and family (27% vs 8%), or We hope these findings help cancer patients and their withdraw from their 401(k), than their older counterparts (24% vs 9%). loved ones prepare for and overcome the emotional and

financial hurdles of battling this disease.

Making Diagnosis and Treatment a Priority

—Barbara Stewart

More than four in 10 survivors (44%) advise others facing cancer to be proactive about their treatment. They recommend getting involved by doing research, paying attention to warning signs, and discussing treatment with a doctor. “Those battling cancer need to make their diagnosis and treatment a priority,” said Barbara Stewart, President of Washington National. “Selecting the right facility, prioritizing and following treatment protocols, and seeking outside support are key for good outcomes.” A broad range of support systems are available to those who are facing

Better; Grocery delivery services, and online shopping, such as Amazon.com Social media is a tool used by more than one-quarter of survivors (28%) to find and share information. Among those who used social media, Facebook was most popular, chosen by threefourths (74%) of social media users.

Lasting impact The long-term challenges of physical and financial recovery after cancer treatment are undeniable: 44% report less physical strength; 31% are less financially secure; 24% feel their career prospects are worse.

of diagnosis and treatment,” Ms. Stewart added. “We hope these findings help cancer patients and their loved ones prepare for and overcome the emotional and financial hurdles of battling this disease.” Insights from Survivors: Managing the Personal, Emotional and Financial Impact of Cancer is part of a series of studies commissioned by the Washington National Institute for Wellness Solutions. It was conducted in May 2014 by Zeldis Research, an independent research firm. The full report can be viewed at WNInstituteforWellness .com.n

Contact The ASCO Post Advertising

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NOW

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 Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. mCRC = metastatic colorectal cancer; OS = overall survival.

Boxed 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®. Rare cases of StevensJohnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Lifethreatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. 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. • 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 overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). 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% 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. • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

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 mCRC

• Keratitis and ulcerative keratitis, known risk factors for corneal • Because many drugs are excreted into human milk and because of

perforation, have been reported with Vectibix® use. Monitor for evidence the potential for serious adverse reactions in nursing infants from of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for Vectibix®, a decision should be made whether to discontinue nursing acute or worsening keratitis. or to discontinue the drug, taking into account the importance of • In an interim analysis of an open-label, multicenter, randomized the drug to the mother. If nursing is interrupted, it should not be clinical trial in the ﬁrst-line setting in patients with mCRC, the resumed earlier than 2 months following the last dose of Vectibix®. addition of Vectibix® to the combination of bevacizumab and ® chemotherapy resulted in decreased OS and increased incidence • Women who become pregnant during Vectibix treatment are of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC encouraged to enroll in Amgen’s Pregnancy Surveillance Program. grade 3-4 adverse reactions occurring at a higher rate in Vectibix®- Women who are nursing during Vectibix® treatment are encouraged treated patients included rash/acneiform dermatitis (26% vs 1%), to enroll in Amgen’s Lactation Surveillance Program. Patients or diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring their physicians should call 1-800-77-AMGEN (1-800-772-6436) in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/ to enroll. mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). ® • NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate • In Study 1, the most common adverse reactions (≥ 20%) with Vectibix in Vectibix®-treated patients (7% vs 3%) and included fatal events were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in three (< 1%) Vectibix®-treated patients. • As a result of the toxicities experienced, patients randomized to in the Vectibix® arm were general physical health deterioration and Vectibix®, bevacizumab, and chemotherapy received a lower mean intestinal obstruction. relative dose intensity of each chemotherapeutic agent (oxaliplatin, • In Study 3, the most commonly reported adverse reactions (≥ 20%) irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first in patients with wild-type KRAS mCRC receiving Vectibix® 24 weeks on study, compared with those randomized to bevacizumab (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were and chemotherapy. • Advise patients of the need for adequate contraception in both males diarrhea, stomatitis, mucosal inﬂammation, asthenia, paronychia, and females while receiving Vectibix® and for 6 months after the last anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, dose of Vectibix® therapy. Vectibix® may be transmitted from the pruritus, and dry skin. Serious adverse reactions (≥ 2% difference mother to the developing fetus, and has the potential to cause fetal between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. harm when administered to pregnant women. 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. 05/14 80389-R1-V1

Visit www.vectibix.com

® Vectibix (panitumumab) PAGE 96

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION

Direct From ASCO

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)]. 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 in Full Prescribing Information]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1) in Full Prescribing Information]. Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1) in Full Prescribing Information]. 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 skin disease has also been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. 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 KRAS-Mutant mCRC 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 Full Prescribing Information]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). 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 KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)]

The ASCO Post | OCTOBER 15,Vectibix 2014Plus FOLFOX ®

• 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 available from two clinical trials in which patients received Vectibix®: Study 1, an open-label, 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 frequently reported (> 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)

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)

116 (36) 96 (30) 68 (21) 26 (8)

46 (14)

14 (4) 21 (7) 32 (10) 8 (2)

SYSTEM ORGAN CLASS Preferred Term SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

(n = 322) Any Grade Grade 3-4 n (%) n (%)

179 (56) 104 (32) 75 (23) 68 (21) 50 (16) 50 (16) 47 (15) 44 (14) 32 (10)

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1) 10 (3) 4 (1)

14 (4) 13 (4) 14 (4) 1 (< 1) 30 (9) 1 (< 1) 4 (1)

30 (9)

6 (2) 1 (< 1) 15 (5) 5 (2)

24 (7)

30 (9)

4 (1)

9 (3)

1 (< 1)

2 (< 1)

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: Stevens-Johnson syndrome, toxic epidermal necrolysis, skin necrosis, angioedema [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)]

22 (7)

85 (26) 26 (8) 42 (13) 10 (3)

FOLFOX Alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

This brief summary is based on the Vectibix® Prescribing Information v20, 5/14. 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. v20 05/14

ASCOPost.com | OCTOBER 15, 2014

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Direct From ASCO

Fellows’ Expectations of Work-Life Balance Not in Line With Realities of Practice

ncology fellows just years away from entering the profession full time may have unrealistic expectations of their future career, according to data published recently in the Journal of Clinical Oncology. The study by Tait D. Shanafelt, MD, of the Mayo Clinic, Rochester, Minnesota, and colleagues found that U.S. oncology fellows’ future expectations of their work hours were 5 to 6 hours fewer per week than the actual work hours reported by oncologists.1

number of hours and spend more time there than expected, there is great potential for higher job dissatisfaction, which could lead to burnout earlier in a career.”

Assessing Burnout, Well-Being The assessment of fellows was part of an initiative started by ASCO to address the health and well-being of its members. Partnering with ASCO, Dr. Shanafelt and colleagues sur-

If you go into a situation expecting to work ‘X’ number of hours and spend more time there than expected, there is great potential for higher job dissatisfaction, which could lead to burnout earlier in a career. —Michael P. Kosty, MD, FASCO

“What this study confirms for us is that people in training today, compared with their practicing peers, want to have a better work-life balance with the expectation that they will work fewer hours per week,” said study author Michael P. Kosty, MD, FASCO, of Scripps Clinic, San Diego. “If you go into a situation expecting to work ‘X’

veyed 3,000 ASCO members in fall 2012 and spring 2013 about career satisfaction and burnout. Results published earlier this year indicated that although 82.5% of respondents indicated career satisfaction, 44.7% of surveyed members also reported being burned out.2 The researchers were also inter-

ested to find out if burnout or career satisfaction was caused by unrealistic expectations when entering the specialty. The recent study published in JCO surveyed 1,345 oncology fellows taking the 2013 Medical Oncology In-Training Examination on their career plans and professional expectations; it also measured burnout, quality of life, fatigue, and satisfaction with work-life balance. “It occurred to us that it would be good to assess fellows, and, ideally, do repeated assessments to track how burnout or concerns about work-life balance changed as individuals moved through their careers,” Dr. Kosty said. By piggybacking the survey on the fellows’ examinations, the researchers were able to get a 97.9% response rate. Dr. Kosty pointed out that the survey gathered data from a very wellbalanced group of fellows: 47.2% were women, 49.5% had children, and 73.6% were married. Respondents were also well distributed across their first, second, and third years of training.

Fellows’ Expectations Survey results showed that fellows had a similar rate of burnout as did their practicing oncologist counterparts (34.1% vs. 33.7%), and that the

Tait D. Shanafelt, MD

rate of burnout decreased with each year of fellowship training. In contrast, fellows were found to have significantly higher fatigue and lower overall quality-of-life scores compared with practicing oncologists, but they were also more satisfied with their work-life balance and choice of medical specialty. Interestingly, survey results indicated that fellows may not have realistic expectations of their future work hours. Fellows who planned to enter a career in private practice expected to work 56.9 hours per week, whereas practicing oncologists report actually working 62.9 hours per week (P = .25). Fellows who planned to enter academic practice expected to work 53.5 hours per week, whereas practicing oncologists reported working 58.6 hours per week (P = .004). According to Dr. Kosty, these re-

For Your Patients: Video Series for Newly Diagnosed Patients on Navigating Common Challenges to Quality Care

he American Society of Clinical Oncology (ASCO) recently launched a new video series for people newly diagnosed with cancer through its patient education website, Cancer.Net. This initiative was made possible by a grant from the LIVESTRONG Foundation to the Conquer Cancer Foundation. After a cancer diagnosis, patients are faced with numerous challenges, including managing the shock and fear associated with cancer for themselves and others, language barriers, complex medical decision-making, and the potential financial burden in receiving care. The new video series, titled “Navigating Challenges: Perspectives from Survivors and Doctors,” is aimed at helping patients with these challenges, offering practical advice and guidance on navigating cancer care and treat-

ment in today’s health-care system, and addressing some of the barriers to high quality care that patients may face. The video titles in the series include: • Talking With Your Cancer Care Team • Making Decisions About Your Cancer Treatment • Managing the Cost of Your Cancer Care • Finding Emotional Support After a Cancer Diagnosis The “Navigating Challenges” video series is available to patients at no charge at cancer.net/navigatingchallenges or via Cancer.Net’s channel on YouTube at youtube.com/ cancerdotnet. n © 2014. American Society of Clinical Oncology. All rights reserved.

continued on page 99

The ASCO Post | OCTOBER 15, 2014

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New Series Features Interviews With Authors of JCO and JOP Research

ournal of Clinical Oncology (JCO) and Journal of Oncology Practice (JOP) “Exclusive Coverage” summaries, available on ASCO.org and ASCO Connection, are designed to provide quick insight and

Stephen Cannistra, MD, FASCO

additional author perspectives on select recently published studies. Based on interviews conducted with the lead or corresponding researchers behind JCO and JOP original research, Exclusive Coverage articles convey the authors’ thoughts on their study’s key points and significance for clinical practice. The articles are written in an accessible style designed for quick reading and provide take-away “Key Points.”

Exclusive Coverage articles can be accessed several ways, via: • The online article on the JCO and JOP website by clicking on “Author Interview by ASCO” • The ASCO.org homepage by clicking on “Exclusive Coverage” • ASCOconnection.org by selecting “Online Exclusives” • ASCO’s Twitter account, @ASCO “The Exclusives are part of JCO’s author-centric approach to publishing, which acknowledges that the authors of JCO studies have often dedicated years of hard work to carrying out the highestquality research,” said JCO Editor-in-Chief Stephen Cannistra, MD, FASCO. “Our goal is to give those authors high visibility, and the Exclusives do just that by enabling authors to share their unique perspectives.”

Take-Home Summaries on a Wide Array of Research To date, JCO and JOP Exclusives have covered a wide array of research, both U.S.-

CONQUERING

based and international, and have included additional author insights on such timely topics as: how chemotherapy changes brain activity in patients with breast cancer, how calcium and milk are tied to higher overall survival among people with colorectal cancer, and how new findings are fueling the ongoing debate about robotassisted radical prostatectomy. The following is a sampling of quotes from recent Exclusive Coverage articles: • “It turns out that when the technology and the cost allowed us to throw a wide net on patients’ DNA, we actually found many more actionable mutations that we never would have looked for before. The fact is—it’s a whole new world.” —James Ford, MD, commenting on the JCO Original Report, “Clinical Evaluation of a MultipleGene Sequencing Panel for Hereditary Cancer Risk Assessment.” • “This current study shows that for women with larger tumors, or who have [hormone receptor–negative]

tumors, we can probably appropriately discuss the use of chemo among those patients. On the other hand, for patients with low-grade, hormone receptor–positive tumors and HER2receptors, we can be very confident that the majority of these patients can do well without chemotherapy.” —Ines Vaz-Luis, MD, commenting on the JCO Original Report, “Outcomes by Tumor Subtype and Treatment Pattern in Women with Small, Node-Negative Breast Cancer: A Multi-Institutional Study.” n © 2014. American Society of Clinical Oncology. All rights reserved.

Cancer. Together, anything is possible. The Conquer Cancer Foundation. Our name says a lot. Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supportingthe world’s preeminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

DONATE TODAY! ConquerCancerFoundation.org

ASCOPost.com | OCTOBER 15, 2014

PAGE 99

Direct From ASCO Work-Life Balance continued from page 97

sults could reflect a trend that could ultimately have a negative effect on the future of the oncology workforce. “If people graduating from training now want to work 5 to 6 hours less per week, as the study would indicate, that would mean less productivity for oncologists and the cumulative effect could be significant,” Dr. Kosty said. “Already facing a shortage of about 4,000 oncologists by 2020, the trend moving forward could be exacerbated.”

comes to expected work hours. “In days past, the clinical experience for fellows was largely patient tertiary or academic-center based, but the truth of the matter is that most individuals will end up in a clinical practice situation where care is delivered largely in an outpatient setting,” Dr. Kosty said. “Training programs are beginning to migrate

their fellows experience to this outpatient setting and, hopefully, that will begin to help normalize expectations.” n References 1. Shanafelt TD, Raymond M, Horn L, et al: Oncology fellows’ career plans, expectations, and well-being: Do fellows know what they are getting into? J

Clin Oncol. July 21, 2014 (early release online). 2. Shanafelt TD, Gradishar WJ, Kosty M, et al: Burnout and career satisfaction among US oncologists. J Clin Oncol. January 27, 2014 (early release online).

WHAT CREATES A GREAT SURVIVAL CURVE?

Taking Action Now that the potential for a problem has been identified, the next important step is developing strategies to correct it. The topic of how to take the results of this fellows’ survey and use them to change training programs has been added to the agenda at 2014 ASCO Program Directors Retreat taking place in October. Dr. Kosty acknowledged though that the way forward is still a bit unclear. Some studies have suggested that peer support groups may be an effective strategy to reduce stress and burnout that occur during fellowship, but strategies are also needed to normalize or reset fellows’ expectations when it

The Latest Information for Patients From ASCO’s Symposia

he 2014 ASCO Quality Care Symposium is taking place this week, from October 17 to 18, and the new Palliative Care in Oncology Symposium is next week, from October 24 to 25. Direct your patients to www.cancer .net/blog to learn what the research announced prior to the symposia means and how it relates to their cancer care and treatment. n

L E V I N E C A N C E R INS TITUTE’S MO DEL OF C ARE

Hematologic Oncology and Blood Disorders Program The Hematologic Oncology and Blood Disorders program at Levine Cancer Institute, part of Carolinas HealthCare System, has built its foundation not only on providing excellent care, but on changing the delivery model of that care. Reaching patients – no matter where they live – through the newest treatments delivered by world-class oncologists has been its priority since day one. The result? Improving the survival curve and changing the course of cancer itself.

CLINICAL EXPERTISE More than a dozen of the Institute’s nationally recruited physicians, from the top cancer programs in the country, are dedicated to hematology and blood cancers. This team of subspecialists provides cutting-edge care and expertise in specific malignancies, including leukemia, plasma cell disorders, transplantation and lymphoma, and non-malignant hematology. Our Leadership Team Ed Copelan, MD, FACP CHAIR

Hematologic Oncology and Blood Disorders program

Belinda Avalos, MD VICE-CHAIR

Hematologic Oncology and Blood Disorders program

TRANSPLANTATION In addition to multiple care locations across the Carolinas, Levine Cancer Institute opened a new transplantation unit in early 2014. Staffed by some of the world’s foremost experts in hematological malignancies, the 16-bed unit also includes:

CLINICAL TRIALS AND RESEARCH Physicians at the Institute participate in leading-edge clinical trials related to most types of blood cancers and blood disorders. The Institute is expected to be one of the leading enrolling sites for blood cancer clinical trials in the country by the end of 2014. Our specialized Phase 1 unit provides:

• Six-bed apheresis unit, adjacent to the transplant unit, to obtain stem • First-in-man clinical trials testing cells for peripheral blood transplants novel therapies and treatment options • Four ICU beds integrated with Carolinas HealthCare System’s • Access to high-quality care, and virtual ICU, which provides 24/7 expertise from physicians who oversight of all patients subspecialize in treating specific • Patient support, including familydiseases friendly patient rooms, an exercise • The ability to enroll patients in room, a laundry room and lounge the newest, most promising trials, • Patient navigation whether that patient lives down the street or out of state, through the Institute’s decentralized model of care

For more information, visit CarolinasHealthCare.org/ModelOfCare

The ASCO Post | OCTOBER 15, 2014

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ASCO, AACR Urge FDA to Regulate All Tobacco Products— Including E-Cigarettes

CMS Announces ICD-10 Testing Weeks in Preparation for October 1, 2015, Compliance Deadline

SCO and the American Association for Cancer Research (AACR) sent a joint letter to the U.S. Food and Drug Administration (FDA) urging the agency to regulate electronic cigarettes, cigars, and all other tobacco products and to strengthen the proposed regulations for newly deemed products. The letter was in response to an FDA proposal to extend its regulatory authority over tobacco products. ASCO and the AACR applauded the FDA’s proposal to regulate electronic cigarettes. “It is vitally important that the FDA begin regulating these products as little is known about the health effects of e-cigarette use,” said ASCO President Peter P. Yu, MD, FASCO. “The potential use of e-cigarettes to assist smokers in quitting is unknown at this time. Ecigarettes may increase the likelihood

that nonsmokers or former smokers will use combustible tobacco products or that smokers will be discouraged from quitting.” ASCO and the AACR support many of the FDA’s proposals for regulating e-cigarettes and other products, but encourage the agency to do more. Specifically, preventing children from using tobacco products is crucial and can be achieved by efforts such as banning youthoriented advertising and marketing, self-service product displays, and tobacco company sponsorship of youth-oriented events, in addition to restricting sales to minors and implementing age-verification procedures for Internet sales. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCO Seeks Editor for New Global Oncology Journal

he American Society of Clinical Oncology (ASCO) is seeking candidates for the position of founding Editor-in-Chief for a new onlineonly, open-access journal focusing on cancer care, research, and care delivery issues unique to limited health-care resource countries and settings. The new journal will publish high-quality original research, reviews, editorials, commentaries, policy papers, position statements, case reports, and correspondence. The Editor-in-Chief will be responsible for assembling a team of Associate Editors and an editorial board, helping to set the editorial scope and vision for the new journal, and overseeing the annual publication of six issues. By November 3, 2014, interested candidates should submit a curriculum vitae and completed application available from David Sampson, ASCO’s Senior Director and Publisher, Journals. Ideal candidates will be active in global oncology and have experience as a journal Associate/Section Editor (or equivalent) or Editor-in-Chief. Candidates must also be ASCO members. This role is eligible for an annual stipend and reimbursement for journal-related travel. Request an application and submit nominations to: David Sampson Senior Director and Publisher, Journals American Society of Clinical Oncology 2318 Mill Road, Suite 800 Alexandria, VA 22314 Candidates may also request more information by sending an e-mail to david.sampson@asco.org n

eading up to the October 1, 2015 ICD-10 compliance deadline, the Centers for Medicare and Medicaid Services (CMS) has announced the following three ICD-10 testing weeks: • November 17 to 21, 2014 • March 2 to 6, 2015 • June 1 to 5, 2015 These weeks are intended to cre-

ate provider interest and awareness for ICD-10 testing implementation. To learn more about ICD-10, please go to ASCO’s ICD-10 resource center at: www.asco.org/practice-research/ icd-10. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCO President Peter P. Yu, MD, FASCO, Discusses CancerLinQ at Stanford Medicine X Conference

SCO President Peter P. Yu, MD, FASCO, recently delivered a talk entitled “Learning from Every Patient” at the 2014 Stanford Medicine X Conference. Dr. Yu’s presentation focused on CancerLinQ and ASCO’s vision for

Save the Date Gastrointestinal Cancers Symposium January 15-17, 2015 Moscone West Building San Francisco, California

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

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Direct From ASCO Hippocratic Oath continued from page 1

first formulated in Greece almost 2,500 years ago—remain, in our opinion, as important today as they have always been. Human technology has changed dramatically in the past 25 centuries; human nature has not.

Ancient Pledge The Oath is an ancient pledge of medical ethical conduct. It addresses two important tenets: benefitting the ill and protecting patients against personal and social harm and injustice. There are many translations of the Oath, but the essential meaning remains the same. It prohibits giving a lethal drug or using “a pessary to cause an abortion,” encourages practicing “in purity and according to divine law” and admonishes physicians not to “use the knife,” but rather, to “leave this to those who are trained in this craft.” It prohibits acts “of impropriety or corruption, including the seduction of women or men.” It advocates for patient privacy and concludes with the oath-taker’s need to strive for respect. Many of these ancient pledges are highly relevant to our modern practice of medicine and oncology. While attributed to the Greek physician Hippocrates of Kos, the most well-known doctor of his era, the real original author of this most famous text in Western medicine is unknown, and there may have been several authors.2 After Greek political power collapsed and the influence of the Hippocratic school faded, the Oath fell into obscurity for nearly 2,000 years, only to be rediscovered by Medieval Christian scholars and used in a ceremony at the University of Wittenberg in 1508 CE. By 1750, the Oath had been translated into English and other contemporary European languages, and for the past several centuries, a version of the Oath has often been recited by physicians graduating from medical school—a ritual that at times seems to have little significance beyond a general upholding of the medical tradition, and a rite of passage relegated to the attic of sterile memory shortly after completion. The use of the Oath in these graduation ceremonies has been challenged. Many contemporary medical ethicists dismiss the original Hippocratic Oath as antiquated because of enormous scientific, social, economic, and political changes in the intervening centuries.3-6 As a consequence of contemporary sensitivities, several modernized versions

of the Oath have been proposed,3,6 including a few witty parodies highlighting modern medical conundrums— eg, “I swear by Humana and … health maintenance organizations….”7 Most of these modern versions have avoided certain hot-button, politically divisive topics. In a 1993 survey of how the Oath was being used at 150 U.S. and Canadian medical schools, only 14% mentioned prohibition of euthanasia, 11% called upon deities, 8% foreswore abortion, and 3% forbade sexual contact

God, or by Brahma, Krishna-Vishnu, Buddha, or other Eastern deities— or by no god at all? Several solutions to this uncomfortable dilemma have been proposed, including keeping the Apollonian reference as a historical reference, or replacing it with whatever one holds most sacred or loved (hopefully not something as banal as money or a treasured new house).8 Bioethicist Steven Miles, MD, has urged focus on the messages behind the opening invocation, seeing in

[T]he ideals of the Hippocratic Oath—first formulated in Greece almost 2,500 years ago—remain, in our opinion, as important today as they have always been. Human technology has changed dramatically in the past 25 centuries; human nature has not. —Hagop Kantarjian, MD, and David P. Steensma, MD

with patients.6 Yet some physicians have countered that the older Oath, despite its historical trappings and archaisms, is more authentic and relevant than many of the diluted or “bowdlerized” modern versions.4,5

Uncomfortable Statements Hippocrates, who died around 370 BCE, became the most well-known physician of classical Greece, yet little is known about the historical details of his life. In addition to the Oath, Hippocrates’ chief contribution to posterity is often cited as the separation of medicine as a discipline from religion. Influenced by Pythagorean rationalism, Hippocrates is credited with being among the first to disentangle causes of disease from ancient superstitions, attributing illnesses to poor diet and unhealthy environment rather than divine punishment. Perhaps it is ironic, then, that the Oath that bears his name starts by swearing by the gods “Apollo the physician, and Asclepius, and Hygieia and Panacea.” While swearing by Greek gods may have been appropriate for Hippocrates and his contemporaries, should one not swear an Oath today instead by the Christian Lord, or Allah, or the Jewish

this statement an opportunity for reflection.5 By naming gods, Dr. Miles points out, the Oath asks physicians to remember, through specific names and attributions, several important messages of medicine: dedication to healing, acceptance of human mortality, and gentleness in healing (the etymology of the name Asclepius, which may literally mean “unceasingly gentle”). Another uncomfortable prohibition in the original Oath, especially for medical students intending to spend much of their careers in the operating room, is the statement, “I will not use the knife, even upon those suffering from stones, but I will leave this to those who are trained in this craft.” Yet the Oath does not disavow surgery itself, and the Hippocratic Corpus and other historical records suggest that Greek doctors were in fact aggressive surgeons—at times far more aggressive than indicated. This statement has been interpreted to mean that the physician should yield to “better professionals” whenever needed, whenever such professionals are available. In the modern context of medical specialization, surgeries should be done by practiced surgeons, radiotherapy by radiotherapists, can-

cer therapy by oncologists, and so on. Physicians must practice to the extent of their ability but not beyond; it is important for each of us to know our limits and seek the help of experts, as needed.

Other Troubling Passages “I will not give a lethal drug to anyone if I am asked,” another controversial phrase in the Oath, has had many interpretations, one of which is the prohibition of euthanasia (literally “good death”). Historical context is again important here: in ancient Greece, doctors were sometimes used as skilled political assassins. There was thus a legitimate fear of the physician as a poisoner. The word euthanasia was coined in about 280 BCE, a century after the oath was written. It referred to easeful or peaceful death, but there is no evidence in Greek medicine of active participation in accelerating such a death. The meaning of euthanasia in the sense of “assisted suicide” was instead coined by the historian William Lecky in 1869,9 and was not likely to have been a consideration of Hippocrates. This is relevant to our oncology practice today, where many cancer patients suffer from terminal disease, and at times severe pains and poor quality of life. This statement has also been interpreted to condemn complicity of physicians in acts of torture, executions, and inhuman treatment procedures, particularly after the disclosure of atrocities in the Second World War that led to the World Medical Association’s 1948 Declaration of Geneva, a new “Charter of Medicine” that echoes many of the concerns of the Hippocratic Oath. The moral stance is unequivocal and condemns any physician or medical association that is complicit in, collaborates with, conceals, or aids in torture, even if such a person claims fear of retribution or is “just following orders.”10 A prohibition of abortion, which was a legal practice in ancient Greece, is inferred by the Oath’s statement, “I will not give a woman a pessary.” Some translations here refer to “a destructive pessary” without mention of abortion. Nevertheless, many have interpreted this as a prohibition on any abortion; others point out that this statement only mentions the pessary, a soaked piece of wool inserted in the vagina to induce abortion, which could cause lethal infections. The objection was perhaps to the specific dangerous method continued on page 104

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Perspective Hippocratic Oath continued from page 101

rather than a moral objection to abortion, but this remains an area of debate.

Less Difficult Statements In ancient times, distrust of healers was common because of the abundance of quacks. The Hippocratic Oath included a statement regarding entering the patient’s house, where a physician would go only “for the benefit of the sick, avoiding any voluntary act of impropriety or corruption, including the seduction of women or men.” Quacks and charlatans are still with us, only a desperate Google search away, and patients continue to be exploited in a variety of ways. Patients are often highly vulnerable and continue to require protection from the undue influence of a selfish physician.11,12 Confidentiality is also less controversial: “Whatever I see or hear in the lives of my patients, whether in con-

nection with my professional practice or not, which ought not to be spoken of outside, I will keep secret, as considering all such things to be private.” Just as was the case in healing relationships formed 2,500 years ago, confidential and personal information shared by patients with doctors must not be disclosed, in order to preserve trust and facilitate treatment. Without trust, patients may withhold facts that help physicians formulate an accurate diagnosis and therapeutic plan. Disclosing confidential information could be detrimental to the patient, unless not sharing such information could harm part of the physician’s larger circle of trust (for example, reporting cases of tuberculosis, syphilis, or other transmissible illnesses). Finally, the Oath includes a statement about respect for teachers and about sharing information learned in the practice of medicine with students and other practitioners. While

Hippocratic Oath

swear by Apollo the physician, and Asclepius, and Hygieia and Panacea and all the gods and goddesses as my witnesses, that, according to my ability and judgement, I will keep this Oath and this contract: To hold him who taught me this art equally dear to me as my parents, to be a partner in life with him, and to fulfill his needs when required; to look upon his offspring as equals to my own siblings, and to teach them this art, if they shall Hippocrates, the father of medicine, wish to learn it, without fee or contract; and that lived in the early 5th century B.C., the by the set rules, lectures, and every other mode oath that bears his name emerged of instruction, I will impart a knowledge of the a century later. Photo credit: Peter Paul Rubens/public domain. art to my own sons, and those of my teachers, and to students bound by this contract and having sworn this Oath to the law of medicine, but to no others. I will use those dietary regimens which will benefit my patients according to my greatest ability and judgement, and I will do no harm or injustice to them. I will not give a lethal drug to anyone if I am asked, nor will I advise such a plan; and similarly I will not give a woman a pessary to cause an abortion. In purity and according to divine law will I carry out my life and my art. I will not use the knife, even upon those suffering from stones, but I will leave this to those who are trained in this craft. Into whatever homes I go, I will enter them for the benefit of the sick, avoiding any voluntary act of impropriety or corruption, including the seduction of women or men, whether they are free men or slaves. Whatever I see or hear in the lives of my patients, whether in connection with my professional practice or not, which ought not to be spoken of outside, I will keep secret, as considering all such things to be private. So long as I maintain this Oath faithfully and without corruption, may it be granted to me to partake of life fully and the practice of my art, gaining the respect of all men for all time. However, should I transgress this Oath and violate it, may the opposite be my fate. n Translated by Michael North, National Library of Medicine, 2002.1

interpreted at times as exclusionary because of the mention of a written contract—limiting the spread of medical knowledge to only those who have paid for it can lead to disasters (as when the Chamberlen family’s preservation of their “trade secret” of obstetrical

Today, we face (and may swear by) old and new deities, including one perhaps more powerful and capable of extremes of good and evil than any other: money. We face problems that are intensely relevant to modern cancer research and care, and which (of course)

Physicians should argue not simply to preserve the Affordable Care Act, which is a step forward but flawed, but also to improve on it and strive to extend future health-care coverage to become universally available to all Americans. —Hagop Kantarjian, MD, and David P. Steensma, MD

forceps for over a century contributed to countless needless deaths in childbirth)—this statement is primarily a reminder that the individual physician has an obligation to collaborate with and edify others. Life is short, the art of medicine is long, and the individual’s contribution to it tiny.

The Oath and Injustice The most inspiring and perhaps most important statements of the Oath address harm and injustice: “I will do no harm or injustice to them.” The Oath contains two passages related to injustice, one upon entering the patient’s house as mentioned above (ie, injustice against a specific patient) and the other against social injustice. While preventing personal and social injustice is a major concern of the Oath, physicians in general shy away from issues of social injustice, and when they do engage with societal issues, may at times have favored their own financial or personal interests. The American Medical Association (AMA), for instance, states that physicians have an obligation to provide some free care to the “indigent,” and that, as a group, they should work with policymakers to help society provide adequate health care to all.13 Yet, as an institution, the AMA has historically worked against the adoption of universal health care and other policies that could expand access to care but decrease the incomes of practitioners, and criticized professional medical organizations that disagreed with their position. Many physicians likewise have organized against efforts to address the lack of affordable health care, opposing reforms proposed by Presidents Roosevelt, Truman, and Eisenhower, fighting the passage of Medicare in 1965, and later failing to support or influence reform efforts proposed by the Clinton administration.14

did not exist at the time of the Oath: new types of medical and cancer research that include human experimentation, interactions with pharmaceutical and insurance companies, different practices and care patterns, unique stress from the cost of care and of drugs, and financial conflicts of interest.15-19 Most of these problems are directly or indirectly connected with two large looming factors: universality of healthcare accessibility and affordable cost. Stated simply, lack of health care for a substantial portion of patients can contribute to social injustice and medical harm. High costs of health care and high drug prices prevent patients from affording and benefitting from them, thus causing harm. Adherence to the Hippocratic Oath requires physicians to address and advocate for better access to health care and for more affordable cost structures.15-19

Coverage and Costs Because of how health care is financed in the United States, every physician knows of patients who have been denied access to health care perceived as necessary or received delayed treatment, and who have been harmed or humiliated by the process.20,21 The Affordable Care Act offers many advantages to patients that did not exist with the previous health-care order.17-19 In the context of oncology, it broadens cancer care to millions more, expands Medicaid, and eliminates some ethical dilemmas associated with cancer care in previously uninsured patients. Broader insurance is associated with better access to cancer screening, earlier diagnosis, earlier treatment, and better outcomes. Patients with cancer are better covered on clinical trials. Closing the hole in Medicare Part D should reduce out-of-pocket expenses. Essential elements in cancer care such as emer-

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Perspective

gency care and physical rehabilitation are covered. Annual and lifetime coverage in cancer care, which can be very expensive, are not capped.17,18 That said, the Affordable Care Act has many limitations, which should be addressed. The initial rollout of HealthCare.gov and the insurance exchanges was a disappointment, and while this is now improving, other uncertainties and challenges remain. It is yet unclear whether the Affordable Care Act will increase or reduce the insurance premiums or alter the overall cost of care, whether bargain-basement policies sold as part of health-care exchanges will actually allow patients to receive appropriate care, and whether the Act will simplify or complicate the inefficiencies of the health-care system. Physicians should argue not simply to preserve the Affordable Care Act, which is a step forward but flawed, but also to improve on it and strive to extend future health-care coverage to become universally available to all Americans.22 [Editor’s note: See “Does the United States Have the Best Health-Care System in the World?” in the August 15 issue of The ASCO Post for more commentary from Dr. Kantarjian on healthcare costs and the Affordable Care Act, or visit http://bit.ly/1whwepf .] The high and growing cost of drugs, particularly cancer drugs, is another issue that should be viewed through the social justice lens of the Oath. Many patients cannot afford high drug prices and out-of-pocket expenses. About 10% to 20% of patients decide not to take their medicines or modify their dosages significantly. This worsens outcome and causes harm. These two issues—health-care coverage and cost of health care and drugs, which also raise issues of physicians’

conflicts of interests23-27—have slowly and subtly evolved into enormous problems facing our patients and our society, and causing personal and social injustice and harm. In addressing them, physicians should put patients first. Patients are our most sacred duty, and perhaps the Oath should begin with this invocation: “I swear by what is most sacred, my patients….”

Primum Non Nocere Notably, what many people consider to be the paramount principle and most famous statement attributed to the Oath—“First do no harm”—is actually not in the Oath. Instead, this principle most likely evolved from works in the 19th century, such as Florence Nightingale’s writing on hospital architecture, which states, “the very first requirement … it should do the sick no harm.”5 Unfortunately, this mythic statement is incomplete, since all therapies entail risk. This risk must be weighed against potential benefits every time a treatment is considered. As medical ethicist Daniel Sokol has proposed, a better enunciation of the principle would be “First do no net harm,”28 always considering the two most important guiding principles of the Oath: beneficence and justice. n Disclosure: Drs. Kantarjian and Steensma reported no potential conflicts of interest.

References 1. Hippocratic Oath. Translated by Michael North, National Library of Medicine, 2002. Available at http://www.nlm. nih.gov/hmd/greek/greek_oath.html. Accessed September 10, 2014. 2. Nittis S: The authorship and probable date of the Hippocratic Oath. Bull Hist Med 8:1012-1021, 1940. 3. Lasagna L: Hippocratic Oath: Modern Version. Tufts University, 1964. Avail-

able at http://www.pbs.org/wgbh/nova/ body/hippocratic-oath-today.html. Accessed September 10, 2014. 4. Hulkower R: The history of the Hippocratic Oath: Outdated, inauthentic, and yet still relevant. Einstein J Biol Med 25:4144, 2010. 5. Miles SH: The Hippocratic Oath and the Ethics of Medicine, pp 22-23. New York, Oxford University Press, 2004. 6. Orr R, Pang N, Pellegrino E, et al: Use of the Hippocratic Oath: A review of twentieth century practice and a content analysis of oaths administered in medical schools in the U.S. and Canada in 1993. J Clin Ethics 8:377-388, 1997. 7. Schiedermayer DL: The Hippocratic Oath: Corporate version. N Engl J Med 314:62, 1986. 8. Verhey A: The doctors’ oath—and a Christian swearing in. Linacre Q 51:139158, 1984. 9. Lecky W: History of European morals. Citation from Compact Oxford English Dictionary, 2nd ed. Oxford, Clarendon Press, 1991. 10. American College of Physicians: The role of the physician and the medical profession in the prevention of international torture and in the treatment of its survivors. Ann Intern Med 122:607-613, 1995. 11. American Medical Association, Council on Ethical and Judicial Affairs: Sexual misconduct in the practice of medicine. JAMA 266:2741-2745, 1991. 12. Gartrell N, Milliken N, Goodson W, et al: Physician-patient sexual contact: Prevalence and problems. West J Med 157:139-143, 1992. 13. Council on Ethical and Judicial Affairs, American Medical Association: Opinions 9.065 and 2.095. 1999. 14. Starr P: What happened to health care reform? Am Prospect 20(Winter):20-31, 1995. 15. Kantarjian H, Fojo T, Mathisen M,

et al: Cancer drugs in the United States: Justum pretium—the just price. J Clin Oncol 31:3600-3604, 2013. 16. Kantarjian H, Steensma D, Rius Sanjuan J, et al: High cancer drug prices in the United States: Reasons and proposed solutions. J Oncol Pract 10(4):e208e211, 2014. 17. Kantarjian HM, Steensma DP, Light DW: The Patient Protection and Affordable Care Act: Is it good or bad for oncology? Cancer 120(11):1600-1603, 2014. 18. Kantarjian H, Steensma D, Light D: Should oncologists support the Affordable Care Act? Lancet Oncol 14:1258-1259, 2013. 19. Zwelling L, Kantarjian H: Obamacare: Why should we care? J Oncol Pract 10(1):12-14, 2014. 20. Miles S: What are we teaching about indigent patients JAMA 268:2561-2562, 1992. 21. Stillman M, Tailor M: Dead man walking. N Engl J Med 369:1880-1881, 2013. 22. Berwick D: The toxic politics of health care. JAMA 310:1921-1922, 2013. 23. Rettig RA: The Industrialization of clinical research. Health Aff 19:129-146, 2000. 24. Boyd EA, Bero LA: Assessing faculty financial relationships with industry: A case study. JAMA 284:2209-2214, 2000. 25. Campbell EG, Seashore L, Blumenthal D: Looking a gift horse in the mouth: Corporate gifts supporting life sciences research. JAMA 279:995-999, 1998. 26. Bodenheimer T: Uneasy alliance: Clinical investigators and the pharmaceutical industry. N Engl J Med 342:1539-1544, 2000. 27. Nathan DG, Weatherall DJ: Academic Freedom in clinical research. N Engl J Med 347:1368-1370, 2002. 28. Sokol D: “First do no harm” revisited. BMJ 347:f6426, 2013.

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Announcements

Louis J. DeGennaro, PhD, Named President and Chief Executive Officer of The Leukemia & Lymphoma Society Opportunities to Defeat Blood Cancer Never Greater

he Leukemia & Lymphoma Society has announced that Louis J. DeGennaro, PhD, has been appointed as President and Chief Executive Officer, effective immediately. “Dr. DeGennaro has tirelessly dedicated himself for almost a decade of service to the Leukemia & Lymphoma Society mission and to the patients whom

Louis J. DeGennaro, PhD

we all serve, and this appointment is in recognition of his vision, leadership, and commitment to the Leukemia & Lymphoma Society mission,” said the Society’s Board of Directors Chairman James H. Davis, PhD. “The opportunity to defeat blood cancer has never been greater. Several innovative blood cancer treatments have been approved in the last 12 months, and the research pipeline of exciting new therapies continues to grow. Over the past 65 years, the [Leukemia & Lymphoma Society] has played a significant role in funding promising research from bench to bedside, investing more than $1 billion in blood cancer research to date. Our patient support and advocacy programs help ensure that patients have affordable access to the latest therapies. Under Dr. DeGennaro’s leadership [Leukemia & Lymphoma Society] will continue to advance our mission and help save the lives of blood cancer patients not someday, but today,” Dr. Davis added.

Executive Leadership Team Dr. DeGennaro has served as Interim President and Chief Executive Officer of Leukemia & Lymphoma Society since February 2014 and leads the operations of this $300 million cancer patient advocacy agency with headquarters in White Plains, New York. A critical member of the Leukemia & Lymphoma Society executive leadership team, he joined Leukemia & Lymphoma Society in 2005 and was named Chief Mission Officer in 2009, with responsibility for leadership of Leukemia & Lymphoma Society mission functions of research,

patient access, education, public policy and advocacy. Dr. DeGennaro is recognized as the key architect of Leukemia & Lymphoma Society cures and ac-

cess agenda to help save lives of blood cancer patients and the Leukemia & Lymphoma Society Therapy Acceleration Program—a venture philanthropy

endeavor that defined the role of nonprofit organizations in supporting drug discovery and development with the biotechnology industry.

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Announcements Extensive Experience Dr. DeGennaro has more than 25 years of research, drug development and executive management experience in academic and private sector settings. He received his doctorate in biochemistry from the University of California at San Francisco and did his post-doctoral research at the Yale University School

of Medicine. His previous academic appointments include research group leader, Max Planck Institute in Munich, Germany, where his laboratory was among the first to clone genes expressed exclusively in the nervous system; and Associate Professor of Neurology and Cell Biology, University of Massachusetts Medical School.

Dr. DeGennaro’s private-sector positions include: Senior Director of Molecular Genetics at Wyeth Pharmaceuticals, Princeton, where his department contributed to the development of pantoprazole (Protonix) to treat acid reflux disease, venlafaxine (Effexor) for anxiety and depression, and gemtuzumab (Mylotarg) for leukemia;

Executive Vice President for Research and Development, SynX Pharma, Inc. in Toronto, Canada, where he was responsible for the development of a point-of-care diagnostic test for congestive heart failure; and research manager at Streck, Inc., Omaha, where he helped develop an FDA-cleared diagnostic test for AIDS/HIV.

Translational Sciences Advisory Council

We want to change the face of EGFR-targeted therapy Rash is caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2 In the treatment of EGFR mutation–positive non–small cell lung cancer (NSCLC), rash and other skin toxicities are wellestablished side effects of EGFR tyrosine kinase inhibitors.3,4

90% of patients treated with approved EGFR inhibitors experience rash3,4 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.3,4

Dr. DeGennaro was appointed by the U.S. Secretary of Health and Human Services in 2012 to serve as a member of the National Center for Advancing Translational Sciences Advisory Council, and the Cures Acceleration Network Review Board at the National Institutes of Health (NIH). He also serves on the boards of BioTheryX, Inc., an early-stage biotechnology company and the Health Research Alliance, an alliance of non-profit funders of research. Dr. DeGennaro’s appointment follows a thorough national search conducted by Russell Reynolds considering both internal and external candidates. n

Don't Miss Through the Lens of Oncology History

Rash and its symptoms can negatively affect both patient quality of life and patient compliance, while its psychosocial impact contributes to the assessment of severity.5,6 Beyond the clinical symptom burden, rash visibility can cause significant patient distress even when it is not severe.5 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

Clovis Oncology is leading the fight

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals LLC; 2014. 4. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 5. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurse. 2011;15(1):88-96. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed August 26, 2014. Copyright © 2014 Clovis Oncology. DARO-101 8/14

See pages 146 - 151 in this issue of The ASCO Post.

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Journal Spotlight Neuro-oncology

CENTRIC Trial Shows No Benefit of Adding Cilengitide to Therapy in Glioblastoma With Methylated MGMT Promoter Development of the drug for cancer stopped. By Matthew Stenger

n the phase III CENTRIC/European Organisation for Research and Treatment of Cancer (EORTC) 2607122072 trial reported in The Lancet Oncology, Roger Stupp, MD, of University Hospital Zurich, and colleagues found that adding the selective αvβ3 and αvβ5 integrin inhibitor cilengitide to standard temozolomide chemoradiotherapy produced no survival benefit in patients with newly diagnosed glioblastoma and methylated MGMT promoter.1 The authors stated that development of cilengitide as an anticancer agent has been halted.

Study Background Cilengitide is a selective inhibitor of αvβ3 and αvβ5 integrins, which appear to mediate communication between glioblastoma cells and the brain microenvironment and are overexpressed on tumor cells and vasculature. These cellcell and cell-matrix adhesion molecules are involved in angiogenesis, as well as in cellular survival, proliferation, migration, and invasion. Since glioblastoma cells exhibit high motility and invasiveness mediated by cell-matrix interactions, integrins are a target in drug development. Methylation of the promoter for MGMT, which encodes the DNA repair protein MGMT, preserves sensitivity of glioblastoma to the cytotoxic effects of temozolomide. Phase I/II data suggested a potential synergistic effect of cilengitide and temozolomide in glioblastoma with MGMT promoter methylation.

Brain Tumor Consortium, as well as researchers from South Korea, India, and the United States, among others. For patients with newly diagnosed glioblastoma, standard treatment includes surgery followed by temozolomide chemoradiotherapy (radiotherapy with concomitant and adjuvant temozolomide). In this open-label trial, 545 adult patients (from 3,471 screened) from 25 countries were treated with surgery and were randomly assigned between October 2008 and May 2011 to receive temozolomide chemoradiotherapy with intravenous cilengitide at 2,000 mg twice weekly (n = 272) or temozolomide chemoradiotherapy alone (n = 273). Prior to randomization, an independent pathology review was performed and MGMT promoter methylation status was centrally determined. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxicity. Randomization was stratified for prognostic Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis class and geographic region. The primary endpoint was overall survival analyzed in the intention-totreat population. The cilengitide and control groups were generally balanced for age (median, 58 years in both), sex (54% and 52% male), region (North America for 12% in both, Europe for 68% and 67%),

End of the Line for Cilengitide in Cancer Treatment ■ The addition of cilengitide to temozolomide chemoradiotherapy was not associated with any overall or progression-free survival benefit. ■ Development of cilengitide as an anticancer agent has been halted.

Previous randomized trials assessing the addition of the antiangiogenic agent bevacizumab (Avastin) to standard temozolomide and radiotherapy in newly diagnosed glioblastoma have shown improved progression-free survival but not overall survival.

CENTRIC Trial Details The CENTRIC trial was an international endeavor including investigators from the EORTC and the Canadian

Eastern Cooperative Oncology Group performance status (0 in 57% and 55%, ≥ 1 in 43% and 44%), RTOG recursive partitioning analysis class (III in 16% and 15%, IV in 68% and 63%, V in 16% and 20%), Mini-Mental State Examination score (≥ 27 in 83% and 76%), extent of resection (gross total in 49% and 50%, partial in 48% and 47%, biopsy in 3% in both), antiepileptic use (enzyme-inducing antiepileptic drug [EIAED] in 20% and 21%, non-EIAED only in 36% and

This trial has shown the feasibility of upfront central histological review and molecular testing with no substantial delay in an international multicentre trial setting, which is a prerequisite for further drug development towards personalised medicine. —Roger Stupp, MD, and colleagues

44%, none in 44% and 34%), steroid use (38% and 41%), and weeks from diagnosis to radiotherapy (median, 6.2 and 5.4).

No Survival Differences Median overall survival was 26.3 months (95% confidence interval [CI] = 23.8–28.8 months) in the cilengitide group vs 26.3 months (95% CI = 23.9–34.7 months) in the control group (hazard ratio [HR] = 1.02, P = .86) and was similar in the two groups irrespective of stratification factors. Two-year overall survival was 56% in both groups. Median progression-free survival was 13.5 vs 10.7 months (HR = 0.93, P = .46) on investigator assessment and 10.6 vs 7.9 months (HR = 0.92, P = .41) on independent radiologic review committee assessment at an average of one assessment time point earlier in each group. No benefit of cilengitide for overall or progression-free survival was observed in any predefined patient subgroups.

Toxicity The most common adverse events of any grade in the cilengitide group were nausea (49% vs 49% in control group), headache (45% vs 34%), fatigue (39% vs 33%), and constipation (39% vs 30%). The most common adverse events of grade ≥ 3 were lymphopenia (12% vs 10%), thrombocytopenia (11% vs 18%), neutropenia (7% vs 9%), leukopenia (7% vs 8%), and convulsion (5% vs 6%). Grade 3/4 hemorrhage occurred in 2% of both groups. Serious adverse events occurred in 52% vs 45%, and adverse events leading to death occurred in 4% vs 3%.

Three deaths in each group (1%) were considered treatment-related, consisting of two deaths due to pulmonary embolism and one due to aspiration pneumonia in the cilengitide group, and deaths due to pancytopenia/ pneumonia, pneumonia, and septic shock in the control group. The investigators concluded: “The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma.” The authors noted that the CENTRIC trial involved screening and molecular assessment of nearly 3,500 patients with a relatively rare disease over the course of 2 years and that, despite the time required for molecular assessment, the median time to treatment was only 5 to 6 weeks. In this regard, they stated: “This trial has shown the feasibility of upfront central histological review and molecular testing with no substantial delay in an international multicentre trial setting, which is a prerequisite for further drug development towards personalised medicine.” n

Disclosure: The study was funded by Merck KGaA. For full disclosures of the study authors visit www.thelancet.com/oncology.

Reference 1. Stupp R, Hegi ME, Gorlia T, et al: Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 2607122072 study): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 15:1100-1108, 2014.

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Perspective

Failure of Cilengitide in Newly Diagnosed Glioblastoma With Methylated MGMT Promoter By Elizabeth R. Gerstner, MD

emozolomide in combination with radiation for newly diagnosed glioblastoma was approved by the U.S. Food and Drug Administration in 2005—almost 10 years ago— but we have unfortunately made little progress in improving survival for this incurable brain tumor. Despite recent completion of three large, randomized phase III trials, management of newly diagnosed glioblastoma remains a therapeutic challenge. Two of these recent trials, Radiation Therapy Oncology Group (RTOG) 0825 and AVAglio, randomly assigned patients with newly diagnosed glioblastoma to chemoradiation plus bevacizumab (Avastin) or placebo.1,2 Both studies failed to show improvement in overall survival in the bevacizumab-treated arm although AVAglio did show modest improvement in progression-free survival with bevacizumab.

The Need for ‘Smart’ Clinical Trials The CENTRIC study, reported by Stupp and colleagues in The Lancet Oncology and reviewed in this issue of The ASCO Post, adds to the list of trials failing to impact overall survival.3 The therapeutic challenge that has emerged in the past 10 years is that the underlying heterogeneous biology of these tumors (eg, MGMT methylation status, IDH mutation status, and other unknown molecular markers) largely dictates individual tumor behavior and our current drugs are doing little to affect this biology. In an effort to more narrowly define the molecular characteristics of glioblastoma, CENTRIC was performed in patients with MGMT methylation, a marker thought to be both prognostic and predictive of response to temozolomide. The study confirmed the prognostic significance of this marker: Patients experienced a median overall survival of 23.6 months, which was similar to the 21.7 months of the MGMT-methylated cohort in the original European Organization for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) trial Dr. Gerstner is a member of the Department of Neurology, Massachusetts General Hospital Cancer Center, Boston.

of radiation and temozolomide (and better than the 14.6 months reported in the unselected patients).4 Unfortunately, though, the results of CENTRIC, RTOG 0825, and AVAglio suggest we have done little to deflect the survival curve of specific tumor subtypes by adding additional drugs. As our knowledge of the heterogeneity of tumor molecular makeup increases, we will be increasingly challenged to design “smart” clinical trials that more selectively target specific tumor subtypes—the elusive holy grail of personalized medicine.

What Can We Learn From CENTRIC? Perhaps the most useful lesson learned from CENTRIC was the feasibility of timely central tumor tissue analysis. The authors were able to assess an impressive 3,060 tumor

pressed on glioma and endothelial cells and that integrins were important in multiple cell survival processes: proliferation, migration, angiogenesis—all key cancer targets.5-7 There was even evidence of possible synergy between cilengitide and radiation.8 Phase I and II trials had suggested improvement in survival compared to historical controls.9,10 Nevertheless, despite these promising early results, CENTRIC failed to improve survival. Similar strong biologic rationale and promising early clinical trial data preceded the failed RTOG 0825 and AVAglio trials, raising the question of how can we improve the likelihood of success. One proposal has been randomized phase II trials, but these can be unpalatable to patients facing an incurable disease when there is a placebo or control arm. Thus, more innovative work needs

What we need now are better drugs and a better understanding of why drugs did or did not work in individual patients so we can move the field beyond radiation and temozolomide. —Elizabeth R. Gerstner, MD

samples from 146 study sites in 25 countries without significant delay in starting chemoradiation after surgery. This ability to rapidly collect and process tissue suggests that we may be able to design those smart, targetedagent clinic trials in a multicenter setting. Given the likelihood of increasingly smaller samples sizes as we hone down tumor subtypes, multicenter collaborative trials will be critically important. CENTRIC demonstrated that this process is feasible, but what we need now are better drugs and a better understanding of why drugs did or did not work in individual patients so we can move the field beyond radiation and temozolomide. Disappointingly, there appeared to be strong biologic rationale for adding cilengitide, an αvβ3 and αvβ5 integrin inhibitor, to chemoradiation in this setting. Preclinical models showed that αvβ3 and αvβ5 integrins were ex-

to be done to clarify the biologic impact of tumor molecular subtypes and making sure the drug matches the molecular subtype. Increasingly, phase I and II trials are focusing on highly selected tumor populations, which may help address this issue. In addition, to the extent possible, correlative studies of tissue, blood markers, or imaging markers of response that help elucidate the biological mechanism of tumor response to treatment are needed. If patients are going to participate in a trial, we should hopefully learn as much as possible from their commitment. Of course, all of this comes with additional cost. In summary, there have been several recent disappointments for patients and health-care providers caring for glioblastoma patients. Nevertheless, with each failure, we hopefully can still take a half step forward. For example, can the 3,060 glioblastoma

samples collected in CENTRIC become a tissue repository to help clarify tumor heterogeneity and associated response to therapy or survival? Ultimately, we need better drugs and this will require a better understanding of the complexity of glioblastoma pathophysiology. n

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

References 1. Gilbert MR, Sulman EP, Mehta MP: Bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:2048-2049, 2014. 2. Chinot OL, Wick W, Mason W, et al: Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709-722, 2014. 3. Stupp R, Hegi ME, Gorlia T, et al: Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 15:1100-1108, 2014. 4. Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005. 5. Bello L, Francolini M, Marthyn P, et al: Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery 49:380-389, 2001. 6. Roth P, Silginer M, Goodman SL, et al: Integrin control of the transforming growth factor-beta pathway in glioblastoma. Brain 136:564-576, 2013. 7. Schnell O, Krebs B, Wagner E, et al: Expression of integrin alphavbeta3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol 18:378-386, 2008. 8. Mikkelsen T, Brodie C, Finniss S, et al: Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int J Cancer 124:2719-2727, 2009. 9. Stupp R, Hegi ME, Neyns B, et al: Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 2010;28:2712-2718. 10. Nabors LB, Mikkelsen T, Hegi ME, et al: A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306). Cancer 118:5601-5607, 2012.

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Journal Spotlight Psycho-oncology

Integrated Collaborative Care Program Highly Successful in Treating Major Depression in Patients With Cancer By Matthew Stenger

n the Scottish SMaRT Oncology-2 study reported in The Lancet, Michael Sharpe, MD, and Jane Walker, PhD, of University of Oxford, United Kingdom, and colleagues found that an integrated collaborative treatment program for depression (“depression care for people with cancer”) was associated with significantly higher depression response and remission rates compared with usual care in cancer patients with major depression, and also resulted in significant improvements in health, functioning, and quality of life.1

activation), and monitored patient progress using the Patient Health Questionnaire (PHQ)-9 depression severity scale. Psychiatrists supervised treatment with the aim of achieving a treatment target of PHQ-9 score < 10 and ≥ 50% below baseline score, advised primary care physicians on prescribing antidepressants, and provided direct consultations with patients not exhibiting improvement. The initial treatment phase consisted of a maximum of 10 sessions with the nurse over 4 months, after which PHQ9 scores were monitored monthly by

Study Details In the trial, 500 cancer outpatients with major depression from three cancer centers and associated clinics in Scotland were randomly assigned between May 2008 and May 2011 to the depression care for people with cancer intervention (n = 253) or usual care (n = 247), with stratification by trial center and minimization by age, primary cancer, and sex. The primary outcome measure was treatment response defined as a ≥ 50% reduction in Symptom Checklist Depression Scale [SCL-20] score (range, 0–4) at 24 weeks in the intention-to-treat population. This degree of improvement is considered comparable to no longer meeting diagnostic criteria for major depression. Outcome data were collected up until 48 weeks. Analysis was adjusted for stratification and minimization variables and baseline scores.

Program Description Depression care for people with cancer is a manualized, multicomponent collaborative care treatment that is delivered systematically by a team of cancer nurses and psychiatrists in collaboration with patients’ oncology teams and primary care physicians. The nurses established a therapeutic relationship with the patient, provided information about depression and treatment, delivered brief psychological interventions (problem-solving therapy and behavioral

cancer (breast in 55% and 53%, gynecologic in 23% and 26%, genitourinary in 5% and 6%, other in 17% and 15%), cancer treatment within previous 2 months (none in 38% and 35%, surgery in 6% and 4%, hormone therapy in 38% in both, radiotherapy in 9% and 7%, chemotherapy in 19% and 22%), cancer status (nonactive disease in 79% in both, active disease with radical treatment in 8% and 5%, active disease with palliative treatment in 13% and 16%), and perceived quality of depression care (poor in 32% and 25%, fair in 33% and 36%, good in 21% and 27%, very good

The most important implication of this study is that paying the same systematic attention to the management of comorbid major depression as we presently do to the associated medical condition achieves much better outcomes for patients. —Michael Sharpe, MD, Jane Walker, PhD, and colleagues

telephone for 8 months, with additional nurse sessions being provided for patients not meeting treatment targets. Usual care was provided by patients’ oncologists and primary care physicians.

Treatment Group Characteristics Patients in the intervention and control groups were generally balanced for age and age range (mean age, 57 and 56 years; range, 23–85 and 26–84 years; 31% and 32% aged > 60 years), sex (90% women in both), marital status (62% and 61% with spouse/partner), and employment status (54% and 51% not working). The groups were also well balanced for duration of current depressive episode (1–6 months in 52% and 50%, ≥ 1 year in 27% and 19%), number of previous depressive episodes (0 in 31% and 35%, > 1 in 33% and 22%), antidepressant use (at any dose in 40% and 38%, at ≥ minimum effective dose in 28% and 26%), primary

Depression in Cancer Patients ■ An integrated collaborative care program significantly improved rates of depression response and remission in cancer patients with major depression. ■ The program was also associated with significant improvements in anxiety, pain, fatigue, physical functioning, social functioning, role functioning, overall health, and quality of life throughout the study.

in 8% and 10%, excellent in 6% and 2%). Patients had similar baseline scores on the SCL-20 and anxiety scores on the SCL-10 anxiety scale and similar scores for pain, fatigue, physical functioning, social functioning, role functioning, overall health, and quality of life on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30).

Major Outcomes Response was observed in 62% of patients in the intervention group vs 17% of those in the usual-care group (absolute difference = 45%, 95% confidence interval = 37%–53%, adjusted odds ratio [OR] = 8.5, P < .0001). The intervention group also had a significantly greater frequency of depression remission, defined as SCL-20 score < 0.75 at weeks 24, 36, and 48 (33% vs 4%, adjusted OR = 13.1, P < .0001) and significantly lower average depression severity (score of 0.94 vs 1.71, P < .0001). Self-rated assessment of depression at 24 weeks was “better/much better” for 79% vs 49%, “has not changed” for 17% and 33%, and “worse/much worse” for 4% and 17% (P < .0001). Anxiety assessed by SCL-10 anxiety

score and pain, fatigue, physical functioning, social functioning, role functioning, overall health, and quality of life on the EORTC-QLQ-C30 were all consistently better in the intervention group at 12, 24, 36, and 48 weeks (all P < .05). Ratings of quality of depression care at 12 weeks were “excellent/very good” by 72% of the intervention group vs 25% of the usualcare group (P < .0001), with this difference persisting through 48 weeks. Cancer-related death occurred in 19 patients in the intervention group and 15 in the usual-care group. One intervention group patient was admitted to a psychiatric ward, and one attempted suicide during the trial, with neither of these events considered to be related to trial procedures. The mean additional cost per patient for providing the depression care for people with cancer intervention was £613 (roughly equivalent to US$1,020 at current exchange rates). The investigators concluded: “Our findings suggest that depression care for people with cancer is an effective treatment for major depression in patients with cancer. It offers a model for the treatment of depression comorbid with other medical conditions.” They noted: The findings of this trial add to the accumulating evidence for the effectiveness of collaborative care approaches to the treatment of depression comorbid with medical conditions. They also provide new evidence that large and sustained treatment effects can be achieved if depression treatment is integrated with medical care, intensive, and systematically delivered by a well-trained and supervised team. Furthermore, the additional cost of delivering depression care for people with cancer was quite modest, especially in the context of cancer treatment. The most important implication of this study is that paying the same systematic attention to the management of comorbid major depression as we presently do to the associated medical condition achieves much better outcomes for patients. n

Disclosure: The study was funded by Cancer Research UK and the Chief Scientist Office of the Scottish Government. The study authors reported no potential conflicts of interest.

Reference 1. Sharpe M, Walker J, Hansen CH, et al: Lancet. August 27, 2014 (early release online).

Drs. Sharpe and Walker are the joint first authors of the Lancet article.

Anticancer quinolone derivatives Exploring novel applications with a familiar molecule Quinolones have been used by oncologists to combat infection for decades.1,2 Their effectiveness at also inhibiting mammalian topoisomerase II prompted study into whether that quality could induce antineoplastic activity through similar mechanisms.3,4 Thus, anticancer quinolone derivatives (AQDs) were born.4-6 Preclinically, AQDs have been observed to cause site-selective, double-strand DNA damage.6,7 By virtue of a stable quinolone core, AQDs appear to produce few reactive oxygen species, thus projecting a low potential for off-target organ damage and cardiotoxicity,6 an ability to evade P-gp and p53 drug resistance pathways,8,9 and a low risk for drug-drug interaction.10,11 AQDs have demonstrated single-agent activity across a broad spectrum of aggressive drugresistant tumor models12,13 and have shown in vitro additive or synergistic effects in combination with cytarabine, clofarabine, azacitidine, and decitabine.8,12,14 Sunesis is committed to pursuing the clinical relevance and therapeutic utility of AQDs to prolong survival for patients with cancer. Data from VALOR, the largest industry-sponsored multinational study on relapsed and refractory AML, is expected later this year.

References: 1. Engels EA, Lau J, Barza M. Efficacy of quinolone prophylaxis in neutropenic cancer patients: a meta-analysis. J Clin Oncol. 1998;16(3):1179-1187. 2. Andriole VT. The quinolones: past, present, and future. Clin Infect Dis. 2005;41(suppl 2):S113-S119. 3. Yamashita Y, Ashizawa T, Morimoto M, Hsomi J, Nakano H. Antitumor quinolones with mammalian topoisomerase II mediated DNA cleavage activity. Cancer Res. 2004;52(10):2818-2822. 4. Tomita K, Tsuzuki Y, Shibamori K-I, et al. Synthesis and structureâ&#x20AC;&#x201D;activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-nathyridine-3-carboxylic acids as antitumor agents. Part 1. J Med Chem. 2002;45(25):5564-5575. 5. Tsuzuki Y, Tomita K, Shibamori K-I, Sata Y, Kashimoto S, Chiba K. Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-nathyridine-3-carboxylic acids as antitumor agents. Part 2. J Med Chem. 2004;47(8):2097-2109. 6. Hawtin RE, Stockett DE, Byl JAW, et al. Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II. PLoS One. 2010;5(4):e10186. doi:10.1371/journal.pone.0010186. 7. Hawtin RE, Stockett DE, Wong OK, Lundin C, Helleday T, Fox JA. Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks. Oncotarget. 2010;1(7):606-619. 8. Walsby EJ, Coles SJ, Knapper S, Burnett AK. The topoisomerase II inhibitor voreloxin causes cell cycle arrest and apoptosis in myeloid leukemia cells and acts in synergy with cytarabine. Haematologica. 2011;96(3):393-399. 9. Hoch U, Lynch J, Sato Y, et al. Voreloxin, formerly SNS-595, has potent activity against a broad panel of cancer cell lines and in vivo tumor models. Cancer Chemother Pharmacol. 2009;64(1):53-65. 10. Evanchik MJ, Allen D, Yoburn JC, Silverman JA, Hoch U. Metabolism of (+)-1,4-Dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid (voreloxin; formerly SNS-595), a novel replication-dependent DNA-damaging agent. Drug Metab Dispos. 2009;37(3):594-601. 11. Hoch U, Evanchik MJ, Silverman JA. CYP450 inhibition, induction, metabolism, and routes of elimination of SNS-595, a novel cell cycle inhibitor in phase 1 clinical trials. Poster presented at: 2005 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; November 14-18, 2005; Philadelphia, PA. 12. Scatena CD, Kumer JL, Arbitrario JP, et al. Voreloxin, a first-in-class anticancer quinolone derivative, acts synergistically with cytarabine in vitro and induces bone marrow aplasia in vivo. Cancer Chemother Pharmacol. 2010;66(5):881-888. 13. Hoch U, Hyde J, Nannini MA, et al. SNS-595, a novel cell cycle inhibitor in phase I clinical trials, causes tumor regressions, cell-cycle arrest, and apoptosis in murine models of cancer. Poster presented at: 96th Annual Meeting of the American Association for Cancer Research; April 16-20, 2005; Anaheim, CA. 14. Stockett DE, Kumer JL, Scatena CD, Silverman JA, Hawtin RE, Fox JA. Voreloxin is synergistic in in vitro combination with cytarabine and additive in combination with azacitidine, decitabine and clofarabine. Poster presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; November 15-19, 2009; Boston, MA.

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Perspective Psychosocial Oncology

Improving Treatment of Depression in Patients With Cancer: The SMaRT Oncology-2 Trial By William Breitbart, MD, and Yesne Alici, MD

linical depression is highly prevalent, associated with significant morbidity, often underrecognized, and inadequately treated in cancer patients. Professor Michael Sharpe and Jane Walker, PhD, and their colleagues’ seminal work on enhancing treatment of depression in cancer patients using a collaborative practice model—in the SMaRT Oncology-2 Trial—is thus a great step forward in this setting.1 Most studies report rates of depression in cancer patients at two to three times that seen in the general population.2 Walker and colleagues recently published data on prevalence of major depression among 21,151 patients in cancer clinics in Scotland.2 The point prevalence of major depression was highest in patients with lung cancer (13.1%), followed by gynecologic cancer (10.9%), breast cancer (9.3%), colorectal cancer (7.0%), and genitourinary cancer (5.6%). Similarly, two meta-analyses reported prevalence rates of 16% and 13% of depression for patients with all types of cancer.3,4 Depression in patients with cancer is associated with significant morbidity and increased health-care costs.5 Worse pain, anxiety, fatigue, treatment adherence, and overall functioning have been reported among depressed cancer patients,5,6 and suicide and desire for hastened death are highly prevalent.7 An example of underrecognition and inadequate treatment is provided by a recent study showing that 73% of cancer patients with major depression were reported not to have had any treatment for their depression.2

Recognition an Important First Step Such data are of significant concern and highlight the need for more effective approaches to the management of depression in the oncology setting. There are a number of barriers to assessment and management of depression in oncology clinics. The American College of Surgeons’ Dr. Breitbart is Interim Chairman, and Dr. Alici is Assistant Attending Psychiatrist in the Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York.

Commission on Cancer has recently mandated that, as of 2015, all cancer centers in the United States screen patients for psychosocial distress.8 This represents an important step towards improving screening, assessment, and recognition of depression in oncology settings. Development of effective management approaches for cancer patients with depression is an important next step. Collaborative care interventions have evolved out of the need to assess and manage depression better among the medically ill. These interventions integrate a number of components into the medical setting to improve assessment and management of depression

sion, referred to as “depression care for people with cancer.”1 The study was conducted in three cancer centers in Scotland. All enrolled cancer patients had a predicted survival of ≥ 12 months estimated by their oncologists. Major depression diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria with an additional requirement to fulfill the diagnostic criteria for at least 4 weeks. The primary outcome was treatment response, defined as a ≥ 50% reduction in Symptom Checklist Depression Scale (SCL-20) score at 24 weeks. The outcome data were collected up until 48 weeks.

These [psycho-oncology] programs are critically important and should be increasingly used to aid oncologists in the care of their patients with depression or other forms of psychological distress that often interfere with treatment adherence or completion of treatment. —William Breitbart, MD, and Yesne Alici, MD

for such patients. The interventions typically include a systematic psychiatric assessment, use of a non-physician care manager responsible for monitoring depressive symptoms, treatment responses, and care coordination, and stepped-care recommendations provided by a psychiatrist. Collaborative care interventions for depression have been evaluated in a wide range of care settings and have been shown to increase quality of patient care and reduce health-care costs.9,10

SMaRT Oncology-2 Trial The SMaRT Oncology-2 trial, reviewed in this issue of The ASCO Post, is a randomized controlled effectiveness trial for an integrated collaborative care treatment model for cancer patients with major depres-

Collaborative care was delivered systematically by a team of oncology nurses and psychiatrists in collaboration with primary care physicians. Usual care was provided by primary care physicians. In the collaborative care intervention, nurses established a therapeutic relationship with the patients, provided information about depression and its treatment, delivered brief evidence-based psychological interventions (namely, problem-solving therapy and behavioral activation), and monitored patients’ progress over a period of 4 months in a maximum number of 10 sessions in person or over the phone. After the initial 4 months, Patient Health Questionnaire (PHQ)-9 depression severity scale scores were monitored monthly by telephone for another 8

months; additional sessions with the nurse were provided for patients not meeting treatment targets. The psychiatrists supervised treatment on a weekly basis, aiming to achieve and maintain treatment targets, advised primary care physicians about prescribing antidepressants, and provided direct consultations to patients who were not improving. Of the 500 participants, 253 cancer patients with major depression received the intervention and 247 patients received usual care. About 70% of all patients were 60 years or older and 90% of all participants were women. More than two-thirds of patients had a history of depressive episodes. Around 50% of all patients had the current depressive episode for longer than 6 months. Seventy-nine percent of patients did not have active disease. Only 13% of patients in the integrated care arm and 16% of patients in the usual-care arm were receiving palliative treatment. The mean SCL-20 depression scores were 2.10 in the intervention group and 2.11 in the usual-care group at baseline. Sixty-two percent of participants in the collaborative care group and 17% of participants in the usual-care group responded to treatment at 24 weeks. Cancer patients with major depression who received the integrated collaborative care treatment model were found to have less depression, anxiety, pain, and fatigue and better functioning, health, quality of life, and perceived quality of depression care at 24 and 48 weeks (all P < .05). More than half of the participants in each group received antidepressants. Minimum effective doses of antidepressants were used more commonly in the collaborative care group, and adjustments to antidepressant medications were more frequent. The mean additional cost per patient of providing integrated care was around $1,000. The treatment effects of the collaborative intervention in this study are significantly greater than those observed in similar collaborative intervention trials in cancer patients, in patients with depression comorbid with chronic diseases, and in the general patient population.11-13 The collaborative care used in

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Perspective

SMaRT Oncology-2 included comprehensive depression treatments, namely medications and psychotherapy delivered primarily face-to-face, and intensive education provided to nurses delivering care via formal training and close supervision throughout the study. Involvement of primary care providers increased treatment acceptability and adherence. It might be difficult to simulate all these treatment components in all oncology care settings. Thus, it might be most valuable to identify which components provide the most benefit. For example, in a randomized controlled trial of collaborative depression care in obstetrics and gynecology clinics, patients with no insurance and patients with public coverage were found to benefit most significantly from this comprehensive approach for management of their depression.14

Referral Critical for Treatment of Depression One of the important findings of the study is that the primary care physicians and oncologists in the usualcare arm had the option of seeking consultation from a mental health professional for patients with major

depression. Although oncologists were informed of a patient’s depression diagnosis, less than 20% of patients were referred to a mental health professional for consultation. More and more cancer centers have robust psycho-oncology programs staffed by psychiatrists, psychologists, social workers, and mental health nurses. Such programs are now mandated in all National Cancer Institute–designated cancer centers. Further, these programs are critically important and should be increasingly used to aid oncologists in the care of their patients with depression or other forms of psychological distress that often interfere with treatment adherence or completion of treatment. n

Disclosure: Drs. Breitbart and Alici reported no potential conflicts of interest.

References 1. Sharpe M, Walker J, Hansen CH, et al: Integrated collaborative care for comorbid major depression in patients with cancer (SMaRT Oncology-2): A multicentre randomised controlled effectiveness trial. Lancet 384:1099-1108, 2014. 2. Walker J, Hansen CH, Martin P, et al: Prevalence, associations, and adequacy of treatment of major depression in patients with cancer: A cross-sectional anal-

ysis of routinely collected clinical data. Lancet Psychiatry 15:1168-1176, 2014. 3. Mitchell AJ, Chan M, Bhatti H, et al: Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: A meta-analysis of 94 interviewbased studies. Lancet Oncol 12:160174, 2011. 4. Krebber AM, Buffart LM, Kleijn G, et al: Prevalence of depression in cancer patients: A meta-analysis of diagnostic interviews and self-report instruments. Psychooncology 23:121-130, 2013. 5. Wilson KG, Chochinov HM, Skirko MG, et al: Depression and anxiety disorders in palliative cancer care. J Pain Symptom Manage 33:118-129, 2007. 6. Brown LF, Kroenke K, Theobald DE, et al: The association of depression and anxiety with health-related quality of life in cancer patients with depression and/or pain. Psychooncology 19:734-741, 2010. 7. Breitbart W, Rosenfeld B, Pessin H, et al: Depression, hopelessness, and desire for hastened death in terminally ill patients with cancer. JAMA 284: 29072911, 2000. 8. American College of Surgeons: Cancer program standards 2012. Available at www.facs.org/quality%20programs/cancer/coc/standards. Accessed September 17, 2014.

9. Huffman JC, Niazi SK, Rundell JR, et al: Essential articles on collaborative care models for the treatment of psychiatric disorders in medical settings: A publication by the Academy of Psychosomatic Medicine Research and Evidence-Based Practice Committee. Psychosomatics 55:109-122, 2014. 10. Green C, Richards DA, Hill JJ, et al: Cost-effectiveness of collaborative care for depression in UK primary care: Economic evaluation of a randomised controlled trial (CADET). PLoS One 9:e104225, 2014. 11. Archer J, Bower P, Gilbody S, et al: Collaborative care for depression and anxiety problems. Cochrane Database Syst Rev 10:CD006525, 2012. 12. Ekers D, Murphy R, Archer J, et al: Nurse-delivered collaborative care for depression and long-term physical conditions: A systematic review and meta-analysis. J Affect Disord 149:14-22, 2013. 13. Strong V, Waters R, Hibberd C, et al: Management of depression for people with cancer (SMaRT Oncology 1): A randomised trial. Lancet 372:40-48, 2008. 14. Katon W, Russo J, Reed SD, et al: A randomized trial of collaborative depression care in obstetrics and gynecology clinics: Socioeconomic disadvantage and treatment response. Am J Psychiatry. August 26, 2014 (early release online).

Don’t Miss These Important Reports in This Issue of The ASCO Post Benjamin Movsas, MD, on Stereotactic Body Radiation Therapy see page 3

Theodore DeWeese, MD, on Radiation Therapy in Early Hodgkin Lymphoma see page 5

Tracy Balboni, MD, on Radiation vs hemoradiation for Advanced Esophageal Cancer see page 15

Phillip J. Gray, MD, on Androgen-Deprivation Thereapy Duration see page 16

Alan P. Venook, MD, on Best of ASCO see page 21

Andrew M. Evens, DO, MSc, on exciting Highlights in Lymphomas at Best of ASCO see page 22

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | OCTOBER 15, 2014

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In the Clinic Genitourinary Oncology

Enzalutamide in Metastatic Castration-Resistant Prostate 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 September 10, 2014, the androgen receptor inhibitor enzalutamide (Xtandi) was approved for use in men with metastatic castrationresistant prostate cancer who have not received chemotherapy. Enzalutamide was approved in 2012 for use in men with castration-resistant prostate cancer who had previously received docetaxel.

Supporting Trial The new indication is based on results of the double-blind phase III PREVAIL trial, in which 1,717 patients with minimally symptomatic or asymptomatic metastatic castration-resistant prostate cancer who had not received cytotoxic chemotherapy were randomly assigned to receive oral enzalutamide 160 mg/ day (n = 872) or placebo (n = 845) until disease progression and the initiation of cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Continued androgen-deprivation therapy was required. Patients with visceral metastases or history of mild to moderate heart failure and patients taking medications associated with lowering seizure threshold were permitted to enroll.

OF NOTE Enzalutamide carries warnings/precautions for seizure.

Those with history of seizure or a condition that might predispose to seizure and those with moderate or severe pain from prostate cancer were excluded. The co-primary endpoints were overall survival and radiographic progressionfree survival. Patients had a median age of 71 years (range, 42–93 years), 77% were white and 10% were Asian, Eastern Cooperative Oncology Group performance status was 0 in 68% and 1 in 32%, baseline pain assessment was asymptomatic in

67% and mildly symptomatic in 32%, 54% had radiographic evidence of progression and 43% had prostate-specific antigen–only progression, and 12% had visceral (lung or liver) involvement. During the study, 27% of enzalutamide patients and 30% of placebo patients received glucocorticoids. Subsequent therapy was received by 40% of enzalutamide patients and 70% of placebo patients. Enzalutamide was associated with significantly prolonged median overall survival (32.4 vs 30.2 months, hazard ratio [HR] = 0.71, P < .0001) and radiographic progression-free survival (not reached, 95% confidence interval = 13.8 months– not reached, vs 3.7 months, 95% CI = 3.6–4.6 months, HR = 0.17; P < .0001). Enzalutamide also significantly

OF NOTE Enzalutamide is an androgen receptor inhibitor that inhibits androgen receptor nuclear translocation and interaction with DNA. It has been shown to decrease proliferation and induce death of prostate cancer cells in vitro and reduce tumor volume in a prostate cancer xenograft model. Concomitant use of a strong CYP2C8 inhibitor should be avoided. If one must be used, the enzalutamide dose should be reduced to 80 mg once daily and can be returned to the prior dose level when use of the strong inhibitor is discontinued. Concomitant use of strong or moderate CYP3A4 or CY-

Enzalutamide in Metastatic Castration-Resistant Prostate Cancer ■ Enzalutamide was approved for use in men with metastatic castrationresistant prostate cancer who have not received chemotherapy. ■ Enzalutamide is administered orally at 160 mg once daily.

prolonged median time to initiation of cytotoxic chemotherapy (28.0 vs 10.8 months, HR = 0.35, P < .0001) and time to first skeletal-related event (31.1 vs 31.3 months, HR = 0.72, P < .0001).

How It Works Enzalutamide acts at a number of steps in the androgen receptor signaling pathway. It has been shown to competitively inhibit androgen binding to androgen receptors and to inhibit androgen receptor nuclear translocation and interaction with DNA. Enzalutamide decreased proliferation and induced death of prostate cancer cells in vitro and reduced tumor volume in a prostate cancer xenograft model.

How It Is Given The recommended dose of enzalutamide is 160 mg once daily. Treatment should be withheld for 1 week or until symptoms improve to grade ≤ 2 in patients with a grade ≥ 3 or intolerable adverse event and then resumed at the same dose or at reduced doses of 120 or 80 mg once daily if warranted. Enzalutamide should be permanently discontinued in patients with seizure.

P2C8 inducers (which may decrease enzalutamide exposure) and CYP3A4, CYP2C9, and CYP2C19 substrates (exposure levels of which may be reduced with enzalutamide coadministration) with a narrow therapeutic index should be avoided. No initial dose adjustment is necessary in patients with mild to moderate renal or hepatic impairment. Enzalutamide has not been assessed in patients with severe renal impairment or endstage renal disease or severe hepatic impairment.

Safety Profile In PREVAIL, median durations of treatment were 17.5 months with enzalutamide and 4.6 months with placebo. The most common adverse events of any grade in the enzalutamide group were asthenic conditions (47% vs 33% in the placebo group), back pain (29% vs 22%), constipation (23% vs 17%), and arthralgia (21% vs 16%). Grade 3 or 4 adverse events occurred in 44% vs 37% of patients, with the most common being hypertension (7.2% vs 2.3%), asthenic conditions (3.4% vs 2.8%), back pain (2.5% vs 3.0%), and nonpatholog-

ic fracture (2.1% vs 1.1%). Discontinuations due to adverse events occurred in 6% vs 6% of patients, with the most common cause being fatigue/asthenia (1% vs 1%). In combined data from PREVAIL and a randomized trial in patients previously treated with docetaxel (AFFIRM), any grade neutropenia occurred in 15% of enzalutamide patients vs 6% of placebo patents (grade 3 or 4 in 1% vs 0.5%) and thrombocytopenia occurred in 6% vs 5% (grade 3 or 4 in 0.3% vs 0.5%). Death due to infection/ sepsis occurred in 1% vs 0.3% in AFFIRM and in 0.1% vs 0.1% in PREVAIL. Seizure occurred in 0.9% of patients receiving enzalutamide in AFFIRMED and in 0.1% of enzalutamide patients in PREVAIL. In the combined trials, falls, including fall-related injuries, occurred in 9% vs 4% and were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in enzalutamide patients, including nonpathologic fractures, joint injuries, and hematomas. Hypertension occurred in 11% vs 4% of patients, and led to discontinuation in < 1% vs < 1%. Enzalutamide carries warnings/precautions for seizure. There is no clinical trial experience with the drug in patients with a history of seizure. n References 1. XTANDI® (enzalutamide) capsules prescribing information, Astella Pharma US, Inc, September 2014. Available at www.astellas.us/docs/us/12A005-ENZ-WPI.pdf. 2. Beer TM, Armstrong AJ, Rathkopf DE, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 371:424-433, 2014.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/ medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

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Expert’s Corner Sarcoma

Treating Sarcomas in 2014

A Conversation With George D. Demetri, MD By Ronald Piana

George D. Demetri, MD

n 2014, about 15,000 people in the United States will be diagnosed with some form of sarcoma, and of those, approximately 5,000 adults and children are expected to die of the disease. Sarcomas are a heterogeneous group of mesenchymal malignancies that have historically been difficult to diagnose and treat, resulting in confusion, fear, and poor survival outcomes for patients with metastatic disease while nonetheless bringing cures to many patients with early-stage disease. To bring our readers up to date on the current state of sarcoma treatment and the advances that lie ahead, The ASCO Post recently spoke with George D. Demetri, MD, Director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston.

except for a couple of pediatric sarcomas, such as Ewing’s or osteosarcoma, which were potentially curable by conventional chemotherapy. Another important stride was the recognition that sarcoma subtypes are vastly different from one another, and now we finally have the tools to separate these subtypes and categorize them into bins that are rational and potentially targetable. This has been a dramatic conceptual change that began in sarcomas and has now permeated all of oncology. In many ways, sarcomas led the way forward for the modern approach to solid tumor oncology.

Improvements in Diagnosis Diagnosis in this disease has always been difficult. Have we made headway in that clinical challenge? Yes, we’ve made headway, thanks to the dedication and improved tools for our pathologists. The diagnostic technology has improved dramatically, not just immunohistochemistry, which was a big

the reference centers into the care of their patients. If we centralize the system, the whole oncology community throughout the country can get by with a limited number of such centralized expert reference centers.

Avoiding Loss of Function From Surgery Loss of a limb is one of the complicated issues in sarcoma. Has limb-sparing surgery improved markedly over the past decade? We rarely see amputations in sarcomas any more, as expert surgeons have been able to reconstruct limbs and avoid the need for amputation. However, there are a small number of cases in which prosthesis might be more functional than a limb after treatment. For instance, you can’t really irradiate a foot and have it remain highly functioning, so at that point, amputation might be called for. That said, prosthetic and robotic technology has advanced to a point of

The advent of tyrosine kinase inhibitors has dramatically changed the overall survival of patients with GIST…. This remarkable innovation has set the stage for the second biggest advance in sarcomas, which is the absolute destruction of the nihilism surrounding this disease. —George D. Demetri, MD

Greatest Advances What has been the most important advance in sarcoma during your career? Unquestionably, the most important advance was the demonstration that tyrosine kinase inhibitors can durably control disease in patients with gastrointestinal stromal tumors (GIST). In fact, nearly 20% of advanced GIST patients taking imatinib (Gleevec) treated on our very first clinical study have now survived more than 14 years, which is absolutely remarkable. The advent of tyrosine kinase inhibitors has dramatically changed the overall survival of patients with GIST, not only in the advanced-disease setting, but also in the high-risk adjuvant setting. Moreover, this remarkable innovation has set the stage for the second biggest advance in sarcomas, which is the absolute destruction of the nihilism surrounding this disease. When I was in training, most people looked at sarcomas as this clinical black box of futility,

deal in the 1990s, but the fluorescence in situ hybridization (FISH) and genomic sequencing technologies. Simply put, the quality of sarcoma diagnoses are improving every day at reference centers. To that end, an important issue is whether the U.S. Food and Drug Administration (FDA) tackles the nationwide problem of variable results coming out of laboratory-developed tests so that we have full confidence that the labs to which we entrust our patients’ materials are accurate and reliable. In sarcoma, we’ve been used to the idea that expert reference centers obviate the need for every community hospital to have robust expertise in sarcoma pathology, which is impossible. We only need the expertise of a few expert reference centers around the country to handle the samples and aid in the diagnosis. Then the community doctors become part of this larger network and implement the guidance of

sophistication that actually gives the patient requiring amputation an outstanding quality of life. We have examples of competitive athletes with prosthetics, so it’s a much easier doctor-patient conversation that it was a decade or so ago.

New Therapy Options for Sarcomas Other Than GIST You’ve stated that the most important advance in sarcoma is the use of tyrosine kinase inhibitors such as imatinib in GIST. Are there any other promising agents in the sarcoma field? Yes, there are many new targeted therapies in development. The most recently approved agent is the tyrosine kinase inhibitor pazopanib (Votrient), which was the first FDA-approved drug since the early 1980s for use in soft-tissue sarcomas. This drug was the result of an international academic industrial collaboration that was originally designed jointly by colleagues at the Eu-

ropean Organisation for Research and Treatment of Cancer (EORTC) and GlaxoSmithKline. The international sarcoma community works very well together, and that is something that I’m very proud to be a part of. It’s important to note that the activity of pazopanib in a broad range of sarcomas is nowhere near that of imatinib in GIST, because most other soft-tissue sarcomas have more complex “wiring” problems than the single oncogene “driver” that is at the heart of most GISTs. Nonetheless, pazopanib’s activity in sarcomas was sufficient to garner FDA approval, which is a good step forward in these diseases.

Current Research Are there ongoing studies in sarcoma that the readers should be aware of? There are numerous promising and exciting areas of active clinically relevant research in sarcomas. For instance, liposarcoma is the “proof-of-concept” disease for a new class of drugs to inhibit MDM2. Liposarcoma is one of only a very few types in which the MDM2 gene is amplified, but there are many other cancers in which MDM2 might play a role, and where inhibiting the protein derived from this gene might be helpful to many other cancers beyond sarcomas. In most liposarcomas, there are too many copies of the MDM2 gene, which creates too many copies of a protein that “neutralizes” p53. So the idea behind this might be phrased “the enemy of my friend is my enemy.” In other words, if having normal p53 as my friend, too much MDM2 is my enemy; by inhibiting MDM2 we hope to reconstitute the tumor-suppressor action of p53. We’ve seen this promising activity in translational studies on human tumors. MDM2 inhibitors are currently being produced by several biotech and pharmaceutical companies, and we’re testing them in late-stage phase I and II studies. Also, about 9 of 10 liposarcomas express CDK4. As readers of The ASCO Post know, CDK4 inhibition has achieved “breakthrough drug” status in hormone receptor–positive breast cancers, and several ongoing studies are evaluating different CDK4 inhibitor drugs. This is another exciting therapeutic avenue in sarcomas, and we’re continued on page 118

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Expert’s Corner George D. Demetri, MD continued from page 117

also looking at the promising possibilities offered by combination targeting to inhibit both MDM2 and CDK4. Very interesting work has also come out of the University of Michigan, Massachusetts General Hospital, and St. Jude Children’s Research Hospital, which have independently identified and confirmed PARP inhibition as a previously unsuspected way to treat Ewing sarcoma. My colleague, Edwin Choy, MD, PhD, at Massachusetts General Hospital and our team at Dana-Farber/Harvard have developed a

very exciting clinical trial of the PARP inhibitor olaparib, to set up Ewing sarcoma to be more sensitive to chemotherapy, which appears very positive already. There are other larger-scale trials using other PARP inhibitors as well, to explore whether this might be helpful to patients, and the early data certainly appear encouraging. It’s a very exciting and hopeful time for patients as well as physicians in sarcoma research.

Transforming This Disease Any last thoughts on this difficult clinical area?

I started in this field in the 1980s, during which there were very few treatment options other than empiric, highly toxic chemotherapy. Our multidisciplinary team did cure a certain number of these sarcomas, but more importantly, we took the best qualities of the early chemotherapies and built upon them, and now we’re building better therapies on the backs of the new-millennium targeted therapies. I truly believe that we are transforming this disease in a way that will bring the same extraordinary advances seen in hematologic malignancies, such as leukemias and lymphomas.

It’s also important to note that we could not have made these advances without the Internet. The fact that patients with rare diseases now have the ability to connect with each other and share information with their physicians has accelerated the ability of patients to find our research and help us place those patients into the clinical trial system. This has been key to the past 15 years of advances in sarcomas and other rare cancers. n Disclosure: For Dr. Demetri’s full disclosure of all potential conflicts of interest, please view the online version of this article at ASCOPost.com.

Cancer Prevention

IARC Calls on Countries With High Stomach Cancer Burden to Act to Prevent the Disease

new report from the International Agency for Research on Cancer (IARC), an agency of the World Health Organization, urges health authorities of countries with high stomach cancer burden to include stomach cancer in their national cancer control programs and allocate more resources to control the disease. A Working Group of international experts convened by IARC reviewed evidence to evaluate strategies for stomach cancer prevention based on the eradication of Helicobacter pylori, a bacterium that is the primary cause of stomach cancer. The Working Group’s report “Helicobacter pylori Eradication as a Strategy for Preventing Gastric Cancer” is accessible free of charge on IARC’s website, and its recommendations are summarized in a Viewpoint article published recently in JAMA.1 “Although stomach cancer is the third most common cause of cancer death worldwide, until now it has not been given the attention it deserves,” explains Rolando Herrero, MD, Head of the Prevention and Implementation Group at IARC. “We know the main cause of the disease, which is a bacterium that can be treated with antibiotics. Screening people in high-risk groups for infection with H pylori and treating them could play a key role in reducing the burden of stomach cancer in these populations.”

A Neglected Cancer Stomach cancer is particularly common in low- and middle-income countries and is more frequent among the most deprived populations but, with few exceptions, there are no public health programs for its prevention. In 2012, almost 1 million new cases occurred worldwide. The majority of these occurred in East Asia, and nearly one-half occurred in China. Relatively high rates of stomach cancer have also

H pylori Eradication as a Strategy for Preventing Stomach Cancer H pylori has been classified by IARC as carcinogenic to humans (group 1) and is considered to be the cause of 80% of all stomach cancers. Several trials have shown that H pylori treatment is effective in preventing a significant fraction of stomach cancers, but uncertainties remain about the feasibility and impact of population-based

Screening people in high-risk groups for infection with H pylori and treating them could play a key role in reducing the burden of stomach cancer in these populations. —Rolando Herrero, MD

been reported in Latin America and eastern Europe. Stomach cancer is usually diagnosed at advanced stages, and survival rates are therefore low in most geographical areas. This makes the disease the third leading cause of cancer death globally, with an estimated 723,000 deaths in 2012. Although incidence rates are declining, the numbers of cases and deaths will remain high for decades due to growth and ageing of the global population.

stomach cancer prevention programs based on antibiotic treatment of the infection. The Working Group recommended that countries explore the introduction of population-based H pylori screening and treatment programs to reduce stomach cancer incidence. The implementation and modalities of these programmes should be based on local considerations of disease burden, competing health priorities, and cost– effectiveness analyses.

The experts strongly recommended that national health authorities in highincidence countries consider conducting demonstration programmes of H pylori screening and eradication using designs that provide a comprehensive assessment of programme effectiveness and potential risks. “Unless effective control measures are established, thousands of unnecessary deaths will continue to occur each year. Ignoring stomach cancer in the hope that it will soon disappear on its own is not a tenable health policy,” says Christopher Wild, MD, Director of IARC. “Evaluation of the implementation of large population-based programmes of H pylori screening and treatment is now a priority and provides the potential means of preventing deaths from this lethal cancer.” n References 1. Working Group Report: IARC Helicobacter pylori Working Group (2014). Helicobacter pylori Eradication as a Strategy for Preventing Gastric Cancer. Lyon, France: International Agency for Research on Cancer (IARC Working Group Reports, No. 8). Available at http://www. iarc.fr/en/publications/pdfs-online/wrk/ wrk8/index.php 2. Herrero R, Parsonnet J, Greenberg ER: Prevention of gastric cancer. JAMA. September 24, 2014 (early release online).

indications

ignited we stand with

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

Important Safety Information CONTRAINDICATIONS WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

Important Safety Information WARNINGS AND PRECAUTIONS (cont’d) • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis • Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

(cont’d)

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with singleagent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/ asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported • Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229) • In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%) • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Please see next page for adverse events in the NSCLC study. Pancreatic Adenocarcinoma Study • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%) • Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%) • Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/ gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%),

arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%) Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN • For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium®): Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

For more information, please visit www.abraxane.com.

ABRAXANE® is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

significantly superior ORR in first-line ITT population with advanced NSCLC Primary end point: First-line ABRAXANE + carboplatin significantly improved ORR in the phase 3 NSCLC trial (ITT population)

CATEGORY 1 ABRAXANE + carboplatin %

n=521

(170/521) 95% CI: 28.6%-36.7%

Paclitaxel injection + carboplatin %

n=531

A National Comprehensive Cancer Network ® (NCCN ®) Category 1 recommendation1,2,b,c

(132/531) 95% CI: 21.2%-28.5% 30

First-line albumin-bound paclitaxel (ABRAXANE) + carboplatin is recommended for PS 0-1 patients with advanced NSCLC of negative or unknown EGFR mutation and ALK status.

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

ORR (%)

ITT=intent-to-treat; ORR=overall response rate. a P value based on chi-square test.

P=0.005a

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PS=performance status.

There was no statistically significant difference in overall survival between the 2 study arms.

41% ORR in squamous patients ORR by histology in the phase 3 NSCLC trial 50 45 40

ABRAXANE + carboplatin

41%

ORR (%)

35 30

24%

26% 27

Paclitaxel injection + carboplatin

33% 24% 15%

15%

20 15 10 5 0

94/229

54/221

Squamous cell carcinoma

66/254

71/264

3/9

Carcinoma/adenocarcinoma

2/13

Large cell carcinoma

7/29

5/33

STUDY DESIGN • Multicenter 1:1 randomized, phase 3 study comparing ABRAXANE (100 mg/m2 IV; Days 1, 8, and 15 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) with paclitaxel injection (200 mg/m2 IV, Day 1 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) in 1052 chemonaïve patients with advanced NSCLC

Other

Adverse events in the NSCLC study • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin– treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group

• Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively • Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary; refer to full Prescribing Information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies (14.2)]. 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)]. 2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc MBC NSCLCc Adenocarcinoma Mild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2 ≤ 1.25 x ULN Moderate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not 2 x ULN recommended 50 mg/m2 not Severe < 10 x ULN AND 2.01 to 130 mg/m2 b 5 x ULN recommended > 10 x ULN OR > 5 x ULN not not not recommended recommended recommended MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer. 2.5 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. • In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2. • Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL) Neutropenic Fever (ANC less than First 75 4.5 500/mm3 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm3 OR ANC less than 500/mm3 for more than 7 days Platelet count less than 50,000/mm3 Severe sensory Neuropathy – Grade 3 or 4

Second

Third First Second First Second Third

Discontinue Treatment 75 4.5 Discontinue Treatment 75 4.5 50 3 Discontinue Treatment

Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3. Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2) Full dose 125 1000 1st dose reduction 100 800 2nd dose reduction 75 600 If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine Day 1 < 1500 OR < 100,000 Delay doses until recovery Day 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count. Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5. Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at Febrile Neutropenia: Grade 3 or 4 next lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at next No dose reduction lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at Grade 3 mucositis or diarrhea next lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)]. 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)]. 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine. 5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%). In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%). 6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 175 mg/m2 over 3 hb 260 mg/m2 over 30 min (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of doseand schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (200 mg/m2 every 3 weeks) (100 mg/m2 weekly) plus carboplatin plus carboplatin Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 MedDRA v 12.1 Toxicity Toxicity Toxicity Toxicity System Organ Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General disorders Edema peripheral 10 0 4 <1 and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0 and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective Myalgia 10 <1 19 2 tissue disorders a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%. Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/ Gemcitabine Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group. Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE Gemcitabine (N=402) (125 mg/m2) and gemcitabine (N=421) Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%) General disorders and administration site Peripheral conditions edema 194 (46%) 13 (3%) 122 (30%) 12 (3%) Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%) Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%) Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%) 228 (54%) 27 (6%) 192 (48%) 14 (3%) Gastrointestinal disorders Nausea Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%) Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%) Alopecia 212 (50%) 6 (1%) 21 (5%) 0 Skin and subcutaneous tissue disorders Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%) Nervous system disorders Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%) Dysgeusia 68 (16%) 0 33 (8%) 0 Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%) Metabolism and nutrition Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%) disorders Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%) Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%) Respiratory, thoracic and Cough 72 (17%) 0 30 (7%) 0 mediastinal disorders Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%) Infections and infestations Urinary tract infectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%) Musculoskeletal and Pain in connective tissue extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%) disorders Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%) Myalgia 44 (10%) 4 (1%) 15 (4%) 0 Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0 a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died. 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history. Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)]. • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)]. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)]. • Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)]. Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: See www.celgene.com. ABR_ALL_HCP_BSv007 10_2013

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Professional Development

The Value of Lifelong Mentorship in Career Development A Conversation With Jennifer R. Brown, MD, PhD By Jo Cavallo

Jennifer R. Brown, MD, PhD

hile the development of mentorship relationships is critical in launching and nurturing the academic careers of young investigators, it is also an essential component for continued success throughout their careers, according to Jennifer R. Brown, MD, PhD. Dr. Brown, Director of the CLL Center at Dana-Farber Cancer Institute, and Associate Professor in the Department of Medicine at Harvard Medical School in Boston, is currently mentoring Matthew S. Davids, MD, MMSc, Attending Physician in the Lymphoma Program at Dana-Farber and Instructor of Medicine at Harvard Medical School. Dr. Davids, a recipient of a Conquer Cancer Foundation of ASCO 2014 Career Development Award, is evaluating the investigational agent IPI-145 in combination with FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]) as a possible treatment for younger patients with chronic lymphocytic leukemia (CLL).1 (See “A Conversation With Matthew S. Davids, MD, MMSc,” on page 127.) Dr. Brown said the experience of having mentors during her undergraduate and graduate laboratory studies in molecular biophysics and molecular genetics, and later during her residency in internal medicine at Massachusetts General Hospital and fellowship in hematology and medical oncology at Dana-Farber, was crucial in cultivating an early clinical and research interest in lymphoma. These experiences also helped steer her toward a subspecialty in chronic lymphocytic leuke-

mia. The support and encouragement she received from her mentors were so important to her academic career she continues to seek the guidance of mentors today. “The developmental needs change,” said Dr. Brown, “but we all need to be mentored to some extent throughout our careers.” The ASCO Post talked with Dr. Brown about her experience as both a mentee and a mentor and how the partnership helps establish lifelong clinical and research careers in oncology.

Finding the Right Niche Please describe how being mentored helped you launch your academic career. I have had mentors throughout my medical career starting with labora-

Stem Cell Transplantation Program at Dana-Farber, and Margaret Shipp, MD, Chief, Division of Hematologic Neoplasia and Program Director for the Lymphoma Program, are good mentors to me, as are other specialists in the field such as John Byrd, MD, Director of the Division of Hematology and D. Warren Brown Chair of Leukemia Research at Ohio State University Comprehensive Cancer Center.

Novel Skills and Experiences Would you say that maintaining mentorship relationships is important at every stage in an individual’s career? Yes, absolutely. The developmental needs change, but I think we all need to be mentored to some extent throughout

You move from mentor to mentor over your career depending on what your needs are at the time. You can also acquire different skills from different individuals at a given point, so oftentimes you need to collect a variety of mentors who can help you in various aspects of what you are doing. — Jennifer R. Brown, MD, PhD

tory mentors during both my undergraduate and graduate studies. I was also mentored during my residency at Massachusetts General Hospital by David Kuter, MD, Director, Center for Hematology at Massachusetts General Hospital, when I had an interest in benign hematology. Then as I moved toward fellowship in hematology and medical oncology at Dana-Farber, I became more interested in lymphoma and CLL. I worked with Arnie Freedman, MD, Clinical Director at Dana-Farber/Brigham and Women’s Cancer Center Adult Lymphoma Program, in clinical research as I transitioned to the faculty and decided to subspecialize in CLL. One of my laboratory interests is in the heritability of CLL and lymphoma and what the genetics are that underlie the inheritance of these diseases—CLL is, in fact, the most heritable of the lymphomas—so specializing in this disease was a very good niche for me. It also gave me the opportunity to develop my own clinical research program in CLL at DanaFarber, which has worked out very well. Today, my Division Chiefs, Robert Soiffer, MD, Chief, Hematologic Malignancies, and Co-Chief of the

our careers. You move from mentor to mentor over your career depending on what your needs are at the time. You can also acquire different skills from different individuals at a given point, so oftentimes you need to collect a variety of mentors who can help you in various aspects of what you are doing.

Role as a Mentor Please talk about your experience mentoring Dr. Matthew Davids in his research efforts and career development at DanaFarber Cancer Institute. Dr. Davids worked with me as a fellow on our in-patient service and he subsequently became interested in CLL (see Dr. Davids’ interview on page 127). He worked in the laboratory of Anthony Letai, MD, PhD, Associate Professor of Medicine, Hematologic Neoplasia/Malignancies, Dana-Farber Cancer Institute, and in the clinic with me. I am mentoring Dr. Davids on his study of IPI-145 in combination with FCR (fludarabine/cyclophosphamide/ rituximab [Rituxan]) for which he received the Career Development Award. I have mentored him on several other grants as well. We have been working together now

for 4 years and it is a very satisfying, mutually beneficial relationship. I have the opportunity to help him develop as an academic physician, which includes being a specialist in CLL in the clinic as well as learning how to design protocols for clinical trials, write grants for clinical trials, oversee clinical trials, and then publish their results. None of these academic-type activities are explicitly taught in medical school and oftentimes people aren’t exposed to them until they get to the end of their fellowships. They may have given a couple of talks or written an occasional paper, but usually not at the same systematic level that one needs to develop to succeed in academia. Also, there are usually a lot of competing demands on physicians’ time. If you are taking care of patients and running an inpatient service, obviously patients come first, so one has to take care of the patients, but also learn how to carve out some time for these academic activities. And having done that myself, I have experiences I can share in that regard as well as help junior investigators develop these necessary skills. As a mentor, I can also provide support when there are too many things going on or a particularly stressful event happens. So it is very helpful for junior investigators to have the support of someone who can say, “That’s happened to me before,” or, “I’ve been there before and this is how I managed it.” Today, it is harder and harder to do clinical research because of the regulatory environment and payer reimbursement issues, so getting established is difficult and it helps greatly, it is essential in fact, to have the support of someone in your institution, as well as support from other people around the country who work in your area. How long have you been a mentor; and how many young investigators have you mentored? I have been in mentorship relationships for about 10 years. And over that time, I have mentored between 10 and 12 young investigators and postdoctoral fellows.

Career Development Award How important is it to a young investigator’s career to be awarded a Conquer Cancer Foundation Career Development Award? continued on page 128

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Professional Development

On Being A Mentee and the Value of the Conquer Cancer Foundation’s Career Development Award A Conversation With Matthew S. Davids, MD, MMSc By Jo Cavallo

Matthew S. Davids, MD, MMSc

t the ASCO Annual Meeting in June, the Conquer Cancer Foundation presented the 2014 recipients of prestigious grants and awards, including the Young Investigator Award, Career Development Award, and the Advanced Clinical Research Award in Breast Cancer. In announcing the awards, Charles W. Penley, MD, FASCO, Chair of the Conquer Cancer Foundation Board of Directors, said, “These three awards support the development of cancer doctors during different phases of their careers; from the beginning of their research endeavor and faculty appointments through advanced clinical study. The Conquer Cancer Foundation is proud to support researchers at all stages, so they can focus on learning, innovating, and—most importantly—improving the care of patients worldwide.” Those words are especially meaningful to Matthew S. Davids, MD, MMSc, Attending Physician in the CLL Center of the Lymphoma Program in the Division of Hematologic Malignancies at Dana-Farber Cancer Institute; Instructor in Medicine at Harvard Medical School; and one of the recipients of this year’s Career Development Award (CDA). Dr. Davids received a $200,000 3-year grant, which is helping fund his early-phase clinical study of the investigational agent IPI-145, a small-molecule PI3K inhibitor, given in combination with the standard chemoimmunotherapy regimen FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]) in previously untreated, younger patients with chronic lymphocytic leukemia (CLL).1 Launching the study,

said Dr. Davids, most likely would not have been possible without the Career Development Award grant, because it is providing him with the financial support and dedicated research time necessary to write the study protocol, accrue patients, conduct laboratory studies, analyze the data, and eventually publish the study results. Dr. Davids also credits the support of his mentor, Jennifer R. Brown, MD, PhD, Director of the CLL Center at Dana-Farber Cancer Institute, and Associate Professor in the Department of Medicine at Harvard Medical School, with helping to make his research possible. (See “The Value of Lifelong Mentorship in Career Development: A Conversation With Jennifer R. Brown, MD, PhD,” on page 126). The ASCO Post talked with Dr. Davids about his research, the importance of mentorship in a young investigator’s career development, and the outlook for more effective therapies in the treatment of CLL.

Clinical Study Goals Please talk about the aim of your clinical study of IPI-145 plus FCR (iFCR) in patients 65 and younger with CLL. Unfortunately, CLL is not a curable cancer. Although we have a lot of effective therapies that can put the disease in remission temporarily, inevitably it will recur. There are many new drugs recently approved and in development for patients with CLL, which hold great promise. Most of them are oral agents that are well tolerated, and there are a few different approaches researchers are taking to explore how best to incorporate them into treating CLL. One idea is to rationally combine the new drugs together to get away from standard chemotherapy, and we believe that will likely be the best approach for older patients who do not tolerate chemotherapy very well. Although this may not cure the disease, it is likely to keep it in remission for years. On the other hand, younger, fit patients typically tolerate chemotherapy better, so our idea for the iFCR study was to add one of

the most promising new drugs to our most powerful chemoimmunotherapy regimen to see if the combination regimen will lead to cure, at least in a subset of patients with CLL. It is an ambitious goal because there is no precedence for curing CLL with conventional therapies. On the other hand, we now have an exciting opportunity to combine promising novel agents with chemoimmunotherapy, and this was the inspiration for our study. There are a couple of main components to the trial. One is FCR, which is the gold standard chemoimmunotherapy regimen for treating younger patients with CLL, and the other is IPI-145, an oral drug that targets the delta/gamma isoforms of PI3 kinase. Based on preliminary data from early-phase clinical trials of IPI-145 showing that the drug is well tolerated and has promising efficacy data in CLL, we are hopeful that when we combine it with FCR we are going to see deep, durable responses with good tolerability. One of the aspects that we think is innovative about our trial approach is that we are using a surrogate endpoint of minimal-residual disease negative complete response after 8 months of treatment to evaluate the efficacy of this combination. Minimal residual disease is a well-validated predictor of progression-free and overall survival after FCR, so it will allow us to rapidly get an efficacy readout to compare to the historical experience with FCR alone, without having to wait several years to see differences in survival rates. We see this trial as an initial step to evaluate whether this combination is safe, determine the appropriate dosing, and, hopefully, see a strong efficacy signal. If our study results are positive, there is potential for iFCR to quickly move to a more definitive randomized phase III study. One of the exciting things about receiving a Career Development Award from the Conquer Cancer Foundation is that it is allowing me to conduct this trial and the laboratory correlative studies, which, if successful, could represent the first steps toward a major advance for patients with CLL. This is an

amazing opportunity to have so early in my career.

Award Invaluable to Research Would your study be possible without the Career Development Award? I don’t believe so. It takes so much time to get a clinical trial off the ground and the award has given me the salary support for dedicated research time. The grant allowed me to finish writing the study protocol and launch the study and is now helping me manage patient accrual, oversee management of the clinical study, and supervise the laboratory correlative studies. Please talk about the importance of a mentor in career development for a young investigator such as yourself. Having a mentor has been a tremendous help in so many ways. Dr. Brown has given me career advice and perspective on the field of CLL and helped me to recognize what the key issues are and why trials like this one are needed. She helped connect me to the key researchers developing IPI-145, which allowed me to get access to the drug. She has also provided much appreciated advice on the nittygritty details to include in the protocol document and continues to advise me as medical issues arise with patients on the trial. Launching this and other clinical trials would not have been possible without mentorship from Dr. Brown. She has been a phenomenal source of support for me. Has your experience as a mentee encouraged you to become a mentor to young investigators coming up behind you? Yes, it definitely has, and I am already in the early stages of doing that. I have had a couple of residents and fellows who have approached me and continued on page 128

The ASCO Post | OCTOBER 15, 2014

PAGE 128

Professional Development Jennifer R. Brown, MD, PhD continued from page 126

This gets to the issue of the competing demands on the time of junior investigators both in the clinic and in the laboratory. It is very important during late fellowship or early faculty to be able to carve enough time out of the clinic to acquire the academic skills I mentioned earlier and really develop expertise. This is why grants like the Career Development Award are so important. The Conquer Cancer Foundation provides a large number of grants to

Matthew S. Davids, MD, MMSc continued from page 127

I am starting to work with them informally. This is a critical juncture in my career, so I still need to be mentored, but I am gaining experience, perspective, and knowledge that I can share with people coming up, too, so it is a pretty exciting time for me in that respect as well.

‘Mentorship Mosaic’ You are actively involved in the translational research program in CLL at Dana-Farber. Please talk about some of those efforts. This ties into the second aim of my Career Development Award. I am fortunate to have a true “mentorship mosaic.” While Dr. Brown provides outstanding mentorship on the clinical end of my translational research efforts, on the laboratory side I have benefited tremendously from the mentorship of Anthony Letai, MD, PhD, Associate Professor, Department of Medicine at Harvard Medical School and Associate Professor of Medicine, Hematologic

young investigators both as fellows and junior faculty members and that affords them protected time dedicated to research where they can concentrate on a project and develop the skills to succeed in academia. It really is not possible to overestimate the importance of having that protected time to allow young investigators to pursue their research career, especially in the current environment where everyone is busier and busier and time is limited. Also, there are not as many sources of funding as there used to be, so getting that early foot-

hold is really critical for helping people feel comfortable and develop the skills they need to succeed and want to stay in academia. Dr. Davids’ grant in particular involves a clinical trial that arose out of some experiences I had with several patients with CLL. We believe his trial may lead to a potentially transformative treatment for a certain category of CLL, so we are very excited about it. This is also an especially exciting time in CLL because of the potential of new therapies, and we are figuring out how best to combine the drugs with

Neoplasia/Malignancies at Dana-Farber Cancer Institute, with whom I did my postdoctoral laboratory research as a fellow. Dr. Letai is a leading expert in apoptosis biology and I have maintained strong ties to his laboratory since starting on faculty in order to incorporate novel laboratory correlative studies into my clinical trials. Dr. Letai developed an assay in his lab is called BH3 profiling, which evaluates how close malignant cells are to undergoing apoptosis with the goal of using this information to predict who will respond best to chemotherapy. In my fellowship research, I looked at baseline blood samples from a small group of patients with CLL who were starting chemotherapy regimens such as FCR and was able to distinguish responders from nonresponders. With my Career Development Award grant, I will be thoroughly characterizing all the patients in our iFCR study using the BH3 profiling method. I will test their blood at baseline to see if I can predict who will achieve a minimal residual disease–negative complete response. I will also evaluate the

BH3 profile after patients have been on IPI-145 to determine what effects the drug has on the apoptotic state of their CLL cells in vivo.

On the Horizon What progress has been made in CLL in terms of more effective therapies and overcoming treatment resistance? I have been inspired over the last few years by the progress that has been made in CLL, and I am very optimistic about the future. In the past year, three new drugs have been U.S. Food and Drug Administration (FDA) approved for the treatment for CLL, including obinutuzumab (Gazyva), ibrutinib (Imbruvica), and idelalisib (Zydelig). Hopefully, there will be additional approvals in the near future. IPI-145 is one of these promising new therapies that has not yet been FDA approved. Another exciting new drug I have worked with substantially is the Bcl-2 inhibitor ABT199. This drug is particularly interesting to me since it relates directly to the laboratory research on apoptosis I have done with Dr. Letai.

each other or with standard chemotherapies for maximum patient benefit. The study that Dr. Davids is doing is in that category, and we are hoping that the investigational treatment may prove to benefit patients more than is currently possible. n

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

Reference 1. A Phase Ib/II Study of IPI-145 Plus FCR in Previously Untreated, Younger Patients With CLL. ClinicalTrials.gov identifier NCT02158091.

I think the challenge over the next few years will be how to combine these drugs rationally and devise curative strategies for CLL, perhaps initially with chemotherapy and potentially eventually without the need for chemotherapy. For a young clinical investigator in CLL research, this is a very exciting time. I feel very fortunate to be working in this field at this time. I am constantly humbled by my experiences with CLL patients, both the ones who have done well on new agents and have had their lives transformed and those who have not survived. They all inspire me to work harder to devise safer and more effective combination therapies to eventually cure CLL. n

Disclosure: IPI-145 is being developed by Infinity Pharmaceuticals, which is providing study drug and support for the iFCR trial. Dr. Davids reported no potential conflicts of interest.

Reference 1. A Phase Ib/II Study of IPI-145 Plus FCR in Previously Untreated, Younger Patients With CLL. ClinicalTrials.gov identifier NCT02158091.

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ASCOPost.com | OCTOBER 15, 2014

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Announcements

Radiation Oncologist Stephen Hahn, MD, to Join MD Anderson

tephen Hahn, MD, has been named as the Division Head of Radiation Oncology and Chair of the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center. He joins MD Anderson on January 1, 2015. Dr. Hahn comes to MD Anderson from the University of Pennsylvania’s Perelman School of Medicine, where he

ican Society for Radiation Oncology (ASTRO) Fellow.

Education and Experience Dr. Hahn earned his undergraduate degree from Rice University, his MD degree at Temple University in Philadelphia,

and his internship and residency at the University of California, San Francisco Hospitals. He completed a medical oncology fellowship and radiation oncology residency at the National Cancer Institute. In 1996, Dr. Hahn joined the University of Pennsylvania’s faculty in the Ra-

Now Stephen Hahn, MD

has served as the Henry K. Pancoast Professor and Chair, Department of Radiation Oncology, since 2005. He helped establish the University of Pennsylvania as a clinical, academic, and educational leader within the field and successfully recruited and mentored numerous junior faculty who have gone on to national leadership positions. Dr. Hahn established a state-ofthe-art proton therapy center, increased NIH-funded research and clinical trials at the institution, and served in important university leadership roles. “Dr. Hahn’s expertise will further elevate the excellence established through the hard work and dedication of those who have built and grown MD Anderson’s radiation oncology programs,” said Ethan Dmitrovsky, MD, Provost and Executive Vice President at MD Anderson. “We are delighted that he will be leading this vital area. I am also thankful to Bruce Minsky, MD, who has served with distinction as ad interim Division Head and Department Chair during this search.”

diation Oncology Department and was named Professor in 2005. At Penn, Dr. Hahn served as Director of the Photodynamic Therapy Program, and was the Department’s Director of Clinical Services, Director of Clinical Research and Director of Research. n

Enrolling

BLADDER

A Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (UBC) (NCT02108652, Study ID GO29293)

A Phase II study for patients with locally advanced or metastatic UBC who are treatment-naïve and ineligible for cisplatin-based chemotherapy or have failed platinum-containing therapy Primary Endpoint:

N=330

MPDL3280A1 (an engineered anti-PDL1 antibody)

Secondary Endpoints:

• Objective response rate

• Duration of response • Progression-free survival • Overall survival • Safety: incidence of adverse events • Incidence of antitherapeutic antibodies to MPDL3280A • Maximum serum concentration (Cmax) of MPDL3280A

Key Inclusion Criteria 2:

Key Exclusion Criteria 2:

• Documented locally advanced or metastatic • • • • • •

transitional cell carcinoma of the urothelium Representative tumor specimens ECOG performance status of 0-1 Life expectancy ≥12 weeks Measurable disease, as defined by RECIST v1.1 Adequate hematologic and end-organ function Refractory or ineligible for platinum-based chemotherapy

• History of autoimmune disease • Active hepatitis B or hepatitis C • HIV-positive • Administration of a live, attenuated vaccine

within 4 weeks before Cycle 1, Day 1 • Prior treatment with CD137 agonists, or immune

checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1

Clinical Interests Dr. Hahn’s clinical interests and expertise include both lung cancer and sarcoma. His research focuses on the molecular causes of the tumor microenvironment, particularly the study of aberrant signal transduction pathways, and the evaluation of proton therapy as a means to improve the efficiency of radiation therapy. Dr. Hahn’s research has resulted in numerous publications in peer-reviewed journals. This month, Dr. Hahn will join the Board of Directors for the American Society for Radiation Oncology (ASTRO), and he serves as a Trustee for the American Board of Radiology. In 2013, Dr. Hahn was named as an Amer-

For more information 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

The ASCO Post | OCTOBER 15, 2014

PAGE 130

Breast Cancer

Breaking the Silence About Breast Cancer in the Arab World By Ronald Piana

Samia Al-Amoudi, MB, ChB

n 1974, First Lady Betty Ford spoke publicly about her breast cancer diagnosis and treatment. Remarkably, at the time of her action, public discussion of breast cancer in the United States was seen as off limits. Four decades later, cultural barriers to women’s health still exist, particularly in the developing world. Historically in Arabic culture, open discussion of breast cancer has been strictly taboo. In 2006, Samia Al-Amoudi, MB, ChB, was diagnosed with breast cancer in her native country of Saudi Arabia. She bravely chose to break the culture-bound silence and

speak openly about her breast cancer. Dr. Al-Amoudi is currently Chief Executive Officer, founder, and a board member of Sheikh Mohammed Hussein Al-Amoudi Center of Excellence in Breast Cancer. She is also a consulting obstetrician and gynecologist, and the author of several books on obstetrics/ gynecology and breast cancer, including Breast Cancer, Break the Silence (see sidebar), in both Arabic and English. She recently shared her story with The ASCO Post.

Dealing With the Bad News Please tell the readers about your breast cancer diagnosis. One day after having lunch with my children, I was in my bedroom, and by mere chance I touched my breast and felt a lump. Being a physician, I realized that there was a good chance that I had breast cancer. I remember walking around the room in circles praying loudly. I was concerned about breaking the news to my children so I used a bit of a ploy, telling them that a friend of mine in the United States discovered a lump in her breast that was most likely can-

cer, and she didn’t know how to tell her children. My children listened and said that all children would be scared for their mother, but the best way to tell them was by being straightforward. That was the first hurdle in breaking the bad news. Then, in April 2006, a biopsy test confirmed that the lump was malignant. I was diagnosed with HER2-positive stage II breast cancer; it was on my birthday. Now I needed to have a serious conversation with my children.

ficult moments with my children, but the experience gave my love for them new meaning.

Path to Advocacy How did you transition from a breast cancer patient to an advocate for open dialogue about a disease that is not spoken about publicly in the Arab world? First of all, I decided to remain in my country for my treatment instead of going to a cancer center in the United States. Saudi Arabia is a wealthy coun-

If women can’t talk about breast cancer, it prevents them from accessing regular early detection tests to catch the cancer at an early, curable stage. My mission became to break the silence and spread the message about proper breast health in Saudi Arabia’s conservative community. The ultimate goal was to save women’s lives. —Samia Al-Amoudi, MB, ChB

I told them about the biopsy and explained that there are many different types of breast cancer, some of which a woman can survive more than 20 years. Of course, there were many dif-

try, and I trusted the ongoing medical advances there as well as my people. So many people asked how this could happen to me, a doctor. Of course, cancer can happen to anyone,

Book Review: Breast Cancer, Break the Silence

“T

his date has a special place in my heart, as well as the hearts of my children, my family and my loved ones. It was the day when my life—and my priorities—took a whole new direction.” So begins Breast Cancer, Break the Silence, a slim yet powerful and highly revealing booklet by Saudi Arabian physician and breast cancer survivor Samia Al-Amoudi, MB, ChB. The reader enters Breast Cancer, Break the Silence through the emotional universe that all cancer patients share at the time of diagnosis: fear and a recognition that their life has suddenly changed forever. However, the author, being a Muslim woman in Saudi Arabia, writes about a quandary of cultural isolation most Western women cannot fathom. To that end,

Dr. Al-Amoudi bravely turned her breast cancer diagnosis into a liberating campaign for women’s health that she describes in succinct and heartfelt language. Although much of the book—such as chapters titled “Are You Susceptible to Breast Cancer?” and “The Day My Hair Fell Off ”—serves as a spiritual and practical how-to guide for Muslim women diagnosed with breast cancer, there are chapters that deal with cultural barriers to care that are generalizable through many areas of the developing world, the most telling of which is titled “Letting Men Know.”

Access-to-Care Issues Dr. Al-Amoudi writes, “Because breast cancer has to do with an intimate part of the woman’s body, and

because we are a society that thinks that women’s issues can only be dealt with in total silence, awareness about this killer disease becomes that much more sensitive.” That is why her ongoing campaign concerns empowering women by educating them about their right to consent regarding their own health care. This book offers a sobering example of access-to-care issues faced by women in much of the developing world. For instance, in Saudi Arabia, women must get permission from their husbands before having a medical test or treatment. Hospital appointments are completely dependent on men as well, since women are forbidden from driving. In “Letting Men Know,” the book’s most powerful chapter, Dr. Al-Amoudi tack-

les this cultural barrier to women’s health care head-on, but with a voice that encourages dialogue instead of more silence. In a chapter toward the end of the book, Dr. Al-Amoudi salutes the brave women who preceded her in bringing breast cancer out of the closet. Naturally, Betty Ford is among those pioneers. In 2006, Dr. Al-Amoudi joined that group of courageous women. This is a powerful and instructive book for its intended audience, especially young Arab girls and those who care about them. n Breast Cancer, Break the Silence, by Samia Al-Amoudi, MB, ChB, is available online at http://www.wardymag-en. net/books/break-the-silence/.

ASCOPost.com | OCTOBER 15, 2014

but the message I took away from my diagnosis was that early detection in cancer is so important. In my country, 73% of women diagnosed with breast cancer have advanced-stage disease, and even more worrisome, 30% of those women are younger than 40 years old. The main problem that women confront in the Arab culture, however, is the taboo about discussing medical issues that involve an intimate female body part. So, if women can’t talk about breast cancer, it prevents them from accessing regular early detection tests

to catch the cancer at an early, curable stage. My mission became to break the silence and spread the message about proper breast health in Saudi Arabia’s conservative community. The ultimate goal was to save women’s lives. How did you approach this mission? First, I wrote my story in the local newspaper, Al-Madina. Someone remarked to me that being a well-known physician, publicizing my story was like committing self-defamation. I told him that his remark was the exact kind of at-

PAGE 131

titude that I felt compelled to challenge. That experience inspired me to establish the Sheikh Mohammed Hussein Al-Amoudi Center of Excellence in Breast Cancer within the King Abdulaziz University. Since then, I continued my advocacy for openness in women’s health issues, and people are now talking about subjects that were once forbidden in Saudi Arabia.

Award and Recognition In 2007, then Secretary of State Condaleeza Rice presented you with the In-

ternational Women of Courage Award. You were the first Arab woman to receive it. What did that mean to you? Of course I was honored by the award and the recognition. But my ultimate mission is to help empower women about their health. My focus now is on breast cancer patients’ rights in prevention and treatment. Most important, I will continue to break the silence and taboos that for too long have been a barrier to women’s health. n Disclosure: Dr. Al-Amoudi reported no potential conflicts of interest.

Effective Prevention Measures Urgently Needed to Prevent Global Cancer Crisis

arlier this year the International Agency for Research on Cancer (IARC), an agency of the World Health Organization, launched a World Cancer Report 2014. The report, a collaboration of over 250 leading scientists from more than 40 countries, described multiple aspects of cancer research and control. Based on the latest statistics on trends in cancer incidence and mortality worldwide, this book reveals how the cancer burden is growing at an alarm-

IARC and co-editor of the book. “More commitment to prevention and early detection is desperately needed in order to complement improved treatments and address the alarming rise in cancer burden globally.”

Increasing Global Burden of Cancer In 2012, the worldwide burden of cancer rose to an estimated 14 million new cases per year, a figure expected to

More commitment to prevention and early detection is desperately needed in order to complement improved treatments and address the alarming rise in cancer burden globally. —Christopher Wild, MD

ing pace and emphasizes the need for urgent implementation of efficient prevention strategies to curb the disease. “Despite exciting advances, this Report shows that we cannot treat our way out of the cancer problem,” states Christopher Wild, MD, Director of

rise to 22 million annually within the next two decades. Over the same period, cancer deaths are predicted to rise from an estimated 8.2 million annually to 13 million per year. Globally, in 2012 the most common cancers diagnosed were those of the lung (1.8 million cas-

es, 13.0% of the total), breast (1.7 million, 11.9%), and large bowel (1.4 million, 9.7%). The most common causes of cancer death were cancers of the lung (1.6 million, 19.4% of the total), liver (0.8 million, 9.1%), and stomach (0.7 million, 8.8%).

The Cancer Divide As a consequence of growing and ageing populations, developing countries are disproportionately affected by the increasing numbers of cancers. More than 60% of the world’s total cases occur in Africa, Asia, and Central and South America, and these regions account for about 70% of the world’s cancer deaths, a situation that is made worse by the lack of early detection and access to treatment.

Avoidable Deaths Access to effective and affordable cancer treatments in developing countries, including for childhood cancers, would significantly reduce mortality, even in settings where health-care services are less well developed. However, the spiralling costs of the cancer burden are damaging the economies of even the richest countries and

are way beyond the reach of developing countries, as well as placing impossible strains on health-care systems. In 2010, the total annual economic cost of cancer was estimated to reach approximately US$1.16 trillion. Yet about one-half of all cancers could be avoided if current knowledge was adequately implemented. “The rise of cancer worldwide is a major obstacle to human development and well-being. These new figures and projections send a strong signal that immediate action is needed to confront this human disaster, which touches every community worldwide, without exception,” said Dr Wild.

Vaccination Campaigns and Health Promotion Many developing countries continue to be disproportionately affected by the double burden of high infection-related cancers (including those of the cervix, liver, and stomach) and the rising incidence of cancers (such as those of the lung, breast, and large bowel) associated with industrialized lifestyles. For more information, visit http:// www.iarc.fr/en/publications/books/ wcr/index.php n

Visit The ASCO Post website at ASCOPost.com

NEW PHASE 3 DATA

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

Significantly improved overall survival (OS)—secondary endpoint • 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA® arm (HR=0.43; 95% CI: 0.24, 0.79) • Median OS not yet reached in either treatment arm • 29% of ofatumumab patients crossed over to receive IMBRUVICA® upon progression

Significantly extended progression-free survival (PFS)—primary endpoint 78% statistically significant reduction in the risk of death or progression (independent review) 100

PFS (%)

80 60 40 Hazard ratio (HR) for progression or death: 0.22 (95% CI: 0.15, 0.32) P<0.0001 by log-rank test

20 0

183 161

116 83

Number at risk IMBRUVICA® 195 Ofatumumab 196

Months

Ofatumumab 9

38 15

7 1

0 0

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

Significantly improved PFS in patients with previously treated del 17p CLL • 75% reduced risk of progression or death (HR=0.25; 95% CI: 0.14, 0.45) — Median PFS not reached with IMBRUVICA® vs 5.8 months with ofatumumab

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

ORAL, ONCE-DAILY DOSING

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®. The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving anti-platelet or anti-coagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred with IMBRUVICA®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly. Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly. Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification. Second Primary Malignancies - Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in

patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%). Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. ADVERSE REACTIONS The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® discontinued treatment due to adverse events. These included infections, subdural hematomas, and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose. CYP3A Inducers - Avoid co-administration with strong CYP3A inducers. SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with baseline hepatic impairment. Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit us at

www.IMBRUVICA.com

Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICA® (ibrutinib) capsules

INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Improvements in survival or disease-related symptoms have not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in full Prescribing Information]. Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in full Prescribing Information]. Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Twenty-five percent of patients with MCL and 26% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly. Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in full Prescribing Information]. Second Primary Malignancies: Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%). Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Cytopenias [see Warnings and Precautions] • Atrial Fibrillation [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) System Organ Class Gastrointestinal disorders

Infections and infestations

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis

All Grades (%) 51 31 25 24 23 17 11

Grade 3 or 4 (%) 5 0 0 5 0 1 0

34 14 14 14 13

0 3 7 5 1

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) (continued) System Organ Class

Preferred Term

General disorders and administrative site conditions

Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

All Grades (%)

Grade 3 or 4 (%)

41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

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

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. Approximately five percent of patients receiving IMBRUVICA in Study 1 and 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions

Skin and subcutaneous tissue disorders Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders

Preferred Term Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection Fatigue Pyrexia Peripheral edema Asthenia Chills Bruising Rash Petechiae Cough Oropharyngeal pain Dyspnea Musculoskeletal pain Arthralgia Muscle spasms Dizziness Headache Peripheral neuropathy Decreased appetite

Metabolism and nutrition disorders Neoplasms benign, malignant, Second malignancies* unspecified Injury, poisoning and Laceration procedural complications Psychiatric disorders Anxiety Insomnia Vascular disorders Hypertension *One patient death due to histiocytic sarcoma.

All Grades (%) 63 23 21 21 19 15 13

Grade 3 or 4 (%) 4 2 2 0 2 0 0

48 21 17 10 10 31 25 23 13 13 54 27 17 19 15 10 27 23 19 21 19 10 17

2 6 6 8 0 4 2 0 4 0 2 0 0 0 0 0 6 0 2 0 2 0 2

10*

10 10 17

0 0 8

IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) 71 10 54 27 44 0

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2. Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Vomiting General disorders and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue disorders Rash* Petechiae Bruising* Musculoskeletal and connective tissue disorders Musculoskeletal Pain* Arthralgia Nervous system disorders Headache Dizziness Injury, poisoning and procedural complications Contusion Eye disorders Vision blurred

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%)

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%)

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

28 17

2 1

18 7

1 0

14 11

1 0

6 5

0 0

Subjects with multiple events for a given ADR term are counted once only for each ADR term. The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%) 51 23 52 5 36 0

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%) 57 26 45 10 21 0

* Based on laboratory measurements per IWCLL criteria DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in full Prescribing Information]. Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions]. • Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. • Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration. Active ingredient made in China. Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics, Inc. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 PRC-00526 07/14

The ASCO Post | OCTOBER 15, 2014

PAGE 136

Advocacy in Oncology Now in Its 71st Year, CancerCare Looks to Expand Services to Patients and Caregivers A Conversation With Patricia J. Goldsmith By Jo Cavallo Recently, The ASCO Post spoke with Ms. Goldsmith about her goals for CancerCare, the public’s greatest misperception about the organization, and meeting increasing demand for services.

Four Key Initiatives

Patricia J. Goldsmith

leven days before Patricia J. Goldsmith, joined CancerCare as its CEO last May, she received the unexpected news that she had early-stage colorectal cancer. While the diagnosis was shocking, Ms. Goldsmith said it gave her a unique perspective on what it means to have this serious disease and a greater understanding of the emotional and financial impact cancer has on the more than 170,000 people nationwide who turn to CancerCare each year for support. “Getting my cancer diagnosis made the work we do at CancerCare very personal,” said Ms. Goldsmith. “Having cancer changed everything, including my outlook on what is important in life. I think getting the diagnosis just before starting my new position was meant to be, because it gave me an even greater appreciation of the important services the organization provides to people affected by this disease.” Founded in 1944, CancerCare is the nation’s leading nonprofit organization providing free support services and information to help people manage the emotional, practical, and financial challenges of having cancer. Its services include counseling and support groups by phone, online, and in person; publications; educational workshops; and financial and copayment assistance. All CancerCare services are provided by professional oncology social workers. Each year, CancerCare distributes more than $23 million in financial and copayment assistance to people in need. (See, “CancerCare’s Programs for Cancer Survivors and Caregivers,” on page 53.) Prior to joining CancerCare, Ms. Goldsmith was Executive Vice President and Chief Operating Officer at the National Comprehensive Cancer Network.

Please talk about your vision and goals for CancerCare over the coming decade. My overarching vision is to help the organization further expand its mission to provide support to anyone who has experienced a cancer diagnosis or been touched by cancer in some way. To accomplish that goal, we are focusing on four key initiatives, all of which have equal priority, but will take different amounts of time, effort, and resources to execute. One initiative is in the area of public policy. We have an obligation to be the voice of patients with cancer and caregivers and to educate various stakeholders, including elected officials and health-care policymakers, about the challenges and struggles patients and their caregivers face. We are in the process of defining that agenda now. Another initiative is to build a comprehensive database system that will be the repository of the vast amount of information we collect on patients and their caregivers over a long continuum. The first point of contact for individuals seeking support is our oncology social workers, and often they interact with those patients and caregivers several times for counseling, financial assistance, or some of the many other services we offer. As a result, we have important data regarding the major challenges patients and caregivers are coping with, but the information currently resides in several disparate databases. Having all the information in one system will give us a very broad depth of data and information on individuals’ experiences with cancer and their specific needs and allow us to provide an even more personalized experience to those using our services, as well as to help improve their quality of life. A third initiative is to raise awareness on a nationwide basis of the services CancerCare provides with a new branding strategy so people immediately connect our name to our mission. Because we are headquartered in New

York, some people think we only serve the Greater New York area. Last year, however, we served 170,000 individuals in 92% of U.S. counties with counseling, educational workshops and publications, and financial resources. In addition, we had 1.5 million visits to our website. All of this speaks to the number of people turning to us for assistance, as well as to how many people need help during their journey with cancer. Our fourth initiative is to work with major corporations and insurers to develop a tailored and personalized support product for employees/members and their loved ones diagnosed with cancer. This will include education on becoming an engaged patient to help

tell our story on a national level. It is essential that we raise the funds needed to expand our capacity. We are very proud of the fact that we served 170,000 people last year, but when the word gets out about our services, we could be asked to assist 1,170,000 people given the breadth of programs that we provide. Right now, it would be impossible to meet that demand. The Internet has been a major avenue for reaching more people. As I mentioned, last year we had 1.5 million visits to our website, and many of our services are provided via the Internet or WebEx videoconferencing. For example, we provide 70 Connect Education Workshops through the Internet or by

Having cancer changed everything, including my outlook on what is important in life. I think getting the diagnosis just before starting my new position was meant to be, because it gave me an even greater appreciation of the important services the organization provides to people affected by this disease. —Patricia J. Goldsmith

ensure access to the best care for each individual. Of course, to accomplish all these goals we need increased funding, and we are pursuing a variety of new strategies to raise revenue for our programs.

Keeping Pace Over the next 15 years, the number of Americans diagnosed with cancer will increase by 45% and the number of cancer survivors will rise to over 18 million. How will the services CancerCare provides keep pace with the increasing numbers of cancer survivors? The initiatives I talked about earlier are meant to help us expand our mission to help more people and to become the go-to organization for anyone who has experienced a cancer diagnosis. But our capacity cannot currently accommodate that demand. We recently added four oncology social workers to our staff, which will help with the shortterm increase in the number of clients we can serve. We believe the way to meet a significant growth in demand, however, is to

telephone that feature leading experts in oncology discussing the latest treatments and advances in cancer care. Through those workshops, we reached as many as 43,000 people last year alone. We also have both in-person and online support groups led by oncology social workers. In addition, we distribute 800,000 educational booklets and fact sheets written by oncology experts on a wide range of cancer-related topics from disease-specific information to how the Affordable Care Act is impacting patients with cancer. Those publications are available online or can be mailed directly to clients and providers. And, again, all of our services are free. We are in a moment of transformation as an organization moving from what we currently are to what we will be in the future. Our ultimate aim is to be the most active support and advocacy organization in health care providing the highest-quality services to improve the lives of those affected by cancer. n Disclosure: Ms. Goldsmith reported no potential conflicts of interest.

ASCOPost.com | OCTOBER 15, 2014

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Announcements

ASCO Calls for New Action to Address Obesity and Cancer

SCO has called for increased education, research, and advocacy to reduce the toll of obesity, both as a leading cause of cancer and a complication in the care of patients with cancer. The Society’s recommendations outline four critical priorities, including increased education and awareness about links between obesity and cancer, development of new physician tools and resources, intensified and highly coordinated research, and policy changes to increase access to obesity screening, diagnosis, and treatment. The statement

need to play a lead role in reducing obesity’s impact, both in the care of our patients and as advocates for broader action. We can’t allow obesity to undo decades of progress in prevention, early diagnosis and treatment of cancer.”

Obesity Management in People With Cancer To ensure that oncologists are better equipped to integrate obesity prevention and management into the care of their patients, and that patients have access to needed services, ASCO’s policy

Cancer doctors need to play a lead role in reducing obesity’s impact, both in the care of our patients and as advocates for broader action. We can’t allow obesity to undo decades of progress in prevention, early diagnosis and treatment of cancer. —Clifford A. Hudis, MD, FACP

was published online in the Journal of Clinical Oncology.1

Policy Statement on Obesity and Cancer a First In releasing its first-ever policy statement on cancer and obesity, ASCO underscores that obesity is becoming a central challenge in cancer prevention and care, and is projected to soon overtake tobacco as the leading preventable cause of cancer in the United States. By 2030, almost a half million Americans may be diagnosed with obesity-related cancers annually. Among people with cancer, obesity can increase the risk of cancer recurrence and lower survival. In fact, one study suggests that being overweight or obese contributes to as many as one in five cancer-related deaths.2 “With nearly three in four Americans obese or overweight, obesity has become a tremendous public health challenge that also impacts cancer care and prevention today,” said ASCO Immediate Past President Clifford A. Hudis, MD, FACP. “Cancer doctors

statement calls for: • Practical guidance and tools for physicians and patients—As the leading organization representing cancer physicians, ASCO is working to provide its members and other oncology providers with weight management guidelines for cancer survivors, tools for initiating conversations about weight loss with patients, and resources to help patients manage their weight. Earlier this year, ASCO issued a guide for oncology providers to support conversations with patients about the effects of obesity on cancer risk and cancer-related mortality, along with a companion guide for patients. • Increased access to weight management services—The ASCO statement highlights the need to close major gaps in private and public insurance coverage of weight management services, in general, and among people with cancer, in particular. ASCO calls on the Centers for Medicare and Medicaid Services (CMS) to

add obesity to the list of chronic diseases eligible for the proposed Complex Chronic Care Management Services payments, and encourages the Department of Health and Human Services to clearly define access to obesity treatment services in the new state health-care exchange plans under the Affordable Care Act.

Prevention of Obesity-Related Cancers The statement also includes recommendations to help increase awareness of the obesity-cancer connection and advance policies and collaborations needed to prevent obesity-related cancers. These include: • Increased public education—ASCO aims to partner with other organizations in the cancer community and beyond, fostering greater public awareness about the role of a healthy lifestyle in cancer prevention and building on a wide range of ASCO resources offered for patients with cancer at www.cancer.net/obesity. • Support for healthy community and workplace environments—ASCO will work with other stakeholders to advance necessary policies at the national level, while calling on oncology care providers to help improve health in their communities by serving as role models and advocates for local change. • Policies to improve access to obesity screening, diagnosis, and treatment services—ASCO will advocate for improved coverage of recommended treatments for obesity among public and private payers, and for increased availability of services at the community level.

A Robust Research Agenda While research has documented links between obesity and cancer, many critical areas of research are needed to translate current knowledge into effective treatment and prevention strategies. ASCO’s policy statement calls for the development of a comprehensive, coordinated research agenda to address key questions, including: • Can weight loss actually reduce the

risk of developing or dying from cancer? • Should obesity be treated differently in cancer survivors, vs people at risk for cancer? • How and when should weight management interventions be initiated with cancer patients?

Proven Relationship Between Cancer and Obesity “Research has clearly established that there is a critical relationship between cancer and obesity, but more work is needed to determine whether weight loss, increased physical activity, and improved dietary quality can lower cancer rates and improve outcomes,” said ASCO Energy Balance Working Group Chair Jennifer A. Ligibel, MD, who also serves on ASCO’s Cancer Survivorship and Cancer Prevention Committees. “No single organization or medical specialty can address obesity alone, and we will col-

Jennifer A. Ligibel, MD

laborate with other groups to find evidence-based solutions for our patients.” ASCO will host a research summit on obesity and cancer later this year, bringing together researchers from multiple disciplines to identify specific research priorities and approaches related to obesity and cancer. ASCO will also continue to advocate for sustained funding to support critical research in this area. Watch future issues of The ASCO Post for more in depth coverage of the new ASCO Recommendations on Obesity and Cancer. n Reference 1. ASCO Policy Statement on Obesity and Cancer: J Clin Oncol. September 1, 2014 (early release online).

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | OCTOBER 15, 2014

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ASTRO Annual Meeting Choosing Wisely® Campaign Identifies Five Radiation Treatments Not for Routine Use By Alice Goodman

he American Society for Radiation Oncology (ASTRO) reported a second list of five radiation oncology treatments that should not be used routinely in clinical practice on day 1 of the Society’s 56th Annual Meeting.1 These five treatments should be discussed in depth with patients prior to being pre-

of ASTRO’s lists provide evidencebased recommendations that will foster detailed patient-physician conversations so that patients receive appropriate, high-quality radiation oncology care,” said Colleen A.F. Lawton, MD, Chair of ASTRO’s Board of Directors. Dr. Lawton is Vice-Chair of the De-

Both of ASTRO’s lists provide evidence-based recommendations that will foster detailed patientphysician conversations so that patients receive appropriate, highquality radiation oncology care. —Colleen A.F. Lawton, MD

We believe the Choosing Wisely campaign will have an impact on reserving resources for when they are appropriate. This is so important because of the current cost of health care. —Bruce Haffty, MD

scribed. The new list follows on the heels of the first list of five radiation treatments to question, released in 2013. The newly identified treatments considered not for routine use are part of the Choosing Wisely® initiative of the American Board of Internal Medicine (ABIM), which is aimed at having medical specialties implement appropriate, high-quality care, thereby using resources more wisely and reducing costs of care.

Procedures to Consider Prudently “We are proud to continue our commitment to this campaign and to release our second list of five radiation oncology treatments that we recommend physicians and patients discuss in more detail prior to treatment. Both

partment of Radiation Oncology at the Medical College of Wisconsin in Milwaukee. ASTRO noted that there are situations where all 10 items on the two lists are advisable, and that the lists are not meant to exclude use of these procedures. Rather the goal of the recommendations is to encourage careful consideration of patient and disease characteristics and use the identified treatments only when they are truly appropriate and will improve patient outcomes.

2014 Choosing Wisely Recommendations • Don’t recommend radiation following hysterectomy for cancer patients with low-risk disease. • Don’t routinely offer radiation therapy for patients who have nonresected

non–small cell lung cancer (NSCLC), negative margins, N0-1 disease. • Don’t initiate noncurative radiation therapy without defining the goals of treatment with the patient and considering palliative care. • Don’t routinely recommend followup mammograms more often than annually for women who have had radiotherapy following breast-conserving surgery. • Don’t routinely add adjuvant wholebrain radiation to stereotactic radiosurgery for limited brain metastases. ASTRO’s Choosing Wisely® list was based on a thorough review of current evidence on management and treatment options by a work group consisting of experts in health policy, government relations, and clinical affairs and quality. Nine potential items were identified, and ASTRO’s membership was surveyed to rate the value and relevance of these items. The survey included an option for members to provide comments on these items. ASTRO’s Board of Directors selected the final five items using the survey results. The text for the final recommendations includes selected references for each topic. ASTRO President for 2014, Bruce Haffty, MD, said that the first list of tests released in 2013 has already had an impact. “We believe the Choosing Wisely campaign will have an impact on reserving resources for when they are appropriate. This is so important because of the current cost of health care,” he said at ASTRO’s Annual

Meeting. Dr. Haffty is Chairman of Radiation Oncology at the Cancer Institute of New Jersey at Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey.

2013 Choosing Wisely Recommendations • Don’t initiate whole-breast radiotherapy as a part of breast conservation therapy in women age ≥ 50 years with early-stage invasive breast cancer without considering shorter treatment schedules. • Don’t initiate management of lowrisk prostate cancer without discussing active surveillance. • Don’t routinely use extended fractionation schemes (> 10 fractions) for palliation of bone metastases. • Don’t routinely recommend proton beam therapy for prostate cancer outside of a prospective clinical trial or registry. • Don’t routinely use intensity-modulated radiotherapy (IMRT) to deliver whole breast radiotherapy as part of breast-conservation therapy. For more information, visit choosingwisely.org. n Disclosure: Drs. Lawton and Haffty reported no potential conflicts of interest.

Reference 1. Innovative payment models and the future of radiation oncology: Impact on quality, payment reform, and patient care. 2014 ASTRO Annual Meeting. Presented Sunday September 14, 2014.

Choosing Wisely® ■ ASTRO is continuing its participation in the ABIM’s Choosing Wisely® Campaign announcing a second list of recommendations on radiation treatments that should not be prescribed routinely. ■ These recommendations were made after thorough review of current evidence on management and treatment options by a work group consisting of experts in health policy, government relations, and clinical affairs and quality. ■ The goal of the recommendations is not to exclude the identified treatments but instead to encourage careful consideration of patient and disease characteristics and use these treatments only when they are truly appropriate and will improve patient outcomes.

VOTRIENT is indicated for the treatment of advanced renal cell carcinoma (RCC)1

EFFICACY AGAINST PROGRESSION

VOTRIENT demonstrated an overall median progression-free survival (PFS) of

9.2 months vs 4.2 months with placebo (HR 0.46; 95% CI 0.34-0.62; P<0.001)1*

*Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of VOTRIENT in first-line or cytokine-pretreated patients (N=435) with advanced RCC of clear cell or predominantly clear cell histology. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

Please see additional Important Safety Information for VOTRIENT on subsequent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

EFFICACY LIGHTS THE WAY

®® 1 1 VOTRIENT VOTRIENT (pazopanib) (pazopanib)isisindicated indicatedfor forthe thetreatment treatmentofofpatients patientswith withadvanced advancedrenal renalcell cellcarcinoma carcinoma(RCC). (RCC).

VOTRIENT: Significant PFS improvement in patients with advanced RCC1 Median PFS in patients with advanced RCC receiving VOTRIENT vs placebo1,2

1010

VOTRIENT VOTRIENT Placebo Placebo

11.1 11.1

1212

MONTHS MONTHS

9.2 9.2

MONTHS MONTHS

7.4 7.4

Months Months

8 8 6 6 4 4

MONTHS MONTHS

4.2 4.2

2.8 2.8

MONTHS MONTHS

4.2 4.2

MONTHS MONTHS

2 2 0 0

HRHR 0.46; 0.46; 95% 95% CICI 0.34-0.62 0.34-0.62 (P<0.001) (P<0.001) AllAll patients patients

HRHR 0.40; 0.40; 95% 95% CICI 0.27-0.60 0.27-0.60 (P<0.001) (P<0.001) First-line First-line patients patients

HRHR 0.54; 0.54; 95% 95% CICI 0.35-0.84 0.35-0.84 (P<0.001) (P<0.001) Cytokine-pretreated Cytokine-pretreated patients patients

Randomized, Randomized, double-blind, double-blind, placebo-controlled, placebo-controlled, multicenter multicenter study study to evaluate to evaluate thethe effieffi cacy cacy andand safety safety of VOTRIENT of VOTRIENT in patients in patients (N=435) (N=435) with with advanced advanced RCC. RCC. Patients Patients with with locally locally advanced advanced or metastatic or metastatic RCC RCC of clear of clear cellcell or predominantly or predominantly clear clear cellcell histology histology were were randomized randomized (2:1) (2:1) to receive to receive either either VOTRIENT VOTRIENT 800800 mgmg (n=290) (n=290) once once daily daily or placebo or placebo (n=145). (n=145). TheThe study study included included 1 1 first-line first-line patients patients receiving receiving VOTRIENT VOTRIENT (n=155) (n=155) or placebo or placebo (n=78) (n=78) as well as well as cytokine-pretreated as cytokine-pretreated patients patients receiving receiving VOTRIENT VOTRIENT (n=135) (n=135) or placebo or placebo (n=67). (n=67).

Important Safety Information for VOTRIENT (cont’d) • ardia s n tion: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • e orr agi ents: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • rterial Thromboembolic Events: Arterial thromboembolic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months. • eno s T ro oe oli ents: Venous thromboembolic events (VTEs) have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT and

in 1% of patients treated with placebo. Monitor for signs and symptoms. • T ro oti i roangio at : Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. • astrointestinal Per oration and ist la: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • e ersi le Posterior e oen e alo at ndro e P : RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • ertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension.

ealing: VOTRIENT may impair wound • • o ondndealing: VOTRIENT may impair wound healing. Interruption therapy is recommended healing. Interruption of of therapy is recommended in in patients undergoing surgical procedures; treatment with patients undergoing surgical procedures; treatment with VOTRIENT should stopped least 7 days prior VOTRIENT should bebe stopped at at least 7 days prior to to scheduled surgery. VOTRIENT should discontinued scheduled surgery. VOTRIENT should bebe discontinued in in patients with wound dehiscence. patients with wound dehiscence. roidis: Hypothyroidism : Hypothyroidism was reported • • otot roidis was reported in in (19/290) patients treated with VOTRIENT 7%7% (19/290) of of patients treated with VOTRIENT in in randomized RCC in no patients receiving thethe randomized RCC trialtrial andand in no patients receiving placebo. Monitoring thyroid function tests placebo. Monitoring of of thyroid function tests is is recommended. recommended. • Proteinria:ria: In the randomized RCC trial, proteinuria • Protein In the randomized RCC trial, proteinuria reported adverse reaction in 9% (27/290) waswas reported as as anan adverse reaction in 9% (27/290) of of patients receiving VOTRIENT, leading discontinuation patients receiving VOTRIENT, leading to to discontinuation of treatment 2 patients. There were reports of treatment in 2inpatients. There were nono reports of of proteinuria in patients receiving placebo. Monitor urine proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment 24-hour urine protein protein. Interrupt treatment forfor 24-hour urine protein grams discontinue repeat episodes despite ≥3≥3 grams andand discontinue forfor repeat episodes despite dose reductions. dose reductions. tion: Serious infections (with without • •n en etion: Serious infections (with or or without neutropenia), some with fatal outcomes, have been neutropenia), some with fatal outcomes, have been reported. Monitor signs symptoms treat reported. Monitor forfor signs andand symptoms andand treat active infection promptly. Consider interruption active infection promptly. Consider interruption or or discontinuation VOTRIENT. discontinuation of of VOTRIENT. reased t erananer er • •n nreased ToToi iti it it it t er T Teraera : : VOTRIENT is not indicated forfor useuse in combination with VOTRIENT is not indicated in combination with other agents. Increased toxicity andand mortality have other agents. Increased toxicity mortality have been observed in clinical trials administering VOTRIENT been observed in clinical trials administering VOTRIENT in combination with lapatinib or or with pemetrexed. in combination with lapatinib with pemetrexed. TheThe fatal toxicities observed included pulmonary fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, andand sudden hemorrhage, gastrointestinal hemorrhage, sudden death. A safe andand effective combination dose hashas notnot death. A safe effective combination dose been established with these regimens. been established with these regimens. • •n n reased ToToi iti itin ine eeloeloingingrgans: TheThe safety reased rgans: safety andand effectiveness of VOTRIENT in pediatric patients have effectiveness of VOTRIENT in pediatric patients have notnot been established. VOTRIENT is not indicated forfor useuse been established. VOTRIENT is not indicated in pediatric patients. Animal studies have demonstrated in pediatric patients. Animal studies have demonstrated pazopanib cancan severely affect organ growth andand maturation pazopanib severely affect organ growth maturation during early post-natal development, andand resulted in in during early post-natal development, resulted toxicity to the lungs, liver, heart, andand kidney andand in death. toxicity to the lungs, liver, heart, kidney in death. VOTRIENT may potentially cause serious adverse effects VOTRIENT may potentially cause serious adverse effects

1 1 Once-daily Once-dailyoral oraldosing dosing

• The • The recommended recommended starting starting dose dose of of VOTRIENT VOTRIENT is 800 is 800 mgmg once once daily daily without without food food (at(at least least 1 hour 1 hour before before or or 2 hours 2 hours after after a meal). a meal). Daily Daily dose dose should should notnot exceed exceed 800 800 mgmg • Do notnot crush tablets duedue to to thethe potential forfor increased raterate of of absorption, which may • Do crush tablets potential increased absorption, which may affect systemic exposure affect systemic exposure • If•aIfdose is missed, it should notnot bebe taken if itifisit less than 1212 hours until thethe next dose a dose is missed, it should taken is less than hours until next dose • In• advanced RCC, initial dose reduction should bebe 400 mg,mg, andand additional dose In advanced RCC, initial dose reduction should 400 additional dose decrease or or increase should bebe in 200-mg steps based onon individual tolerability decrease increase should in 200-mg steps based individual tolerability • In• the Phase 3 advanced RCC trial, 42% of of patients onon VOTRIENT required a dose In the Phase 3 advanced RCC trial, 42% patients VOTRIENT required a dose interruption; 36% of of patients onon VOTRIENT were dose reduced interruption; 36% patients VOTRIENT were dose reduced • No dose adjustment is required in patients with mild hepatic impairment • No dose adjustment is required in patients with mild hepatic impairment • In• patients with moderate hepatic impairment, alternatives to to VOTRIENT should bebe In patients with moderate hepatic impairment, alternatives VOTRIENT should considered. If VOTRIENT is used in patients with moderate hepatic impairment, thethe considered. If VOTRIENT is used in patients with moderate hepatic impairment, dose should bebe reduced to to 200 mgmg perper dayday dose should reduced 200 • Treatment with VOTRIENT is not recommended in patients with severe hepatic • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment impairment • Monitor serum liver tests before initiation of of treatment andand at at Weeks 3, 3, 5, 5, 7, and 9. 9. • Monitor serum liver tests before initiation treatment Weeks 7, and Thereafter, monitor at at Month 3 and at at Month 4, 4, andand as as clinically indicated. Periodic Thereafter, monitor Month 3 and Month clinically indicated. Periodic monitoring should then continue after Month 4 4 monitoring should then continue after Month • For additional information onon dosing modifi cations based onon drug • For additional information dosing modifi cations based drug interactions, please seesee Sections 2.22.2 and 7 of accompanying Brief interactions, please Sections and 7 of accompanying Brief Summary of of Prescribing Information Summary Prescribing Information

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

® ® Pazopanib Pazopanib(VOTRIENT (VOTRIENT ) has ) hasa aCategory Category1 1recommendation recommendationasasa afirst-line first-linetherapy therapyininthe theNCCN NCCNClinical ClinicalPractice Practice ® ® Guidelines GuidelinesininOncology Oncology(NCCN (NCCNGuidelines Guidelines) for ) forrelapsed relapsedororStage StageIVIVunresectable unresectableRCC RCCofofpredominant predominantclear clear 3 3 ® ® ® ® cell cellhistology. histology.NCCN NCCNGuidelines Guidelinesalso alsoinclude includetherapies therapiesother otherthan thanpazopanib pazopanib(VOTRIENT (VOTRIENT) as ) asfirst-line first-linetreatment treatmentoptions. options.

Important ImportantSafety SafetyInformation Informationfor forVOTRIENT VOTRIENT(cont’d) (cont’d) onon organ organ development development in pediatric in pediatric patients, patients, particularly particularly in in patients patients younger younger than than 2 years 2 years of age. of age. • Pregnan • Pregnan ategor ategor : VOTRIENT : VOTRIENT cancan cause cause fetal fetal harm harm when when administered administered to to a pregnant a pregnant woman. woman. Women Women of of childbearing childbearing potential potential should should bebe advised advised of of thethe potential potential hazard hazard to to thethe fetus fetus andand to to avoid avoid becoming becoming pregnant pregnant while while taking taking VOTRIENT. VOTRIENT. • •iarr iarrea:ea: Diarrhea Diarrhea occurred occurred frequently frequently andand was was predominantly predominantly mild mild to to moderate moderate in severity. in severity. Patients Patients should should bebe advised advised how how to to manage manage mild mild diarrhea diarrhea andand to to notify notify their their healthcare healthcare provider provider if moderate if moderate to to severe severe diarrhea diarrhea occurs occurs so so appropriate appropriate management management cancan bebe implemented implemented to to minimize minimize its its impact. impact. • •i ase i asele leations: ations: In aInsingle-arm a single-arm RCC RCC trial, trial, increases increases in lipase in lipase values values were were observed observed forfor 27% 27% (48/181) (48/181) of of patients. patients. In the In the RCC RCC trials trials of of VOTRIENT, VOTRIENT, clinical clinical pancreatitis pancreatitis was was observed observed in <1% in <1% (4/586) (4/586) of of patients. patients. • Pne • Pne ototoraora: Two : Two of of 290 290 patients patients treated treated with with VOTRIENT VOTRIENT andand nono patients patients onon thethe placebo placebo armarm in the in the randomized randomized RCC RCC trialtrial developed developed a pneumothorax. a pneumothorax. • Bradycardia: • Bradycardia: In the In the randomized randomized trialtrial of of VOTRIENT VOTRIENT forfor thethe treatment treatment of of RCC, RCC, bradycardia bradycardia based based onon vital vital signs signs (<60 (<60 beats beats perper minute) minute) was was observed observed in 19% in 19% (52/280) (52/280) of of patients patients treated treated with with VOTRIENT VOTRIENT andand in 11% in 11% (16/144) (16/144) of of patients patients onon thethe placebo placebo arm. arm. • •r gr gntera tions: Coadministration with strong ntera tions: Coadministration with strong CYP3A4 Inhibitors (eg,(eg, ketoconazole, ritonavir, CYP3A4 Inhibitors ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib andand clarithromycin) increases concentrations of pazopanib

should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH (eg, esomeprazole) due to the potential to decrease concentrations of pazopanib. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours.

• d erse ea tions in t e ando i ed Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. The most common adverse reactions (≥20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V3.2014. ©National Comprehensive Cancer Network, Inc. 2014. All rights reserved. Accessed April 30, 2014. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Please Please see see additional additional Important Important Safety Safety Information Information for for VOTRIENT VOTRIENT onon adjacent adjacent pages. pages. Please Please see see Brief Brief Summary Summary ofof Prescribing Prescribing Information, Information, including including Boxed Boxed Warning, Warning, for for VOTRIENT VOTRIENT onon adjacent adjacent pages. pages. www.GSKSource.com www.GSKSource.com ©2014 ©2014 GSKGSK group group of companies. of companies. All All rights rights reserved. reserved. Printed Printed in USA. in USA. 66501R0 66501R0 June June 2014 2014

VOTRIENT.com/HCP/aRCC VOTRIENT.com/HCP/aRCC

EFFICACY LIGHTS THE WAY

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients who received placebo on the trial had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood

pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days

old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, doubleblind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290)

(N=145)

All All Gradesa Grade 3Grade 4 Gradesa Grade 3Grade 4 % % % % % % Adverse Reactions Diarrhea 52 3 <1 9 <1 0 Hypertension 40 4 0 10 <1 0 Hair color changes 38 <1 0 3 0 0 Nausea 26 <1 0 9 0 0 Anorexia 22 2 0 10 <1 0 Vomiting 21 2 <1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below: Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms.

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290)

Parameters Hematologic Leukopenia Neutropenia Thrombocytopenia Lymphocytopenia Chemistry ALT increased AST increased Glucose increased Total bilirubin increased Phosphorus decreased

Placebo (N=145)

All All Gradesa Grade 3Grade 4 Gradesa Grade 3Grade 4 % % % % % % 37 34 32 31

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53 41

10 7 <1

2 <1 0

22 19 33

1 <1 1

0 0 0

B:14.25”

T:13”

S:12.5”

Sodium decreased 31 4 1 24 4 0 Magnesium 26 <1 1 14 0 0 decreased Glucose decreased 17 0 <1 3 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to <1% (1/145) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs That Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and Cmax). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and

H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug 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 VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the postweaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is

highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of the GSK group of companies.

GlaxoSmithKline Research Triangle Park, NC 27709

The ASCO Post | OCTOBER 15, 2014

PAGE 144

Palliative Care in Oncology Helping Patients Talk to Their Children About Cancer A Conversation With Paula K. Rauch, MD By Jo Cavallo

lthough the focus of an oncologist’s attention is understandably attuned to the needs of the patient, when a patient is a parent, quality oncology care should also include attention to the patient’s role as a parent and to the needs of the patient’s children, according to Paula K. Rauch, MD, Founding Director of the Marjorie E. Korff Parenting at a Challenging Time (PACT) Program at Massachusetts General Hospital Cancer Center, and Associate Professor of Psychiatry at Harvard Medical School in Boston. Most cancer centers offer some psychosocial services for patients, and by 2015, all centers accredited by the American College of Surgeons will be required to screen patients for distress and refer patients to psychosocial services when necessary. However, these institutions often do not have palliative care or oncology teams that include mental health clinicians trained in child development to assist patients who have children. The medical team of the PACT Program, now in its 15th year, includes child psychiatrists, child psychologists, and oncology social workers who provide free psychoeducational support for parents who are patients at the cancer center. The program offers individual consultations for parents with cancer and/or healthy parents or partners on how to prepare their children for their parents’ cancer diagnosis, treatment, and end-of-life decisions.

The ASCO Post talked with Dr. Rauch about the importance of informing children about a parent’s cancer diagnosis, the questions the oncologist or palliative care specialist should ask patients about their children, and the role of the oncologist in helping children cope with their parent’s illness.

Open Communication Please talk about the importance of informing children about a parent’s cancer diagnosis. What is the appropriate age to have the discussion? What a child understands about the meaning of a cancer diagnosis will vary with the child’s age and past experience with the disease within both the child’s family and community. Regardless of age, a child’s ability to cope is enhanced by open communication between the child and the important adults in her life. Sharing a parent’s diagnosis and identifying it as cancer is really the first step toward making the disease “talk-aboutable” and sends a powerful message to the child that he or she is important enough to be included in the conversations about something that has major impact on the child’s family. Having an open discussion about a parent’s cancer diagnosis lets the child know that the subject is not so scary that no one is able to talk about it together. This reassures the child that she is not going to be left alone with misconceptions or worries and that she can ask questions and expect they will be answered honestly.

Timing of the Discussion When is the appropriate time for that initial discussion to take place? At diagnosis? Yes, usually at diagnosis or soon thereafter. Children are attuned to the emotional atmosphere of the home environment and typically quickly pick up that something is wrong, which leads to worry or feeling unsettled. Acknowl-

Having a medical professional specifically trained in child development on the palliative care team sets the stage for everyone on the team to feel more comfortable entering the zone of talking with patients about their concerns for their children. —Paula K. Rauch, MD

edging symptoms and the diagnosis early using simple language is best. That said, parents are the experts when it comes to their children. They are going to make their own decisions about the timing of the discussion as they see fit. I would encourage parents, if they are going to delay sharing information about the diagnosis, to at least plan what they are going to say if their child initiates the conversation by asking a direct question about the parent’s health. Most of us want our children to receive the clear messages that “in our family we are honest with each other,

Addressing the Needs of Patients With Children

ften, the children of patients with cancer are the invisible sufferers of the disease and its aftermath. These online resources can help patients talk with their children about a cancer diagnosis, treatment, and prognosis, and their potential impact on the children. • American Cancer Society: Helping Children When a Family Member Has Cancer (cancer.org/ treatment/childrenandcancer/ helpingchildrenwhenafamilymemberhascancer). Topics range from dealing with treatment, and what helps, by age of the child, to words to describe cancer and its treatment.

• ASCO’s Cancer.Net section on Family Life (www.cancer.net/ coping-and-emotions/communicating-loved-ones). In addition to such topics as parenting while living with cancer and how a child understands cancer, the Family Life section also contains specific advice on talking with your spouse or partner, talking with your teenager, talking with your children, and talking with your grandchildren. • Marjorie E. Korff Parenting at a Challenging Time Program (mghpact.org). This website provides tips and in-depth information to support children through

even when the news is bad,” and that “we face challenges together.” I’ll often talk with parents, particularly those with older children or teens, about the idea of worrying with each other as opposed to worrying about each other. When we worry with each other we face the challenges together and we can problem-solve most effec-

all phases of a parent’s illness, including a section on parenting principles (mghpact.org/for-parents/parenting-principles), which has advice on end-of-life planning, and a section on useful lessons learned (mghpact.org/for-parents/ a-dozen-lessons-learned). • National Cancer Institute’s Taking Time: Support for People With Cancer: Family Matters (cancer.gov/cancertopics/takingtime/page3). This Web page includes sections on telling children about cancer, teenagers and a parent’s cancer, what children of all ages need to know, and talking with adult children. n

tively. When parents and children worry about each other, often what they are focused on is off the mark, so they have a harder time being effective in addressing each other’s real concerns.

Role of the Oncologist What is the role of the oncologist in helping children cope with their parent’s illness, especially in the palliative care setting? Some children, particularly older children, may want the opportunity to talk directly with the palliative care oncologist. But for many oncologists and palliative care specialists, their role is to be very specific with parents about their cancer diagnosis and treatment, so parents can communicate with their own children and plan for their support. Asking a patient questions about family—such as, Do you have children at home? How old are they? Have you told them about your illness? and Is there a specific worry you have about your children?—invites the patient to share unexpressed worries. It’s also important to ask patients about how their symptoms might be impacting their day-to-day ability to parent effectively. For example, addressing pain is essential. Patients can’t do things with their children if their pain isn’t well managed. Another example is having severe gastrointestinal distress that may make it difficult for parents to attend school functions or take their children to the park.

ASCOPost.com | OCTOBER 15, 2014

PAGE 145

Palliative Care in Oncology Attention to these quality-of-life issues is especially important. Unfortunately, an oncologist may not be able to extend the life of a patient with advanced disease, but being able to address some of the symptoms of the cancer or the treatment can make a big difference in the quality of the precious time the patient has to spend with his or her children.

End-of-Life Issues How can oncologists help parents discuss end-of-life choices with their children? A patient’s role as a parent may play a major role in decision-making about treatment options and end-of-life care, so it is important to tease this out. Sometimes parents will elect to participate in a clinical trial or to continue treatment even when they do not believe that the treatment is going to benefit them, only because they want to be able to say to

their child that they did everything possible to get well and they never gave up fighting. The parent may need guidance in how to explain discontinuing treatment as a loving choice. For example, that discussion could begin like this: “After talking with my medical team and learning about all the different treatment options, I know that none of the treatments would slow down the cancer and give me more time with you. More chemotherapy would most likely just make me feel nauseated and tired and lead to more time spent in the hospital. I want to spend my precious time feeling as good as I can feel and being home, so I can enjoy the time we have together.” This process of helping a parent talk through end-of-life decisions may come up around the time of discussions about do-not-resuscitate and do-not-intubate

orders. Many oncologists are not going to be comfortable guiding parents in how to talk with their 7- or 9-year-old child, and that is why I feel so strongly that a mental health clinician trained in child development should be available to the oncology medical team to facilitate these discussions. One of the barriers that inhibit conversations with patients about their parenting concerns is an oncologist’s inexperience in dealing with children. Having a medical professional specifically trained in child development on the palliative care team sets the stage for everyone on the team to feel more comfortable entering the zone of talking with patients about their concerns for their children, no matter what the children’s ages. n Disclosure: Dr. Rauch reported no potential conflicts of interest.

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.

Psycho-Oncology

One in Three People With Cancer Has Anxiety or Other Mental Health Challenges

esearchers in Germany report that nearly a third of more than 2,100 patients with cancer interviewed at inpatient and outpatient care centers experienced a clinically meaning-

among patients with breast cancer (42%) and head and neck cancer (41%), followed by malignant melanoma (39%). The lowest prevalence was seen among patients with prostate can-

We also want to reassure patients who are struggling that they are not alone or unique, and that these mental and emotional challenges can be temporary, especially with effective psychological support or state-of-the-art mental health treatment. —Anja Mehnert, PhD

ful level of mental or emotional distress that meets the strict diagnostic criteria for mental disorders including anxiety and depressive and adjustment disorders during the prior 4 weeks. The prevalence of these issues varied by cancer type. The highest prevalence was found

cer (22%), stomach cancers (21%), and pancreatic cancer (20%). The study was published recently in the Journal of Clinical Oncology.1

Awareness of Mental and Emotional Distress Critical “These findings reinforce that, as

doctors, we need to be very aware of signs and symptoms of mental and emotional distress. We must encourage patients to seek evaluation, support, and treatment, if necessary, as there are long-term risks often associated with more severe, untreated mental health disorders. This research also sheds light on which patients we should watch more closely,” said lead study author Anja Mehnert, PhD, Professor of Psychosocial Oncology at the University of Leipzig in Germany. “We also want to reassure patients who are struggling that they are not alone or unique, and that these mental and emotional challenges can be temporary, especially with effective psychological support or stateof-the-art mental health treatment.” Psychological support options may include individual, couples, family, and group psychotherapy, and relaxation therapy and imagery, among others, according to the authors.

The authors noted that prior studies have reported elevated levels of distress among people with cancer, but they vary in quality due to small sample sizes, different diagnostic criteria and assessment standards, and an over-representation of women with breast cancer. This multicenter study, funded by the German Cancer Aid, was coordinated by the University Medical Center Hamburg-Eppendorf; participating study centers included the University Medical Centers of Freiburg, Heidelberg, Leipzig, and Würzburg. For a more in-depth report on the study watch future issues of The ASCO Post. Also, for more on depression and cancer, see pages 110–113 in this issue. n Reference 1. One in three people with cancer has anxiety or other mental health challenges. J Clin Oncol. October 6, 2014 (early release online).

The ASCO Post | OCTOBER 15, 2014

PAGE 146

Through the Lens of Oncology History

100 Years

of Progress in Oncology Treatment

Photographs from The Burns Archive document a century of oncology care from its primitive beginnings to the modern era.

Stanley B. Burns, MD, FACS, poses in front of his vintage photo collection at The Burns Archive in New York City.

By Jo Cavallo

n his powerful 2010 best-seller, The Emperor of All Maladies: A Biography of Cancer (Scribner), Siddhartha Mukherjee, MD, chronicles the evolution of cancer from the oldest known description of the disease written on a papyrus from about 1600 BC to the present day’s understanding of the biology of cancer. The papyrus, writes Dr. Mukherjee, “is believed to contain the collected teachings of Imhotep, a great Egyptian physician who lived around 2625 BC.” And while Imhotep’s description of “Bulging tumors of the breast mean the existence of swellings on the breast, large, spreading, and hard; touching them is like touching a ball of wrappings, or they may be compared to the unripe hemat fruit, which is hard and cool to the touch,” conjures up a vivid mental image of a probable case of breast cancer, it does not have the immediate impact a visual image produces. Nor do words tell a complete story

the way a photo does, said Stanley B. Burns, MD, FACS, an ophthalmologist and Clinical Professor of Medicine and Psychiatry at NYU Langone Medical Center in New York, and Founder of The Burns Archive, a treasure trove of more than a million historical and medical photographs dating back to the mid-1800s.

The Burns Archive of Photographs “When you see an original, untouched photograph of an event, it is pretty close to what was going on in that moment,” said Dr. Burns. “Once I realized that a picture gave more than 1,000 words of information, I knew that the written word had to be supplemented by the visual. Many times you have only a visual record [of an event] and no written record and you get much more information from a photograph than the written record because you have information on all different aspects [of that event].”

Established in 1977, The Burns Archive houses one of the world’s largest photographic collections showcasing both the horrors and miracles of early medical and oncology practice, including the first demonstrations of breast surgery, the use of nonsurgical therapies such as radium and radiation, and two major breakthrough advances between 1845 and 1875, the discovery of general anesthesia and the emergence of antiseptic principles. The collection, said Dr. Burns, is the first photographic historical work that documents the establishment of oncology as a modern specialty and provides a chronology of the changing nature of disease, medical advances, and how oncology was practiced.

The Era of Modern Medicine Having a photographic record of medical advances, according to Dr. Burns, took the practice of medicine from the dark to the modern age and provides a vivid legacy of how both

physician and patient coped with disease. “The photographs show the evolution of the physician from butcher to scientist, this is especially true in surgery where you see doctors posing with pieces of people in the early 19th century and then posing with the latest surgical instruments and x-ray and radium devices going into the 20th century to show that they were technologists,” said Dr. Burns. In addition to memorializing the progression of medical achievement, the advent of photography in 1839 also helped alter people’s perception of medicine and their fear of disease. “People were afraid of going to the doctor,” said Dr. Burns. “With these visual images, especially the photos of surgeries, you can see how each year the patient got closer and closer to full visualization of [the advances of] medical practice. Patients’ fear disappeared once doctors were no longer associated with death.” continued on page 149

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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 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 ZYDELIGtreated patients. Discontinue ZYDELIG for intestinal perforation 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 >3x upper limit of normal (ULN), monitor for liver toxicity weekly. If ALT/AST is >5x 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) in clinical studies, when used alone or in combination with rituximab, were diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash • Most frequent serious adverse reactions (SAR) in clinical studies in combination with rituximab were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%); SAR were reported in 49% of patients and 10% of patients discontinued due to adverse reactions. Most frequent SAR in clinical studies when used alone 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) in clinical studies were neutropenia, hypertriglyceridemia, hyperglycemia, and ALT/AST elevations 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 ALT=alanine aminotransferase; AST=aspartate aminotransferase; CLL=chronic lymphocytic leukemia; FL=follicular B-cell non-Hodgkin lymphoma; SLL=small lymphocytic lymphoma.. Please see brief summary of full Prescribing Information, including BOXED WARNING, on the following page.

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.

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• 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): 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%).

• 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

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. © 2014 Gilead Sciences, Inc. All rights reserved. GILP0239 07/2014

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 | OCTOBER 15, 2014

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Through the Lens of Oncology History 100 Years of Progress continued from page 146

Recording History

The Archive’s historical photographic collection spans such diverse categories as medicine, death and memorial, war and conflict, crime and punishment, occupations and industry, social and cultural history, and African American history, among others, and has been called “one of the six most important collections in the world,” by Aperture magazine. The photographs have appeared in over

100 museum exhibitions, including the Metropolitan Museum of Art in New York and the Musée d’Orsay in Paris, and thousands of images have been donated to The Smithsonian Institution, the Museum of Modern Art, and the J. Paul Getty Museum. Images from the Archive have also been used as resource material for several television shows, including The Knick, a period-based medical drama on Cinemax, and appear in a variety of documentaries, including the upcoming 6-hour documentary by filmmaker

Ken Burns (no relation) based on Dr. Mukherjee’s book, The Emperor of All Maladies, scheduled for broadcast on PBS stations next spring. Dr. Burns is also a medical and historical adviser on these programs.

The History of Oncology Dr. Burns has published a four-volume series of books tracking the history of oncology medicine titled Oncology: Tumors & Treatment, A Photographic History, which are divided by year and medical advance. They include, The An-

esthesia Era 1845-1875; The Antiseptic Era 1876-1900; The X-Ray Era 19011915; and The Radium Era 1916-1945. Several images from these books, along with their edited captions, appear below and on the following pages. The photographs are courtesy of Stanley B. Burns, MD, and The Burns Archive. n To learn more about The Burns Archive and to view a sampling of its photographic collection, go to burnsarchive.com. Watch future issues of The ASCO Post for more images from oncology history.

1845-1875 T:13.75”

Photos are courtesy of Stanley B. Burns, MD, and the Burns Archive.

Woman With Ovarian Tumor, Daguerreotype, Wellington, Ohio, June 1851

n June 1851, Philip J. Bruckner, MD, hired a daguerreotypist to photograph this 275-pound, 33-year-old woman, who had borne five children while developing this massive tumor. Dr. Bruckner learned of this patient when Charles Breech, MD, of Wellington, Ohio, presented her case at a medical meeting. Dr. Bruckner published the case history along with a woodcut illustration made from the photograph in the Ohio State Medical Society Transaction in 1851. It was one of the first uses of photography in a medical journal. An earlier surgeon, Ephraim McDowell, MD, performed the first recorded ovariotomy and exploratory laparotomy in 1809, on a 47-year-old woman. Although the surgery was performed before the era of anesthesia and antisepsis, it was successful and the woman, Jane Todd Crawford of Green County, Kentucky, lived another 30 years. Successfully performing ovariotomies defined a master surgeon in the early 19th century, and documenting large ovarian tumors became part of the culture of medicine during this era. Excerpted from Oncology: Tumors & Treatment, A Photographic History, The Anesthesia Era 1845-1875 by Stanley B. Burns, MD, FACS. More photos on pages 150–151

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Through the Lens of Oncology History

1876-1900 First Photographs of Breast Surgery, New York City, 1886

ntiseptic principles delivered the promise of safe surgery, while asepsis allowed safe major dissections and invasion of body cavities. The physicians who were using these techniques recognized the amazing difference in their surgical results and corresponding mortality rates and proselytized to their colleagues. Arpad Gerster, MD, described his aseptic operative procedure and philosophy of management for breast cancers in his Rules of Aseptic and Antiseptic Surgery: Whenever amputation of the breast is performed for malignant tumor, the operation must be radical, or at least as radical as possible. No regard whatever should be paid to cosmetic considerations, the object of the measure being the extirpation of deadly disease, which if not eliminated, is sure to kill. These are the first photographs taken of breast surgery in progress (probably at Mt. Sinai Hospital in New York City). In the top photograph, “the mammary gland is being detached from below, the surgeon (Dr. Gerster) inserts his left hand under the breast to complete the upper section.” The lower photograph shows the “removal of the axillary content. The surgeon holding the detached breast serving as a handle” to keep tension on the tissue for ease of dissection. He removes the breast and its axillary content in one piece. The wound was closed with sutures and a tube placed through the latissimus for drainage. By the mid-1880s most of America’s major surgeons had adapted the aseptic technique, although surgeons still wore their gowns over their street clothes. The lack of hats, gloves, and masks were a portal of infection and the adoption of their use was a major step in prevention. In this photograph, the anesthesiologist holding the patient’s arm is wearing street clothes. It is interesting to note that anesthesiologists were the last to don gowns, hats, and masks in the operating room. Excerpted from Oncology: Tumors & Treatment, A Photographic History, The Antiseptic Era 1876-1900 by Stanley B. Burns, MD, FACS.

Photos are courtesy of Stanley B. Burns, MD, and the Burns Archive.

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Through the Lens of Oncology History

1901-1915

Lympho-Sarcoma Treated by Radiation, Patient of Francis H. Williams, MD, Boston, 1902

Photos are courtesy of Stanley B. Burns, MD, and the Burns Archive.

ne of the miracles produced by the x-ray was the relatively easy treatment of inoperable or disfiguring tumors. If not a cure, the results frequently gave the patients at least some time to look and feel normal. The young patient shown in these photographs had a remarkable response. Images such as these were used by professionals to document the dramatic results possible through the use of radiation treatments for a variety of diseases. Francis H. Williams, MD, reports this case in his 1903, The Roentgen Rays in Medicine and Surgery: as an aid in Diagnosis and as a Therapeutic Agent: The first case, still under treatment, is that of a girl, 12 years of age, who had a growth of 7 years’ duration. Two operations had been done for the removal of large masses of glands in the neck, one by Dr. G.W. Grey and the other by Dr. M.W. Richardson, before she came to me for treatment by the x-rays. The microscopical examination made after the first operation showed that the growth was a lympho-sarcoma, and that after the second it was a round-celled carcinoma. The growth involved the glands of the neck, both axillae, groin, and thorax. The accompanying (photograph) shows how great was the enlargement of the glands in the neck: Those in the other portions mentioned were also very greatly enlarged. Treatment was begun in May 1902, and during the first three weeks the glands became softer and smaller, and the patient’s well being was much improved. She was weak and listless at the beginning of the treatment, but became bright and active after the lapse of 3 or 4 weeks. Exposures have been given once or twice a week, as a rule, during 10 months. During the seventh month of treatment the spleen became enormously large, extending to the right of the umbilicus and nearly down to the iliac crest, but after x-ray exposure it steadily diminished in size; the weight of the patient has constantly increased. Excerpted from Oncology: Tumors & Treatment, A Photographic History, The XRay Era 1901-1915 by Stanley B. Burns, MD, FACS.

Photos are courtesy of Stanley B. Burns, MD, and the Burns Archive.

1916-1945

Sluys-Kessler Radium Apparatus, Paris, 1930

evices to accurately deliver high-dose radium therapy became extremely sophisticated during the late 1920s. In this photograph, the patient is being treated for a carcinoma of the back by a Sluys-Kessler machine. This apparatus could also accurately deliver therapy for a wide variety of internal tumors, including larynx, pharynx, breast, esophagus, and brain. The machine is suspended from the ceiling and manipulated by a series of cable and pulley arrangements that allowed the large hemisphere to be angled in any direction. The hemisphere was composed of 13 radium “cannons,” each consisting of a bronze cylinder containing radium and encased in a lead tube. The angle of the tubes could also be adjusted within their holders and aimed directly at the lesion. A caliper attached to a clamp held the cylinder in the lead shield tube and could also further adjust the beam. During treatment, a special lead shield was placed over the patient with the treatment area open to the radiation beam. The tubes were set about 6 to 8 cm from the skin. The charge in this case was 100 mg per canon. Excerpted from Oncology: Tumors & Treatment, A Photographic History, The Radium Era 19161945 by Stanley B. Burns, MD, FACS.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib 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.

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR)

100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20% 0%

ORR 7.4% (n=8) POMALYST (n=108)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

POMALYST + low-dose dex (n=113)

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

Study design: A phase 2, multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy

For more information visit www.pomalyst.com/hcp or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of 2 reliable methods of contraception POMALYST is only available through a restricted distribution program called POMALYST REMS™. VENOUS THROMBOEMBOLISM • Deep venous thrombosis (DVT) and pulmonary embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. POMALYST is only available through a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep venous thrombosis (DVT) and pulmonary embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. 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 • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of POMALYST therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacies must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436. Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced Grade 3/4 dizziness, and 3% of patients experienced Grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of Grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are

those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low-dose dex arms, the most common adverse reactions (≥30%), respectively, included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low-dose dex arms, the most common Grade 3/4 adverse reactions (≥15%), respectively, included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low-dose dex arms, the most common serious adverse reactions (≥5%), respectively, were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%), dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Avoid the use of strong CYP1A2 inhibitors. If medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce POMALYST dose by 50%. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age

were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS on following pages. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. © 2014 Celgene Corporation 07/14 US-POM120033a(2)

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FDA Update

FDA Grants Orphan Drug Designation to Bivalent Vaccine for Neuroblastoma

treatment. The bivalent vaccine is intended to elicit a targeted immune response against the two most common antigens on neuroblastoma cells, GD2 and GD3. Results of a recent phase I published in Clinical Cancer Research dem-

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full Prescribing Information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS™ [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep venous thrombosis (DVT) and pulmonary embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew, or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

2.2 Dose Adjustments for Toxicities Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity Neutropenia • ANC <500 per mcL or febrile neutropenia (fever more than or equal to 38.5°C and ANC <1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Dose Modification

• For each subsequent drop <500 per mcL • Return to more than or equal to 500 per mcL

Interrupt POMALYST treatment Resume POMALYST treatment at 1 mg less than the previous dose

Thrombocytopenia • Platelets <25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly Resume POMALYST treatment at 3 mg daily

• Platelets return to >50,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly Resume POMALYST treatment at 3 mg daily

• For each subsequent drop <25,000 per mcL • Return to more than or equal to 50,000 per mcL

Interrupt POMALYST treatment Resume POMALYST treatment at 1 mg less than previous dose

ANC, absolute neutrophil count. For other Grade 3 or 4 toxicities, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL and the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 2.3 Dose Adjustment for Strong CYP1A2 Inhibitors in the Presence of Strong CYP3A4 and P-gp Inhibitors Avoid co-administration of strong inhibitors of CYP1A2. If necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce POMALYST dose by 50%. No clinical efficacy or safety data exist [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].

of 10 patients assessable for response. A phase II trial is being planned for 2015. n Reference 1. Kushner BH, Cheung IY, Modak S, et al: Clin Cancer Res 20:1375-1382, 2014.

Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy, and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles, or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST, and comply with REMS requirements. Further information about the POMALYST REMS program is available www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (VTEs) (venous thromboembolism) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

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1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

onstrated encouraging outcomes with the vaccine in a small cohort of patients with relapsed neuroblastoma.1 Antibody responses against GD2 and/ or GD3 were observed in 12 of 15 patients, and disappearance of minimal T:7”documented in 6 residual disease was

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Journal Spotlight Gynecologic Oncology

Genetic ‘Hotspot’ Linked to Endometrial Cancer Aggressiveness

that, on the surface, appear the same. With endometrial cancer, the most common gynecologic cancer in the western world and the fourth most prevalent in the United States, it can literally be a matter of life and death. Mortality T:7” have nearly tripled rates from this cancer

5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%.

treatment cycles was 5. Sixty-three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty-seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%.

Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)].

Tables 2, 3, and 4 summarize all treatment-emergent adverse reactions reported for the POMALYST + Low-dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Low-dose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low-dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia (6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low-dose Dex (69/112).

5.5 Hypersensitivity Reactions Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced Grade 3/4 dizziness, and 3% of patients experienced Grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and to not take other medications that may cause dizziness or confusional state without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of Grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 5.9 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience in Multiple Myeloma 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. In Clinical Trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low-dose Dexamethasone (Low-dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of

in the last 25 years and the increase is thought to be attributed to the rising incidence of obesity. Scientists at The University of Texas MD Anderson Cancer Center in Houston have identified genetic mutations in endometrioid endometrial carcinoma, the most common

form of this cancer of the uterine lining. The mutations revealed a more lethal version of an endometrioid endometrial carcinoma subtype previously thought to respond well to treatment. It’s possible that by identifying these patients early continued on page 158

Serious Adverse Reactions in ≥2 patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: Constipation (1%, 3%); Blood and lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and labyrinth disorders: Vertigo Hepatobiliary disorders: Hyperbilirubinemia Infections and infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis Investigations: Alanine aminotransferase increased Metabolism and nutritional disorders: Hyperkalemia Renal and urinary disorders: Urinary retention Reproductive system and breast disorders: Pelvic pain Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease 6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with POMALYST: Pancytopenia, tumor lysis syndrome. 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. 7 DRUG INTERACTIONS Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP1A2 inhibitors: Pomalidomide exposure is increased when POMALYST is co-administered with a strong CYP1A2 inhibitor (fluvoxamine) in the presence of a strong CYP3A4/5 and P-gp inhibitor (ketoconazole). Ketoconazole in the absence of a CYP1A2 inhibitor does not increase pomalidomide exposure. Avoid co-administration of strong CYP1A2 inhibitors (eg, ciprofloxacin and fluvoxamine) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. If it is medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, POMALYST dose should be reduced by 50%. The effect of a CYP1A2 inhibitor in the absence of a co-administered CYP3A4 and P-gp inhibitor has not been studied. Monitor for toxicities if CYP1A2 inhibitors are to be co-administered in the absence of a co-administered CYP3A4 and P-gp inhibitor, and reduce dose if needed. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Cosmos Communications

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arents of twins often tell them apart through subtle differences such as facial expression, moles, voice tone, and gait. Similarly, physicians treating women with endometrial cancer must be able to distinguish between different versions of this disease form

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on, oncologists can try more aggressive treatment approaches to increase the likelihood for a positive outcome.

Subtypes of Endometrioid Endometrial Carcinoma “[Endometrioid endometrial carci-

noma] is categorized into subtypes that help determine risk of recurrence and guide treatment,” said Wei Zhang, PhD, Professor of Pathology at MD Anderson. “Most patients have Type I, which can be diagnosed early and generally has a good outcome with treatment.” Type I accounts for 70% to 80% of all endometrioid endometrial carcinomas. CYP1A2 inducers: Co-administration of POMALYST with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

and obese that’s typical for Type I. What’s unusual is for patients in this disease category to have decreased survival rates,” said Dr. Zhang. “Molecular subtyping of [endometrioid endometrial carcinoma] may help oncologists with diagnosis and prognosis within this unique subset.” Dr. Zhang believes that by being able to identify molecular “attributes,” physi-

in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg/day. Additional embryo-fetal toxicity included increased resorption.

contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.

8.3 Nursing Mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of POMALYST in patients below the age of 18 years have not been established. 8.5 Geriatric Use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41% were aged 65 years and older, while 12% were aged 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients aged greater than or equal to 65 years were more likely to experience pneumonia than patients aged less than or equal to 65 years. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual

8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 12 monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes, and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males in this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindications (4)]. POMALYST is a thalidomide analogue and may cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

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Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented, and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg/kg/day. Malformations or absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central, and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg/day. Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg/kg/day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg/kg/day. Additional malformations observed at 250 mg/kg/day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs, and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg/kg/day) that resulted in cardiac anomalies

Type II is more troublesome and is usually diagnosed late in the cancer’s progression resulting in a poor prognosis. Dr. Zhang’s team, however, identified a cluster of patients within Type I that appears to have a more virulent form of it previously not recognized. Dr. Zhang labeled this patient group as Cluster II. T:7” mostly younger “The patients were

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cians can identify patients at risk for this more lethal form of the disease. Dr. Zhang’s findings were published recently in the Journal of the National Cancer Institute.

Distinctive Mutations His team discovered distinctive genetic mutations in 87% of the Cluster

POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program called POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements, and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS. Provide patients with the telephone number and Web site for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment [see Venous Thromboembolism (5.3)]. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia, and anemia and the need to report signs and symptoms associated with these events to their healthcare provider for further evaluation [see Hematologic Toxicities (5.4)]. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID® [see Hypersensitivity Reaction (5.5)]. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusional state with the drug, to avoid situations where dizziness or confusional state may be a problem, and not to take other medications that may cause dizziness or confusional state without adequate medical advice [see Dizziness and Confusional State (5.6)].

With the identification of Cluster I (young, obese patients who respond well to treatment and generally have a good prognosis) and the more lethal Cluster II, Dr. Zhang demonstrated that, like twins, the two cancers may appear similar, but they have distinct genetic differences that make them unique. In the case of Cluster II, the discovery of these Neuropathy Inform patients of the risk of neuropathy and to report the signs and symptoms associated with these events to their healthcare provider for further evaluation [see Neuropathy (5.7)]. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown [see Risk of Second Primary Malignancies (5.8)]. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warning and Precautions (5.9)]. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day. • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID®, and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. Pat. http://www.celgene.com/therapies © 2005-2014 Celgene Corporation All rights reserved. POMBS.v.003 05/14

Wei Zhang, PhD

chromosomal quirks could lead to earlier and more effective treatments. “The identification of this second cluster of patients with endometrial cancer helps to refute long-standing teachings that young, obese patients universally have endometrial cancers that are estrogen-driven and thus have a good prognosis,” said Russell Broaddus, MD, PhD, Professor of Pathology at MD Anderson. “Endometrial cancer in this patient population is much more complex than we were previously led to believe. We hope that the study results can help pave the way for more individualized therapy of endometrial cancer patients who have tumors with CTNNB1 mutations.” n Other MD Anderson study participants included Yuexin Liu, PhD, Lalit Patel, and Russell Broaddus, MD, PhD, in the Department of Pathology, Gordon Mills, MD, PhD, Department of Systems Biology, and Karen Lu, MD, and Anil Sood, MD, Department of Gynecologic Oncology and Reproductive Medicine. Collaborative institutions included Washington University School of Medicine, St. Louis, Harvard Medical College, Boston, Memorial Sloan Kettering Cancer Center, New York, and the Institute for Systems Biology, Seattle. T:10”

• Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception, including at least 1 highly effective form, simultaneously during POMALYST therapy, during therapy interruption, and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch, or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm, and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

II patients. The mutations occurred in the CTNNB1 gene, which is necessary for the creation and maintenance of tissue-producing epithelial cells. Within CTNNB1, genetic sequences known as exon 3 created a “hotspot,” a cellular cauldron of biological blunders. This resulted in the normally passive Type I becoming deadly T:7” for some patients.

Disclosure: Dr. Zhang’s study was funded by a Career Development Award from MD Anderson Gynecologic SPORE in Uterine Cancers (NIH 2P50 CA 098258-08), the Genome Data Analysis Centers from the NIH (U24 CA143835), and the National Foundation for Cancer Research. The study authors reported no potential conflicts of interest.

Reference 1. Liu Y, Patel L, Zhang W, et al: Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometriod endometrial carcinoma. J Natl Cancer Inst. September 10, 2014 (early release online).

The ASCO Post Wants to Hear From You

Write to The ASCO Post at editor@ASCOPost.com Cosmos Communications

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Journal Spotlight Genitourinary Oncology

Primary Androgen Deprivation Does Not Improve Long-Term Survival in Older Patients With Localized Prostate Cancer By Matthew Stenger

rimary androgen-deprivation therapy has been widely used in localized prostate cancer, despite the absence of definitive evidence of benefit in early-stage disease. In a large population-based cohort study reported in JAMA Internal Medicine, Grace L. Lu-Yao, MPH, PhD, of Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, and colleagues found that primary androgen-deprivation therapy was not associated with improved 15-year prostate cancer–specific survival or overall survival following diagnosis of localized prostate cancer in Medicare patients aged ≥ 66 years.1

Study Details The study included 66,717 men aged ≥ 66 years with localized prostate cancer (T1/T2) diagnosed between 1992 and 2009 who received no definitive local therapy within 180 days of prostate cancer diagnosis. Data on these patients were obtained from the Surveillance, Epidemiology, and End Results program and linked Medicare files. The primary outcome measures were cancerspecific survival and overall survival. A total of 25,125 patients (37.7%) received primary androgen-deprivation therapy and 41,592 received conservative management. Patients receiving

fied instrumental variable analysis. The Cox multivariate analysis included age, race, comorbidity status, cancer stage, zip code income quartiles, zip code education quartiles, urban area, marital status, year of diagnosis, SEER region, state buy-in status, and cancer grade. The main analysis of the study used a stratified instrumental variable approach, which is intended to account for both measured and unmeasured confounders. Use of primary androgen-deprivation therapy varied widely across the 122 health service areas included in the study. In the main instrumental variable analysis, treatment and region variables were replaced by a single covariate indicating high or low use of primary androgen-deprivation therapy, with the comparison being between the top and bottom use tertiles. Covariates in the instrumental variable analysis consisted of age, race, comorbidity status, cancer stage, zip code income quartiles, zip code education quartiles, urban area, marital status, year of diagnosis, state buy-in status, and cancer grade. Highuse areas and low-use areas were similar with regard to comorbidity score, PSA level, and Gleason score, suggesting that the instrumental variable analysis

Androgen Deprivation for Prostate Cancer ■ Cox multivariate analysis showed significantly worse prostate cancer– specific and overall survival in patients receiving primary androgendeprivation therapy. ■ Instrumental variable analysis comparing primary androgen-deprivation therapy high-use vs low-use areas showed no significant differences in prostate cancer–specific or overall survival.

primary androgen-deprivation therapy were older (median, 79 vs 77 years), had more serious comorbidities (15.2% vs 12.5% with a Charlson score ≥ 2), were more likely to have high-risk disease (47.7% vs 23.0%), and had a higher mean prostate-specific antigen (PSA) level (19.5 vs 11.1 ng/mL). Overall, 29% of patients who initially received conservative management eventually received androgen-deprivation therapy.

Instrumental Variable Analysis Outcomes were assessed using both a Cox multivariate analysis and a strati-

reduced the imbalance in these risk factors observed between the primary androgen-deprivation therapy group and the conservative management group.

Outcome on Cox Multivariate Analysis Median follow-up was 110 months. On the Cox multivariate analysis, primary androgen-deprivation therapy use was associated with significantly increased risk of prostate cancer–specific mortality (adjusted hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.45–1.63) and overall mor-

Primary [androgen-deprivation therapy] is not associated with improved long-term overall or disease-specific survival for men with localized prostate cancer. —Grace L. Lu-Yao, MPH, PhD, and colleagues

tality (adjusted HR = 1.19, 95% CI = 1.17–1.22), including significantly increased risks of both cancer-specific and overall mortality among both patients with moderately differentiated disease (adjusted HRs = 1.65 and 1.20) and poorly differentiated disease (adjusted HRs = 1.37 and 1.16).

No Differences on Instrumental Variable Analysis However, no significant differences in survival were observed on instrumental variable analysis. On the instrumental variable analysis, for high- vs low-use areas, 15-year prostate cancer–specific survival was 85.4% vs 85.4% (adjusted HR = 1.01, 95% CI = 0.90–1.14), with survival rates of 90.6% vs 90.6% (adjusted HR = 1.00, 95% CI = 0.85–1.18) among patients with moderately differentiated disease and 78.6% vs 78.5% (adjusted HR = 0.99, 95% CI = 0.84–1.17) among those with poorly differentiated disease. Death due to another cause was treated as a competing risk in calculating prostate cancer–specific survival. Fifteen-year overall survival was 15.9% vs 16.8% (HR = 1.04, 95% CI = 0.99–1.09), with rates of 20.0% vs 20.8% (HR = 1.03, 95% CI = 0.96– 1.10) in patients with moderately differentiated disease and 8.6% vs 9.2% (HR = 1.03, 95% CI = 0.96–1.10) among those with poorly differentiated disease. Most patients were followed for < 10 years; thus, the observed 15-year overall survival rates are lower than the proportions of patients remaining alive at the end of the study (40%). Regarding the use of the instrumental variable analysis, the investigators explained: Results obtained from a Cox model that

adjusted only for measured confounding factors differed significantly from those derived from the [instrumental variable] approach. Results from the Cox model showed less favorable outcomes among men receiving primary [androgen-deprivation therapy], but this most likely reflects a selection bias toward men with higher risk disease…. Differences in outcomes based on the Cox model vanished when an [instrumental variable]-analysis approach was used. These observations suggest that there is considerable unaccounted residual bias associated with the Cox model analytic methods and demonstrate an important advantage to the [instrumental variable] approach.

They concluded, “Primary [androgen-deprivation therapy] is not associated with improved long-term overall or disease-specific survival for men with localized prostate cancer. Health-care providers and their patients should carefully weigh our findings against the significant adverse effects and costs associated with primary androgen-deprivation therapy before initiating this therapy.” Finally, the authors noted, “Since the study was limited to men 66 years or older, the results might not be applicable younger men.” n

Disclosure: The study was supported by the National Cancer Institute and Cancer Institute of New Jersey. For full disclosures of the study authors, visit archinte.jamanetwork.com.

Reference 1. Lu-Yao GL, Albertsen PC, Moore DF, et al: Fifteen-year survival outcomes following primary androgen-deprivation therapy for localized prostate cancer. JAMA Intern Med. July 14, 2014 (early release online).

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Announcements

James Herman, MD, Named Co-Leader of UPCI Lung Cancer Program

leader in the field of epigenetics whose work has led to important discoveries into how cancer develops and progresses has been named the co-leader of the Lung Cancer Program at the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC

ylation patterns. His work has been supported by a variety of sources, including a V Scholar Award, multiple grants from the National Institutes of Health (including service as a project co-leader on the Hopkins Lung Cancer SPORE), and most recently a Department of Defense grant, all

in the general area of epigenetics of cancer. He has served as a member of the editorial board for a number of journals, including Clinical Cancer Research and Journal of Clinical Oncology. Dr. Herman received his medical degree from Johns Hopkins in 1989, where

he was elected to Alpha Omega Alpha. After completing a residency in internal medicine at Duke, he returned to Hopkins to undertake a fellowship in medical oncology. He joined the Hopkins faculty in 1996, and advanced to Professor of Oncology there starting in 2009. n

For HR+, early-stage invasive breast cancer

James Herman, MD

CancerCenter. James Herman, MD, comes to Pittsburgh from Johns Hopkins School of Medicine, where he joined the faculty in 1996. At Pittsburgh’s School of Medicine, Dr. Herman will be a Visiting Professor of Medicine in the Division of Hematology/Oncology. His appointment is effective November 1. “Jim is a senior scientist who brings extensive experience to UPCI. He will assume leadership of the UPCI Lung Cancer SPORE grant and work closely with Mark Socinski, MD, in our Lung Cancer Program, strengthening an already impressive team,” said Nancy E. Davidson, MD, Director of UPCI and the UPMC CancerCenter. The National Cancer Institute’s prestigious SPORE, or Specialized Program of Research Excellence, is one of four such specialized research grants held at UPCI. In addition to his work as a researcher, Dr. Herman is expected to have an appointment at the Veterans Affairs Hospital in Pittsburgh, where he will work to promote clinical care, education, and clinical trials in thoracic malignancies. He will also serve as a Co-Director of the Medical Oncology Fellowship Program to promote training in basic and translational research.

Vast Knowledge of Cancer Research “Our fellows are very lucky to have the opportunity to work with and learn from Dr. Herman. He has a vast knowledge of cancer research, and we can all benefit from having someone of his caliber on our team,” said Edward Chu, MD, Deputy Director of UPCI and Chief of the Division of Hematology-Oncology. Dr. Herman and his team are especially well known for their development of the methylation-specific PCR assay, which is widely used to characterize DNA meth-

Confidence begins with a highly accurate risk assessment

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To find a Prosigna provider and for a copy of the Package Insert, visit Prosigna.com today. Reference: 1. Prosigna [Package Insert]. Seattle, WA: NanoString Technologies, Inc; 2013.

Prosigna is indicated for use in postmenopausal women with hormone receptor–positive, node-negative or node-positive early-stage (stages I and II) breast cancer to be treated with adjuvant endocrine therapy. Special conditions for use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients. © 2014 NanoString Technologies, Inc. All rights reserved. NanoString, the NanoString Technologies logo, Prosigna and the Prosigna logo are trademarks and/or registered trademarks of NanoString Technologies, Inc. in various jurisdictions. USPS_PM0006 04/14

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Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Breast Cancer Compiled by Jo Cavallo The information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies for people with breast cancer. The studies include phase I and II, interventional, and observational trials evaluating new therapies; diagnostic tools; genetic counseling; the association of radiation and bilateral disease; psychosocial, employment, and quality-of-life issues; and breast cancer risk assessment. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

PHASE I AND II Study Type: Phase I/II interventional/nonrandomized/single-group assignment Study Title: A Phase I/II Trial of Short Course Preoperative Ritonavir to Determine Akt Inhibition in Breast Cancer Study Sponsor and Collaborators: Masonic Cancer Center, University of Minnesota; Susan G. Komen Breast Cancer Foundation Purpose: To study the best dose of ritonavir and its effects on biomarkers in women undergoing surgery for newly diagnosed breast cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Female Accepts Health Volunteers: No Primary Outcome Measures: Inhibition of breast cancer by targeting Hsp90-Akt pathway (time frame: preand post-treatment) Principal Investigator: David A. Potter, MD, PhD, Masonic Cancer Center, University of Minnesota, 612-6258933, dapotter@umn.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01009437 Study Type: Phase II/interventional/randomized Study Title: A Randomized, OpenLabel Comparative Study of Combination Therapy With Cyclophosphamide and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine With or Without Trastuzumab for the Treatment of Metastatic Breast Cancer That Does NOT Overexpress HER-2/Neu Study Sponsor and Collaborators:

Sidney Kimmel Comprehensive Cancer Center; National Cancer Institute Purpose: To study the side effects of giving cyclophosphamide together with vaccine therapy and to see how effective it is compared with giving cyclophosphamide and vaccine therapy together with trastuzumab in treating patients with metastatic breast cancer Ages Eligible for Study: 18years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Toxicity as assessed by NCI CTCAE v3.0 (time frame: 3 years) Principal Investigator: Leisha A. Emens, MD, PhD, Sidney Kimmel Comprehensive Cancer Center. Contact: Maureen Berg, RN, OCN, 443287-6602, mberg1@jhmi.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00971737

INTERVENTIONAL Study Type: Interventional/randomized Study Title: A Cluster Randomized Controlled Trial Comparing Interventions to Enhance Utilization of Genetics Services Among Breast Cancer Patients Study Sponsor and Collaborators: University of South Florida; National Cancer Institute Purpose: To compare active and passive interventions to increase the rate of appropriate genetic counseling referrals of newly diagnosed breast cancer patients at increased risk for hereditary breast and ovarian cancer (HBOC) to genetic counseling in the community oncology setting. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Female Accepts Health Volunteers: No Primary Outcome Measures: Rate of appropriate referral of newly diagnosed breast cancer at increased risk for HBOC to genetic counseling in active vs passive intervention clusters (time frame: 1 year postdiagnosis) Principal Investigator: Rebecca Sutphen, MD, 800-909-1242, ccop@ epi.usf.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01789684

Study Type: Interventional/singlegroup assignment Study Title: A Pilot Study of the Immunogenicity of a 9-Peptide Breast Cancer Vaccine Plus Poly-ICLC in Stage IB-IIIA Breast Cancer Study Sponsor and Collaborators: University of Virginia Purpose: To determine whether a vaccine consisting of nine class I breastspecific peptides plus a class II tetanus toxoid helper peptide is immunogenic when administered with poly-ICLC to participants with stage IB to IIIA breast cancer in the adjuvant setting Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Frequency of dose-limiting adverse events Principal Investigator: Patrick M. Dillon, MD, University of Virginia. Contact: Emily Allred, PhD, 434-9821902, eh4m@hscmail.mcc.virginia.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01532960 Study Type: Interventional/singlegroup assignment Study Title: Light-Scattering Spectroscopy for the Detection of Stage IIIII Breast Cancer: A Pilot Study Study Sponsor and Collaborators: University of Southern California; National Cancer Institute Purpose: To investigate light-scattering spectroscopy in finding disease in patients with stage II-III breast cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Female Accepts Health Volunteers: Yes Primary Outcome Measures: Accurate classifications of women with or without breast cancer (time frame: up to 1 year) Principal Investigator: Jacques Van Dam, MD, PhD, University of Southern California. Contact: Victoria Soto, 323226-6384, Victoria.soto@med.usc.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01755208

OBSERVATIONAL Study Type: Observational Study Title: Helping Ourselves, Helping Others: The Young Womenâ&#x20AC;&#x2122;s

Breast Cancer Study Study Sponsor and Collaborators: Dana-Farber Cancer Institute Purpose: Investigators are conducting a longitudinal cohort study of women age 40 and younger with newly diagnosed breast cancer. The study is investigating short- and long-term disease and treatment issues, tumor biology and the relationship to patient outcomes, and psychosocial concerns at baseline and in follow-up among these patients. Ages Eligible for Study: 18 to 40 years Genders Eligible for Study: Female Accepts Health Volunteers: No Primary Outcome Measures: Identify a cohort of young women newly diagnosed with breast cancer (time frame: 10 years) Principal Investigator: Ann H. Partridge, MD, MPH, Dana-Farber Cancer Institute; 617-632-3800, ahpartridge@ partners.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01468246 Study Type: Observational Study Title: Genome-Wide Association Study of Radiation Exposure and Bilateral Breast Cancer Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center; Translational Genomics Research Institute, University of Southern California, University of Virginia, Lund University, Ontario Cancer Registry and Mount Sinai Hospital-Toronto, Northern California Cancer Center, Fred Hutchinson Cancer Research Center, University of Iowa, Danish Cancer Society, Beckman Research Institute, City of Hope National Medical Center, MD Anderson Cancer Center, Vanderbilt University School of Medicine, New York University School of Medicine, University of Chicago, University of California, Irvine, Stanford University Purpose: To determine what factors may be related to the risk of getting a second breast cancer among women who already have the disease in one breast. The results of the study may help to develop better ways to detect, treat, and prevent breast cancer. Ages Eligible for Study: 18 to 54 years Genders Eligible for Study: Female

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Clinical Trials Resource Guide

Accepts Health Volunteers: No Primary Outcome Measures: Identify single nucleotide polymorphism that interact with radiation exposure (time frame: 2.5 years) Principal Investigator: Jonine Bernstein, PhD, Memorial Sloan Kettering Cancer Center, 646-735-8155 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00903591 Study Type: Observational Study Title: Spousal Relationships and Pain in Metastatic Breast Cancer Study Sponsor and Collaborators: MD Anderson Cancer Center; Department of Defense Purpose: The aims of this study are to examine patient pain, spouse response to patient pain, and patient behaviors in response to pain over the course of 6 months in couples facing metastatic breast cancer; test the biopsychosocial model of chronic pain in breast cancer; and use ecologic momentary assessment to characterize patient pain, spouse response to patient pain, and patient behaviors in response to pain. Ages Eligible for Study: N/A Genders Eligible for Study: Both Accepts Health Volunteers: Yes Primary Outcome Measures: Longitudinal assessment of the psychological and relationship functioning of metastatic breast cancer and their spouses (time frame: 6 months) Principal Investigator: Hoda Badr, PhD, MD Anderson Cancer Center, 713-792-5922 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00386620 Study Type: Observational Study Title: Breast Cancer Molecular Analysis Prior to Investigational Therapy Study Sponsor and Collaborators: Yale University; Foundation Medicine Purpose: To find defects in the DNA of the cancer that could potentially be treated with FDA-approved or investigational drugs Ages Eligible for Study: N/A Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Molecular analysis of metastatic breast cancer using DNA sequencing (time frame: 2 years) Principal Investigator: Lajos Pusztai, MD, Yale University. Contact: Noelle Sowers, RN, 203-737-3472, noelle. sowers@yale.edu

For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01855503 Study Type: Observational Study Title: Breast Cancer and the Workforce: Ethnic Differences in the Impact of Breast Cancer on Employment Status, Financial Situation, and Quality of Life Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center; The City College of New York, Lincoln Medical and Mental Health Center, New York Hospital Queens, Ralph Lauren Center for Cancer Care and Prevention, New York City Health and Hospitals Corporation, Queens Medical Associates Purpose: To learn more about how being treated for breast cancer affects patientsâ&#x20AC;&#x2122; employment, financial situation, and quality of life on both a shortand long-term basis Ages Eligible for Study: 18 to 64 years Genders Eligible for Study: Female Accepts Health Volunteers: Yes Primary Outcome Measures: To compare the impact of breast cancer on employment status, financial situation, and quality of life (time frame: 3 years) Principal Investigator: Victoria Blinder, MD, MSc, Memorial Sloan Kettering Cancer Center, 646-8884808 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01134172 Study Type: Observational Study Title: Developing In Vivo Models of Human Breast Cancer Study Sponsor and Collaborators: Vanderbilt-Ingram Cancer Center; National Cancer Institute Purpose: To develop mouse models of breast cancer using tissue samples that were previously collected from women with breast cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Female Accepts Health Volunteers: No Primary Outcome Measures: Development of new in vivo models of human breast cancer (time frame: 1 year) Principal Investigator: A. Bapsi Chakravarthy, MD, Vanderbild-Ingram Cancer Center, 800-811-8480 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00897468

Study Type: Observational Study Title: Longitudinal Changes in Mammographic Density and Risk of Breast Cancer Study Sponsor and Collaborators: Case Comprehensive Cancer Center; National Cancer Institute Purpose: This natural history study is investigating changes in breast density and gathering information over time to assess breast cancer risk in women with breast cancer and in healthy women. Ages Eligible for Study: 50 years and older Genders Eligible for Study: Female Accepts Health Volunteers: Yes Primary Outcome Measures: Within individual mammographic density longitudinal change and breast cancer risk (time frame: cancer cases diagnosed within the years 2004-2006) Principal Investigator: Li Li, MD, PhD, Case Comprehensive Cancer Center, 216-844-3944, li.li@uhhospitals.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00445445 Study Type: Observational Study Title: Feasibility, Validation, and Implementation of Genomic Testing for Chemotherapy and Endocrine Sensitivity of HER2 Negative Primary Invasive Breast Cancer (Clinical Stage I to III) Study Sponsor and Collaborators: MD Anderson Cancer Center; Susan G. Komen Breast Cancer Foundation, Kellogg Company Purpose: To determine if researchers can use genetic testing on tumor samples to predict if tumors will respond to breast cancer treatments, including chemotherapy or hormonal therapy. The tumor sample will be tested to learn if certain genes are activated in the tumor. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Female Accepts Health Volunteers: No Primary Outcome Measures: Feasibility analysis of genomic predictor from localized invasive breast cancer tumor registry (time frame: 12 months) Principal Investigator: Stacy Moulder, MD, MD Anderson Cancer Center, 713-792-2817 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01334021

Study Type: Observational Study Title: MiRNA Profiling of Breast Cancer in Patients Undergoing Neoadjuvant or Adjuvant Treatment for Locally Advanced & Inflammatory Breast Cancer Study Sponsor and Collaborators: City of Hope Medical Center Purpose: MiRNA dysregulation has been implicated in breast tumorigenic and non-tumorigenic development. MiRNA profiling of treatment-naive and treatment-exposed breast tumors and sequential samples of blood/serum will allow for identification of miRNA markers of prognosis and as indicators and potential targets for personalized therapies. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Female Accepts Health Volunteers: No Primary Outcome Measures: Performance of miRNA profiling from tumor samples from primary breast tumors (time frame: 3 years after completion of sample collection) Principal Investigator: George Somlo, MD, City of Hope Medical Center. Contact: Suzanne Swain-Cabriales, RN, 800-826-4673, sswain-cabriales@ coh.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01231386 Study Type: Observational Study Title: A Feasibility Study of a Novel Technique to Identify Circulating Breast Cancer Cells in Patients With Metastatic Breast Cancer Study Sponsor and Collaborators: Sidney Kimmel Comprehensive Cancer Center; National Cancer Institute Purpose: To study a new way of identifying circulating breast cancer cells in blood and in pleural or peritoneal fluid in women with metastatic breast cancer Ages Eligible for Study: 18 years and older Genders Eligible for Study: Female Accepts Health Volunteers: No Primary Outcome Measures: Feasibility of novel technique to identify and isolate circulating breast cancer cells (time frame: baseline) Principal Investigator: Vered Stearns, MD, Sidney Kimmel Comprehensive Cancer Center, 443-287-6547 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00897338 n

Continue treatment.* 1-4 Extend survival. For patients with advanced nonsquamous† NSCLC Median Overall Survival: 13.9 months with ALIMTA® (pemetrexed for injection) single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02 * Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent. After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA continuation maintenance showed extended overall survival with a safety profile consistent with previously reported ALIMTA single-agent trials

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.

Select Important Safety Information Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. Warnings and Precautions Premedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

Clinically relevant differences in survival probability as compared with placebo in certain patients* with advanced nonsquamous† NSCLC 1,4,5

a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy. b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Select Important Safety Information Warnings and Precautions ALIMTA can suppress bone marrow function as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Frequent blood monitoring is required with ALIMTA therapy. Dose adjustments, modifications, or suspension of therapy may be necessary based on hematologic and nonhematologic toxicities. Monitor renal function during ALIMTA therapy. ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

See the complete data at ALIMTAhcp.com/data See the Important Safety Information and Brief Summary for ALIMTA on the following pages. References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597. 4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Data on file, Eli Lilly and Company. ONC20120911A.

Indications for ALIMTA® (pemetrexed for injection) ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Important Safety Information for ALIMTA Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy. Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. Warnings and Precautions Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities. Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment. ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities. ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function. Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC) The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%). Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%). Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%). Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/ desquamation (10% vs 3%). Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%). Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Brief Summary of Prescribing Information on the adjacent page.

Drug Interactions See Warnings and Precautions for specific information regarding NSAID administration in patients with renal insufficiency.

PM_HCP_ISI_NSCLC1M_17OCT2012

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother. Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea. Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

PM90247

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Announcements

Researchers at Roswell Park Receive Grants to Study New Anticancer Agent in Lung, Colorectal, and Gastrointestinal Cancers

esearchers at Roswell Park Cancer Institute have been awarded three of four grants by the National Comprehensive Cancer Network (NCCN) Oncology Research Program to evalu-

ate and define the clinical effectiveness of the investigational compound nintedanib. Nintedanib is an investigational orally-administered triple angiokinase inhibitor that targets three of the re-

ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information. 1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.2 Nonsquamous Non-Small Cell Lung Cancer — Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information]. 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information. 2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. 2.3 Premedication Regimen and Concurrent Medications Vitamin Supplementation Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)]. Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)]. Corticosteroids Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)]. 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)]. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin. Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3.

75% of previous dose (pemetrexed and cisplatin). Nadir platelets <50,000/mm3 without bleeding 75% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin). Nadir platelets <50,000/mm3 with bleedinga, 50% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin). a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding. If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2. Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b Dose of ALIMTA Dose of Cisplatin (mg/m2) (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous 75% of previous dose dose Any diarrhea requiring hospitalization (irrespective 75% of previous 75% of previous of Grade) or Grade 3 or 4 diarrhea dose dose ALIMTA® (pemetrexed for injection)

PV 8927 AMP

ceptor tyrosine kinases shown to aid in the regulation of angiogenesis: fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.) Grade 3 or 4 mucositis

50% of previous dose

100% of previous dose

NCI Common Toxicity Criteria (CTC). Excluding neurotoxicity (see Table 3). In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity b

Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/ Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)]. 3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed. 4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. 5 WARNINGS AND PRECAUTIONS 5.1 Requirement for Premedication and Concomitant Medication to Reduce Toxicity Vitamin Supplementation Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0]. Corticosteroids Administer dexamethasone the day before, the day of, and the day after ALIMTA administration [see Dosage and Administration (2.3)]. 5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)]. 5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)]. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. 5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)]. 5.5 Required Laboratory Monitoring Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the ALIMTA® (pemetrexed for injection)

PV 8927 AMP

growth factor receptor (VEGFR). It is investigational and has not been approved by the U.S. Food and Drug Administration. These grants were made continued on page 168

The ASCO Post | OCTOBER 15, 2014

PAGE 168

Announcements Roswell Park Grants continued from page 167

possible through general research funding provided to NCCN from Boehringer Ingelheim Pharmaceuticals Inc.

Awards Provide More Than $1 Million to Conduct Studies The three researchers from Roswell

Park, Alex Adjei, MD, PhD, FACP, Patrick Boland, MD, and Renuka Iyer, MD, will collectively receive more than $1.3 million to conduct studies of the agent’s effectiveness in treating non-small cell lung cancer, metastatic colorectal cancer, and gastrointestinal carcinoid tumors, respectively. Angiogenesis, or the formation of

new blood vessels, is also involved in the growth of cancerous tumors by supplying nutrients and oxygen— often referred to as tumor angiogenesis.1 All three receptors, FGFR, PDGFR, and VEGFR. are associated with tumor angiogenesis, and their blockade may lead to the inhibition of tumor growth and spread.2

Funded Concepts Based on Select Criteria The awardees responded to a request for proposals issued by the NCCN Oncology Research Program to the 25 NCCN Member Institutions. Submissions were peer-reviewed by the NCCN Nintedanib Scientific Review Committee. The funded concepts

3 3 platelet is ≥100,000 cells/mm , and creatinine clearance is ≥45 mL/min [see platelet count is ≥100,000 cells/mm , andcount creatinine clearance is ≥45 mL/min [see Dosage Incidence 1%Dosage to 5% Incidence 1% to 5% Body as a Whole — febrile neutropenia, pyrexia Body asinfection, a Whole — febrile neutropenia, infection, pyrexia and Administration (2.4)]. and Administration (2.4)]. lacrimatio General Disorders — dehydrationGeneral Disorders — dehydration Inc 5.6 Pregnancy Category D 5.6 Pregnancy Category D Metabolism and Nutrition — increased AST, increased ALT — increased AST, increased ALT Metabolism and Nutrition Based on its action, ALIMTA can cause fetal harm when administered Based on its mechanism of action, ALIMTA canmechanism cause fetalofharm when administered — creatinine failureclearance decrease, renal failure Renal —renal creatinine to a pregnant woman. Pemetrexed administered intraperitoneally Renal to mice during clearance decrease, to a pregnant woman. Pemetrexed administered intraperitoneally to mice during Special — conjunctivitis Special Senses — conjunctivitis was embryotoxic, andthan teratogenic thanSenses 1/833rd organogenesis was embryotoxic,organogenesis fetotoxic and teratogenic in micefetotoxic at greater 1/833rd in mice at greater Incidence Less than 1% Incidence Less than 1% recommended If ALIMTA used during pregnancy, or if the patient the recommended human dose.theIf ALIMTA is usedhuman duringdose. pregnancy, or ifisthe patient Cardiovascular — arrhythmia Cardiovascular — arrhythmia while taking drug, ofthethepatient should be apprised of the potential becomes pregnant while taking becomes this drug,pregnant the patient should be this apprised potential General Co hazard to the fetus. Women of childbearing potential should be advised to avoid Disorders becoming — chest pain General Disorders — chest pain hazard to the fetus. Women of childbearing potential should be advised to avoid becoming Metabolism and Nutrition — increased GGT and Nutrition — increased GGT Metabolism Ind pregnant. Women should be advisedmeasures to use effective contraceptive measures to prevent pregnant. Women should be advised to use effective contraceptive to prevent Tab during treatment ALIMTA (8.1)]. [see Use in Specific PopulationsNeurology (8.1)]. — motor neuropathy Neurology — motor neuropathy pregnancy during treatment withpregnancy ALIMTA [see Use in Specificwith Populations Non-Small Cell Lung Cancer (NSCLC) – Maintenance Non-Small Cell Lung Cancer (NSCLC) – Maintenance of the 500 ADVERSE REACTIONS 6 ADVERSE REACTIONS 6 ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based maintenanI Therapy Therapy Th 6.1 Clinical Trials Experience6.1 Clinical Trials Experience provides the frequency and severity of adverse reactionsand reported in >5% of reactions reported Table 5 provides the frequency severity of adverse doses ofin Becauseunder clinical trialsvarying are conducted under widely varying Table 5 conditions, adverse Because clinical trials are conducted widely conditions, adverse 438 patients NSCLC ALIMTAwith maintenance the 218 patients with 438 patients NSCLC whoand received ALIMTA maintenance and thereductions 218 patie reactions ratesto cannot directly compared to rates in otherthe clinical trials andwith may not whothereceived reactions rates cannot be directly compared rates inbeother clinical trials and may not NSCLC who received placebo following platinum-based induction therapy. NSCLC awho received placebo following a platinum-based induction therapy. the placeb reflect the rates observed in clinical practice. reflect the rates observed in clinical practice. All patients received following platinum-based patients received study4 cycles therapyofimmediately following 4 cycles arm of platinum and 1 In clinical trials, the most common≥20%) adverseduring reactions (incidence ≥20%) duringstudy therapyAllimmediately In clinical trials, the most common adverse reactions (incidence treatment for locally advanced ortreatment metastaticforNSCLC. study arms werePatients fully in both study locally Patients advancedin orboth metastatic NSCLC. acidarms andwv therapy with a single-agent were fatigue, and anorexia. Additional therapy with ALIMTA as a single-agent wereALIMTA fatigue,asnausea, and anorexia. Additionalnausea, supplemented with folic vitamin B12. with folic acid and vitamin B12. common≥20%) adverse reactions ≥20%) during with ALIMTA when usedacid in andsupplemented common adverse reactions (incidence during therapy(incidence with ALIMTA when usedtherapy in Table combination cisplatin leukopenia, included vomiting, anemia, stomatitis/ combination with cisplatin included vomiting,with neutropenia, anemia,neutropenia, stomatitis/ leukopenia,Table Table 5: Adverse in Patients Receiving ALIMTA versus Placebi 5: Adverse Reactions in Patients ReceivingReactions ALIMTA versus Placebo ALIMTA a a pharyngitis, thrombocytopenia, and constipation. pharyngitis, thrombocytopenia, and constipation. in NSCLC in NSCLC Following Platinum-Based Following Platinum-Based Induction Therapy Induction Therapy Non-Small Cell inLung Cancer (NSCLC) – ALIMTA in Combination with Cisplatin Non-Small Cell Lung Cancer (NSCLC) – ALIMTA Combination with Cisplatin ALIMTA Placebo ALIMTA Placebo Adverse 4 provides the frequency andthat severity of adverse reactions that have been Table 4 provides the frequency Table and severity of adverse reactions have been (N=438) (N=218) (N=438) (N=218) Reactionb Reactionb Syst in >5% 839 randomized patients withtoNSCLC whoreceived were randomized to study and received reported in >5% of 839 patientsreported with NSCLC whoofwere study and Grades Grade Grade3-4 3-4 All Grades Grad ALIMTA plus and were 830 patients withtoNSCLC ALIMTA plus cisplatin and 830 patients with cisplatin NSCLC who randomized study who and were randomized to study and All Grades Grade 3-4 AllAllGrades Toxicity(%) (%) Toxicity Toxicity(%) (%) Toxicity (%) Toxic received gemcitabine plusstudy cisplatin. All as patients received gemcitabine plus cisplatin. All patients received therapy initial received treatmentstudy therapy as initial treatment Toxicity (%) Toxicity (%) Toxicity All Adve locallyand advanced NSCLCgroups and patients in both treatment groups were fully for locally advanced or metastaticforNSCLC patientsorinmetastatic both treatment were fully All66Adverse Reactions 37 All Adverse Reactions 16 3766 416 Laborat supplemented with folic acid andsupplemented vitamin B12. with folic acid and vitamin B12. Laboratory Laboratory Hemat TableSupplemented 4: Adverse Reactions in Fully Supplemented Table 4: Adverse Reactions in Fully Hematologic Hematologic Anem a a Receiving NSCLC Patients Receiving ALIMTA plusPatients Cisplatin in NSCLCALIMTA plus Cisplatin in Anemia 13 6 615 3 15 Anemia Neutro 03 0 06 3 6 Neutropenia Neutropenia ALIMTA/cisplatin Gemcitabine/cisplatin ALIMTA/cisplatin Gemcitabine/cisplatin Clinical 12 1 16 2 6 Leukopenia Leukopenia (N=839) (N=830) (N=839) (N=830) Reactionb Reactionb Constit Hepatic Hepatic Sympto Grades Grade Grade3-4 3-4 All Grades Grade 3-4 All Grades Grade 3-4 AllAllGrades Increased ALT 0 4 Increased ALT (%) 10 410 00 Fatigu Toxicity(%) (%) Toxicity Toxicity(%) (%) Toxicity (%) Toxicity Toxicity (%) Toxicity (%) Toxicity Increased AST 0 4 Increased AST 8 48 00 Gastro All 91 53 All Adverse Reactions 90Adverse Reactions 37 9190 5337 Clinical Clinical Nause Laboratory Laboratory Constitutional Constitutional Vomit Hematologic Hematologic Symptoms Symptoms Mucos 10 106 46 4633 6 33 Anemia Anemia Fatigue 11 Fatigue 25 5 1125 15 Genera 27 2715 38 3829 15 29 Neutropenia Neutropenia Gastrointestinal Gastrointestinal Edem 8 85 21 2118 5 18 Leukopenia Leukopenia 11 6 a 619 1 19 Nausea Nausea 13 134 27 2710 4 10 Thrombocytopenia Thrombocytopenia Adverse 02 5 519 2 19 Anorexia Anorexia adverse Renal Renal 00 1 19 0 9 Vomiting Vomiting Creatinine elevation 7 1 Creatinine elevation 10 1 710 11 01 2 b to those 27 1 7 Mucositis/stomatitis Mucositis/stomatitis NCI CTC 01 3 35 1 5 Diarrhea Diarrhea Clinical Clinical Ad Constitutional Constitutional Infection 2 Infection 5 2 25 02 erythropoi Symptoms Symptoms Neurology Neurology factors (6% Fatigue 45 5 Fatigue 43 7 4543 57 Neuropathy-sensory 4 Neuropathy-sensory 9 1 49 01 Th Gastrointestinal Gastrointestinal frequently Dermatology/Skin Dermatology/Skin 4 47 53 5356 7 56 Nausea Nausea Inc Rash/Desquamation 3 Rash/Desquamation 10 0 310 00 6 66 36 3640 6 40 Vomiting Vomiting a a 24 12 2427 2 27 Anorexia Anorexia Foroffthe purpose of thisfortable a cut off of events 5% waswhere used the for inclusion of all events w For the purpose of1this table a cut of 5% was used inclusion of all 0 a possible relationship 01 20 considered 2021 1 21 Constipation Constipation reporter considered reporter to ALIMTA.a possible relationship to ALIMTA. Inc b b 12 01 1214 1 14 Stomatitis/Pharyngitis Stomatitis/Pharyngitis Refer CTCAE Criteria version 3.0 for each Grade of toxicity. Refer to NCI CTCAE0 Criteria version 3.0toforNCI each Grade of toxicity. 2 21 13 No clinically relevant 1312 1 12 Diarrhea Diarrhea NoGrade clinically differenceswere in Grade 3/4patients adverse reactions were seen in differences in 3/4 relevant adverse reactions seen in 0 ethnic origin, 00 6 on age, gender, 65 0 5 Dyspepsia/Heartburn Dyspepsia/Heartburn basedoronhistology age, gender, origin, or histology except based exceptethnic a higher incidence of Grade 3/4a higher incidence of G fatigue for patients compared non-Caucasian fatigue for Caucasian patients compared to Caucasian non-Caucasian patients (6.5%toversus 0.6%). patients (6.5% versus 0 Neurology Neurology Safety was assessed by exposure for one patients by exposure for patients who received at least dosewho of received at least one Neuropathy-sensory Neuropathy-sensory 9 0 12 Safety was assessed 1 129 10 (N=438). The incidence of adverse reactions ALIMTA of adverse reactions was evaluated for patients whowas evaluated for patie Taste Taste disturbance 8 disturbance 0c 9 (N=438). The 0c incidenceALIMTA 98 0c0c ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of received ≤6 cycles of ALIMTA, andreceived compared to patients who received >6 cycles of ALIMTA. No Dermatology/Skin Dermatology/Skin in adverse reactions (all grades) werehowever observednowith longer exposure; how Increases in adversecreactions (allIncreases grades) were observed with longer exposure; Alopecia Alopecia 12 0c 21 1 2112 1c0c clinically in Grade clinically relevant differences in Grade 3/4relevant adversedifferences reactions were seen.3/4 adverse reactions were seen. increased Rash/Desquamation Rash/Desquamation 7 8 Consistent with 1 the higher incidence 0 87 10 Ada Consistent with(all thegrades) higher incidence of anemia (all grades) on the ALIMTA of anemia on the ALIMTA arm, use Sep a a For purpose of thisfortable a cut off of events 5% waswhere used the for inclusion of all events(mainly where RBC) the andof erythropoiesis For the purpose of this table a cut offthe of 5% was used inclusion of all transfusions (mainly RBC) agents and erythropoiesis stimulating agents (ESAs; eryth of transfusions stimulating (ESAs; erythropoietin Eso reporter considered reporter considered a possible relationship to ALIMTA.a possible relationship to ALIMTA. andALIMTA darbepoetin) were higher in the ALIMTA compared to the placebo arm (tran and darbepoetin) were higher in the arm compared to the placebo armarm (transfusions b NCI CTC Criteria version 2.0 for each Grade of toxicity.9.5% versus 3.2%, ESAs 5.9% versus Refer to NCI CTC Criteria versionb Refer 2.0 fortoeach Grade of toxicity. 6.2 Po 9.5% versus 1.8%). 3.2%, ESAs 5.9% versus 1.8%). c c According to NCI CTC Criteria version 2.0,only thisbe adverse event term should only be reported According to NCI CTC Criteria version 2.0, this adverse event term should reported following reactions were observed in patients withThno The following additional adverse The reactions wereadditional observedadverse in patients with non-small ALIMTA. B as Grade 1 or 2. as Grade 1 or 2. cell lung cancer who received ALIMTA. cell lung cancer who received ALIMTA. size, it is relevant differences in patients No clinically relevant differencesNoin clinically adverse reactions were seen in adverse patients reactions based were seen Incidence 1% to 5% Incidence 1% based to 5% relationsh on histology. on histology. Dermatology/Skin — alopecia, pruritus/itching Dermatology/Skin — alopecia, pruritus/itching Gastrointestinal — constipation Gastrointestinal — constipation Th to thetoxicity lower incidence of hematologic toxicity on the ALIMTA and cisplatin In addition to the lower incidenceInofaddition hematologic on the ALIMTA and cisplatin General edema, fever (in the absence of neutropenia) General (in theDisorders absence — of neutropenia) combinati arm, use ofand transfusions (RBC growth and platelet) wasDisorders lower in — edema, fever arm, use of transfusions (RBC and platelet) hematopoietic factorsand washematopoietic lower in growth factors Hematologic — thrombocytopenia — thrombocytopenia Blo the ALIMTA andgemcitabine cisplatin arm the gemcitabine and cisplatin Hematologic arm. the ALIMTA and cisplatin arm compared to the andcompared cisplatin to arm. — decreased de Renal decreased creatinineRenal clearance, increasedcreatinine creatinine,clearance, decreasedincreased creatinine, Ga following reactions were observed in patients with— non-small The following additional adverse The reactions wereadditional observedadverse in patients with non-small glomerular filtration rate glomerular filtration rate Ge celltolung cancer randomly cell lung cancer randomly assigned receive ALIMTA plus assigned cisplatin. to receive ALIMTA plus cisplatin.

ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection)

PV 8927 AMPfor injection) ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed

® PV 892 ALIMTA

PM HCP BS NSCLC1M 18Nov2013 PV8927 VERSION ALIMTA PM HCP BSALIMTA NSCLC1M 18Nov2013 PV8927 BRF SUM 6.5 x 9.5BRF SUM 6.5 x 9.5 PRINTER VERSION PRINTER 2 OF 4 ALIMTA P

ASCOPost.com | OCTOBER 15, 2014

PAGE 169

Announcements

were selected based on several criteria, including scientific merit, existing data, and the types of studies necessary to further evaluate the efficacy of nintedanib. The NCCN Oncology Research Program draws on the expertise of investigators at NCCN Member Institutions and the NCCN Affiliate

Research Consortium to facilitate all phases of clinical research.

Collaborative Efforts This research is made possible by collaborations with pharmaceutical and biotechnology companies in order to advance therapeutic options for patients with cancer. To date, this

successful research model has received approximately $49.5 million in research grants and supported 113 studies that have produced a number of publications in peer-reviewed journals. For more information about the NCCN Oncology Research Program and ongoing clinical trials, visit NCCN.org/ORP. n

Injury, poisoning, and proceduralrecall complications Injury, poisoning, and procedural complications — Radiation has been — Radiation recall has been Special Senses — ocular surface disease (including conjunctivitis), increased Special Senses — ocular surface disease (including conjunctivitis), increased reported received in patients who have previously received radiotherapy. reported in patients who have previously radiotherapy. lacrimation on Respiratory — interstitial pneumonitis Respiratory — interstitial pneumonitis Incidence Less than 1% cidence Less than 1% SkinStevens-Johnson — Bullous conditions, including Stevens-Johnson Skin — Bullous conditions, including syndrome and toxic epidermal syndrome and toxic epidermal Cardiovascular Cardiovascular — supraventricular arrhythmia — supraventricular arrhythmia necrolysis. Some cases were fatal.necrolysis. Some cases were fatal. Dermatology/Skin — erythema multiforme Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity General Disorders — febrile neutropenia, allergic reaction/hypersensitivity DRUG INTERACTIONS 7 DRUG INTERACTIONS 7 Neurology — motor neuropathy Neurology — motor neuropathy 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Renal — renal failure Renal — renal failure Although (400 mg fourthetimes a day)ofcan decrease the clearance of Although times ibuprofen a day) can decrease clearance ALIMTA ALIMTA as Maintenance Following ALIMTA Plus ibuprofen Platinum(400 mg four ontinuation of ALIMTA as Continuation Maintenance ofFollowing Plus Platinum pemetrexed, it caninbepatients administered with ALIMTA in patients with normal renal function pemetrexed, it can be administered with ALIMTA with normal renal function Induction Therapy duction Therapy clearance ≥80 mL/min). No dosewith adjustment of ALIMTA is needed with concomitant (creatinine clearance ≥80 mL/min).(creatinine No dose adjustment of ALIMTA is needed concomitant Table 6 provides the frequency severityinof>5% adverse reactions reported in >5% ble 6 provides the frequency and severity of adverse reactionsand reported NSAIDs in patients with normal renal function NSAIDs in patients with normal renal function [see Clinical Pharmacology (12.3)].[see Clinical Pharmacology (12.3)]. of the 500 patients non-squamous who received at least one cycle of ALIMTA 0 patients with non-squamous NSCLC whowith received at least oneNSCLC cycle of ALIMTA should NSAIDs be usedconcurrently when administering NSAIDs concurrently with ALIMTA Caution should be used when Caution administering with ALIMTA Induction (n=333) or placebo (n=167) ontrial. the continuation maintenance trial. mild to moderate nce (n=333) or placebomaintenance (n=167) on the continuation maintenance to patients with mild to(creatinine moderate clearance renal insufficiency to patients with renal insufficiency from 45 to(creatinine clearance from 45 to Theadministered median of maintenance cycles administered receiving one or more he median of maintenance cycles to patients receiving one or moreto patients 79 mL/min). 79 mL/min). nmaintenance >5% of doses4 of therapy was on botharms. the pemetrexed and NSAIDs placebo with arms.short Doseelimination NSAIDs therapy was on maintenance both the pemetrexed and 4placebo Dose short elimination half-lives (e.g., half-liveswith (e.g., diclofenac, indomethacin) shoulddiclofenac, indomethacin) should ents reductions for adverse events occurred 3.3%andof 0.6% patients ALIMTA arm and 0.6% in s forwith adverse events occurred in 3.3% of patients in the ALIMTAinarm in in the a period 2 daysfollowing before, the day of, and 2 days following administration be avoided for a period of 2 daysbe avoided before, theforday of, andof2 days administration placebo arm.occurred Dose delays for adverse events of patients in the ALIMTA bo arm. Dose delays forthe adverse events in 22% of patients in theoccurred ALIMTA in 22% of ALIMTA. of ALIMTA. m-based and 16% in the placebo in bothwith studyfolic arms were supplemented withof folic 16% in the placebo arm.arm Patients in both study arms arm. werePatients supplemented In the absence of data regarding potential interaction In the absence data regarding potential interaction between ALIMTA and NSAIDs withbetween ALIMTA and NSAIDs with were fully acid and vitamin B12. vitamin B12. half-livespatients (e.g., meloxicam, patients taking these NSAIDs should interrupt longer half-lives (e.g., meloxicam,longer nabumetone), taking thesenabumetone), NSAIDs should interrupt least2 days 5 daysfollowing before, the day of, and 2 days following ALIMTA administration. If for at Receiving least 5 days before,dosing the dayforof,atand ALIMTA administration. If Table 6:b Occurring Selecteda in e 6: Selecteda Adverse Reactions Adverse Occurring in ≥5%dosing of Patients ≥5% ofReactions Patients bReceiving bo concomitant administration of NSAIDs is necessary, patients concomitant administration is necessary, patients should be monitored closely for should be monitored closely for ALIMTA in Nonsquamous Following ALIMTA Plus Cisplatin Induction Therapy of NSAIDs in Nonsquamous NSCLC Following ALIMTA Plus NSCLC Cisplatin Induction Therapy toxicity, especially myelosuppression, toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.renal, and gastrointestinal toxicity. ALIMTA Placebo ALIMTA Placebo 7.2 Nephrotoxic Drugs 7.2 Nephrotoxic Drugs (N=333) (N=167) (N=333) (N=167) e Reaction Organ Adverse Reaction Organ ALIMTA is renally primarilyaseliminated ALIMTA is primarily eliminated unchanged a result of unchanged glomerular renally filtrationas a result of glomerular filtration a tem and Term System and Term All Grades Gradesa a Grades Grade3-4 3-4aa All Gradesa Grades 3-4a Grade 3-4a AllAllGrades and tubular secretion. Concomitantdrugs administration of nephrotoxic drugs could result in and tubular secretion. Concomitant administration of nephrotoxic could result in de 3-4 Toxicity(%) (%) Toxicity Toxicity(%) (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity delayed clearance of ALIMTA. Concomitantthat administration delayed clearance of ALIMTA. Concomitant administration of substances are also of substances that are also city (%) All53Adverse Reactions 34 secreted 4.8 erse Reactions 17 3453 4.817 tubularly (e.g., probenecid) potentially result in delayed clearance of ALIMTA. tubularly (e.g., probenecid) couldsecreted potentially result in delayedcould clearance of ALIMTA. 4 Laboratory tory 8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS Hematologic tologic 8.1 Pregnancy 8.1 Pregnancy Anemia 4.8 4.8 0.6 mia 15 4.8 4.815 0.6 Teratogenic Effects - Pregnancy Category D(5.6)]. [see Warnings and Precautions (5.6)]. Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions 1 Neutropenia 0.6 0 openia 9 3.9 0.69 03.9 Based on its action, ALIMTA can cause fetal harm when administered Based on its mechanism of action, ALIMTA canmechanism cause fetalofharm when administered 0 Clinical a pregnant are nostudies adequate and wellin controlled studies of ALIMTA in to a pregnant woman. There areto no adequatewoman. and wellThere controlled of ALIMTA 1 Constitutional tutional pregnant women. fetotoxic, Pemetrexed embryotoxic, fetotoxic, pregnant women. Pemetrexed was embryotoxic, andwas teratogenic in mice. In and teratogenic in mice. In Symptoms oms mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis 0 Fatigue 4.5 11 fetal malformations 0.6 ue 18 4.5 1118 0.6 caused ossification fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd caused (incomplete of talus and skull bone; about 1/833rd 0 2 the recommended intravenous dosepalate on a (1/33rd mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m basis),human and cleft Gastrointestinal ointestinal recommended human dose on a was mg/m2 basis). Embryotoxicity was the2.4recommended 0intravenous the human dose on aintravenous mg/m2 basis). Embryotoxicity 00.3 2.412 0.3 12 Nausea ea characterized increased characterized by increased embryo-fetal deathsbyand reducedembryo-fetal litter sizes. Ifdeaths ALIMTAandis reduced used litter sizes. If ALIMTA is used 0 00 1.8 1.86 0 6 Vomiting ting during pregnancy, or if while the patient while taking this drug, the patient during becomes pregnant taking becomes this drug,pregnant the patient 0 if the patient 00.3 2.4 pregnancy, or 2.45 0.3 5 Mucositis/stomatitis sitis/stomatitis 1 should be apprised of theWomen potential hazard to thepotential fetus. Women of childbearing potential should be apprised of the potential hazard to the fetus. of childbearing General Disorders al Disorders be advised to use effective contraceptive measures should be advised to use effectiveshould contraceptive measures to prevent pregnancy during the to prevent pregnancy during the Edema 3.6 with ALIMTA. 0 ma 5 0 3.65 00 treatment with ALIMTA. treatment 1 a reactions of any severity (all grades) more frequently (≥5%) orMothers Grade 3-4 reactions of any severityAdverse (all grades) occurring more frequently (≥5%) occurring or Grade 3-4 0 8.3 Nursing Mothers 8.3 Nursing reactions more frequently in ALIMTA-treatedIt patients reactions occurring moreadverse frequently (≥2%)occurring in ALIMTA-treated patients(≥2%) compared 0 It is ornotitsknown whetherareALIMTA metabolites are excreted in human is not compared known whether ALIMTA metabolites excretedor inits human to those receiving placebo receiving placebo 0 milk. Because manymilk, drugs excreted milk, milk. Because many drugs are excreted in human andarebecause of inthehuman potential forand because of the potential for b CAE 0 Criteria version 3.0 NCI CTCAE Criteria version 3.0 serious adverse ALIMTA, serious adverse reactions in nursing infants fromreactions ALIMTA, ina nursing decisioninfants should from be made to a decision should be made to of RBC (13%versus versus0.6%) 4.8%)transfusions, and platelet (1.5% versus 0.6%) transfusions, dministration of RBC (13% versusAdministration 4.8%) and platelet (1.5% discontinue nursinginto or discontinue drug, taking intodrug account the importance of the drug discontinue nursing or discontinue the drug, taking account the the importance of the 0 (12%colony versusstimulating 7%), and granulocyte colony stimulating for the mother. iesis stimulating agentserythropoiesis (12% versusstimulating 7%), and agents granulocyte for the mother. (6% versus were higher in the ALIMTA % versus 0) were higherfactors in the ALIMTA arm0)compared to the placebo arm.arm compared to the placebo arm. 8.4 Pediatric Use 8.4 Pediatric Use additional or 4 adverse he0 following additional Grade The 3 orfollowing 4 adverse reactionsGrade were3 observed more reactions were observed more Efficacy of in pediatric patients has not Efficacy of ALIMTA in pediatric patients hasALIMTA not been demonstrated. ALIMTA wasbeen demonstrated. ALIMTA was y in the ALIMTA arm. frequently in the ALIMTA arm. intravenous 10 cycle minutes administered as an intravenous administered infusion over as 10anminutes on Dayinfusion 1 of a over 21 day to on Day 1 of a 21 day cycle to Incidence 1% to 5% cidence 1% to 5% 0 patients with recurrent solidpatients) tumors and in a aPhase pediatric patients with recurrent pediatric solid tumors in a Phase 1 study (32 Phase1 study (32 patients) and a Phase Blood/Bone Marrow — thrombocytopenia Blood/Bone Marrow — thrombocytopenia 2 study (72 pretreatment patients). All with patients received pretreatment 2 study (72 patients). All patients received vitamin B12 and folic acid with vitamin B12 and folic acid where the General Disorders — febrile neutropenia General Disorders — febrile neutropenia supplementation and dexamethasone. dosedetermined escalation in the Phase 1 study determined supplementation and dexamethasone. The dose escalation in the PhaseThe 1 study Incidence Less than 1% cidence Less than 1% 2 the1910 maximum 1910 mg/mfor2 and the maximum tolerated dose was mg/mtolerated this dose (or 60 mg/kg for patients and thisdose dosewas (or 60 mg/kg patients Cardiovascular — ventricular tachycardia, syncope <12 months old) was evaluated in<12 months Cardiovascular — ventricular tachycardia, syncope wasofevaluated in therelapsed Phase 2orstudy of patients with relapsed or refractory the Phase 2old) study patients with refractory n patients General Disorders — pain General Disorders — pain osteosarcoma,PNET, Ewing sarcoma/peripheralneuroblastoma, PNET, rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing sarcoma/peripheral rhabdomyosarcoma, Grade 3/4 Gastrointestinal Gastrointestinal — gastrointestinal obstruction — gastrointestinal obstruction ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. 0.6%). Neurologic — depression Neurologic — depression No responses were observed among theThe 72 patients in this Phase 2 trial. The most common No responses were observed among the 72 patients in this Phase 2 trial. most common e dose of Renal — renal failure Renal — renal failure toxicities reported were hematological (leukopenia,anemia, neutropenia/granulocytopenia, anemia, toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, ents who thrombocytopenia, lymphopenia), liver function abnormalities (increased ALT/AST), thrombocytopenia, and lymphopenia), liver functionandabnormalities (increased ALT/AST), fVascular ALIMTA. — pulmonary embolismVascular — pulmonary embolism No relevant effect for ALIMTA due toexcept gender was identified, except an fatigue, and nausea. owever relevant due to gender or race wassafety identified, anor race fatigue, and nausea. no effect for ALIMTA safety increasedcompared incidence to of women (16%). rash in men (24%) compared to women (16%).The single dose pharmacokinetics d incidence of rash in men (24%) The single dose administered pharmacokinetics of ALIMTA of ALIMTA in doses rangingadministered in doses ranging Additional dditional Trials Experience Across Clinical Trials from 400 to 2480 mg/m from 400 to 2480 mg/m2 were evaluated were themales Phaseand 1 trial in 22 patients (13 males and in the Phase 1 2trial in evaluated 22 patientsin(13 arm, useExperience Across Clinical which in insome cases was 1% fatal,ofoccurred of patients. psis, which in some cases wasSepsis, fatal, occurred approximately patients. in approximately females)age aged to 18 Pemetrexed years (average age 12(AUC years). 9 females)1% aged 4 to 18 years 9(average 12 4years). exposure and Pemetrexed exposure (AUC and hropoietin Esophagitis occurred in less than 1% of patients. ophagitis occurred in less than 1% of patients. Cmax) appeared Cmax) appeared to increase proportionally to increase proportionally with dose. The average pemetrexed clearance with dose. The average pemetrexed clearance nsfusions 2 (2.30 L/h/m2) and half-life (2.3 (2.30 ) and half-life in pediatric patients were comparable to values hours)L/h/m in pediatric patients(2.3 werehours) comparable to values 6.2 Postmarketing Experience ostmarketing Experience reported in adults. use of reported in adults. adverse during reactions have been use identified post-approval heon-small following adverse reactionsThe havefollowing been identified post-approval of during Because these reactions are reportedof voluntarily uncertain 8.5 Geriatric Use Because these reactionsALIMTA. are reported voluntarily from a population uncertain from8.5a population GeriatricofUse it is not alwaystheir possible to reliably estimate their frequency orALIMTA establish a causal not always possible tosize, reliably estimate frequency or establish a causal ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse is known to be substantially excreted by the kidney, and the risk of adverse hip to drug exposure. relationship to drug exposure. reactions to thiswith drugimpaired may be greater in patients with impaired renal function. Renal function reactions to this drug may be greater in patients renal function. Renal function occurred ALIMTA when as a single-agent and in withmonitoring hese reactions occurred withThese ALIMTAreactions when used as awith single-agent and inused monitoring is recommended administration of ALIMTA. is recommended administration of ALIMTA. Nowith dose reductions other than No dose reductions other than combination therapies. ion therapies. those all patients areofnecessary for patients those recommended for all patients arerecommended necessary for for patients 65 years age or older [see 65 years of age or older [see Dosage and Administration (2.4)].Dosage and Administration (2.4)]. Blood and Lymphatic Systemanemia – Immune-mediated hemolytic anemia ood and Lymphatic System – Immune-mediated hemolytic ecreased 3,946across patients ≥65) trials studied[see across the five clinical trials [see Clinical Of 3,946 patients (34.0% ≥65) Of studied the(34.0% five clinical Clinical Gastrointestinal — colitis, pancreatitis astrointestinal — colitis, pancreatitis Studies 14.2, 14.3,onand 14.4)],was the similar effect ofinALIMTA the (14.1, effect of ALIMTA survival patientson survival was similar in patients General and—Administration Site Conditions —Studies edema (14.1, 14.2, 14.3, and 14.4)], eneral Disorders and Administration SiteDisorders Conditions edema

27(pemetrexed AMP ALIMTA® (pemetrexed for injection) PV 8927 AMP for injection)

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PAGE 170

Appointments

Ketan K. Badani, MD, Additional Staff, Appointed to Mount Sinai Health System

etan K. Badani, MD, Professor of Urology, Icahn School of Medicine at Mount Sinai in New York, has been named Vice Chairman of Urology and Robotic Operations and Director of the Comprehensive Kidney Cancer Program for the Mount Sinai Health Sys-

tem. Dr. Badani will also serve as Director of Robotic Surgery at Mount Sinai, St. Luke’s, and Mount Sinai Roosevelt. “Dr. Badani brings an innovative approach to treatment of kidney disease,” said Ash Tewari MBBS, MCh, Kyung Hyun Kim, MD, Chair in

Urology, Icahn School of Medicine at Mount Sinai and Chairman, Milton and Carroll Petrie Department of Urology at The Mount Sinai Hospital. “He is one of the most talented physicians in urology and we are fortunate to have him join our team.”

<65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia. 8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment. 8.8 Gender Of 3,946 patients (Male 70.5% ) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients. 8.9 Race Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients. 10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days. The ability of ALIMTA to be dialyzed is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (PPI) Instruct patients to read the patient package insert before initiating ALIMTA. t *OTUSVDU QBUJFOUT PO UIF OFFE GPS GPMJD BDJE BOE WJUBNJOø#12 supplementation to reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. t *OGPSN QBUJFOUT PG UIF SJTL PG MPX CMPPE DFMM DPVOUT BOE JOTUSVDU UIFN UP immediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia. t *OTUSVDU QBUJFOUT UP DPOUBDU UIFJS QIZTJDJBO JG QFSTJTUFOU WPNJUJOH EJBSSIFB PS signs of dehydration appear. t *OTUSVDU QBUJFOUT UP JOGPSN UIFJS QIZTJDJBO PG BMM DPODPNJUBOU QSFTDSJQUJPO or over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)]. To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch. Additional information can be found at www.AlimtaHCP.com

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Extensive Experience Dr. Badani has extensive experience in robotic kidney and prostate cancer surgery. He has performed nearly 4,000 robotic procedures. Dr. Badani developed the breakthrough surgical tech-

Ketan K. Badani, MD

nique known as FAST Robotic Partial Nephrectomy, which removes the cancerous portion of the kidney tiny openings, and leaves the normal, functional kidney tissue in the body. He also led one of the largest studies evaluating genomic biomarkers for the active surveillance or close monitoring of men with low-risk prostate cancer. In joining Mount Sinai, Dr. Badani said, “My goal is to grow our comprehensive kidney program into the world-class center spanning the treatment spectrum including surgery, ablation, surveillance, nephology, interventional radiology, and complementary medicine.” Dr. Badani comes to Mount Sinai from New York Presbyterian Hospital/Columbia University in New York, where he was Director of Robotic and Minimally Invasive Surgery.

Additional Staff Mount Sinai also welcomes Reza Mehrazin, MD, John Sfakianos, MD, and Seema Sheth, MD, as Assistant Professors of Urology, Icahn School of Medicine at Mount Sinai. Dr. Mehrazin has extensive training and certification in minimally invasive organ preservation and reconstructive techniques for patients with kidney and bladder cancer. His expertise includes open, laparoscopic, and robotic surgical techniques for the treatment of various urologic cancers. Dr. Sfakianos is a fellowship-trained urologic oncologist with clinical expertise in bladder and upper urinary tract urothelial carcinoma. An expert in advanced and complicated urological cancers, Dr. Sfakianos is skilled in both open and robotic procedures in the management of kidney, prostate, testicular and penile cancers. Dr. Sheth’s clinical interest include benign to malignant disorders affecting the urologic tract. n

PRINTER VERSION 4 OF 4

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PAGE 171

Integrative Oncology By Jyothirmai Gubili, MS Editor, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center

Milk Thistle Scientific names: Silybum marianum, Carduus marianum Common names: Holy thistle, lady’s thistle, Mary thistle, Marian thistle

he use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. We chose milk thistle for this issue because of its growing popularity among cancer patients.

purple colored flowers, it is considered an ornamental plant. Despite that designation, the medicinal history of milk thistle dates back more than 2,000 years. It was used as a remedy for disorders of the liver, biliary tract, and kidney. The leaves, stalks, and flowering heads of the plant were consumed as food. Today, milk thistle supplements are commonly used in many European countries to help manage liver diseases. Silymarin, the biologically active mixture of flavonoids isolated from milk thistle seeds, has been the focus of research over recent decades. Data from clinical trials show that silymarin is useful for the treatment of alcohol-induced liver disease and for reducing liver toxicity associated with chemotherapy. Silymarin was also found to be an effective antidote to Amanita phalloides, the deathcap mushroom, which is known

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and maintains a free website—About Herbs (www. Barrie R. Cassileth, MS, PhD mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the close to 300 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices. standardized to contain 70% to 80% silymarin.

The Science

Compiled by Barrie R. Cassileth, PhD, and Jyothi Gubili, MS, Memorial Sloan Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, MBA, LAc, Memorial Sloan Kettering Cancer Center.

Overview

Milk thistle is a flowering herb native to the Mediterranean regions of Europe, Africa, and the Middle East. It also grows in many other warm climates of the world. Because it produces bright

GUEST EDITOR

to cause serious liver damage. Milk thistle is available in the form of capsules, liquid extracts, and tinctures. The products are often

Preclinical studies indicate that flavonoids in milk thistle have antioxidant and anticancer effects1,2 and may protect against Alzheimer’s disease.3 Data from randomized clinical trials show that silymarin can reduce aminotransferases in alcoholic liver disease,4 and conclusions from a systematic review suggest that it helps treat liver cirrhosis.5 Silibinin, a constituent of silymarin, reduced liver toxicity associated with chemotherapy in children with acute lymphoblastic leukemia.6 A case study indicates the utility of intravenous silibinin in patients co-infected with human immunodeficiency virus and

hepatitis C virus.7 However, studies in other types of hepatic disease are flawed.8,9 One of the mechanisms underlying the hepatoprotective effects of silymarin is via downregulation of extracellular matrix proteins such as collagen.10 Silymarin supplementation may also play a role in improving the glycemic profile in patients with type 2 diabetes.11 In a recent study, silymarin demonstrated estrogenic activity with mild proliferative effects in rat uteri.12 Human studies are warranted.

Adverse Effects

Intermittent episodes of sweating, nausea, vomiting, diarrhea, abdominal pain, weakness, and collapse were reported following use of milk thistle.13 A 25-year-old man developed a severe

Learn More About

Herbs, Botanicals, & Other Products Visit the free About Herbs website at

http://www.mskcc.org/ cancer-care/herb/milk-thistle

PAGE 172

Integrative Oncology OF NOTE

Physicians should be aware of the potential for interaction between milk thistle and certain prescription drugs.

case of epistaxis, believed to have been due to self-medication with aspirin, garlic, and milk thistle.14 At high doses, silibinin can elevate bilirubin and liver enzymes.15

Herb-Drug Interactions

Cytochrome P450 3A4 substrates: Milk thistle inhibits cytochrome P450 and can affect the intracellular concentration of drugs metabolized by this enzyme.16 However, conflicting data indicate no such effects.17-19 UGT (Uridine 5´-diphospho-glucuronosyltransferase) substrates: Milk thistle modulates UGT enzymes in vitro and can increase the side effects of drugs metabolized by them.20 n

Disclosure: Ms. Gubili reported no potential conflicts of interest.

References 1. Ramasamy K, Agarwal R: Multitargeted therapy of cancer by silymarin. Can-

cer Lett 269:352-362, 2008. 2. Verschoyle RD, Greaves P, Patel K, et al: Evaluation of the cancer chemopreventive efficacy of silibinin in genetic mouse models of prostate and intestinal carcinogenesis: Relationship with silibinin levels. Eur J Cancer 44:898-906, 2008. 3. Yin F, Liu J, Ji X, et al: Silibinin: A novel inhibitor of Aâ aggregation. Neurochem Int 58:399-403, 2011. 4. Fehér J, Deák G, Müzes G, et al: Liverprotective action of silymarin therapy in chronic alcoholic liver diseases. Orv Hetil 130:2723-2727, 1989. 5. Saller R, Brignoli R, Melzer J, et al: An updated systematic review with meta-analysis for the clinical evidence of silymarin. Forsch Komplementmed 15:9-20, 2008. 6. Ladas EJ, Kroll DJ, Oberlies NH, et al: A randomized, controlled, double-blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL).Cancer 116:506513, 2010. 7. Payer BA, Reiberger T, Rutter K, et al: Successful HCV eradication and inhibition of HIV replication by intravenous silibinin in an HIV-HCV coinfected patient. J Clin Virol 49:131-133, 2010. 8. Salmi HA, Sama S: Effect of silymarin on chemical, functional, and morphologi-

New Books Address Aging, Survivorship

The ASCO Post | OCTOBER 15, 2014

cal alterations of the liver: A double blind study. Scand J Gastroenterol 17:517-521, 1982. 9. Ferenci P, Dragosics B, Dittrich H, et al: Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1:105-113, 1989. 10. Chen IS, Chen YC, Chou CH, et al: Hepatoprotection of silymarin against thioacetamide-induced chronic liver fibrosis. J Sci Food Agric 92:1441-1447, 2012. 11. Huseini HF, Larijani B, Heshmat R, et al: The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: A randomized, doubleblind, placebo-controlled, clinical trial. Phytother Res 20:1036-1039, 2006. 12. El-Shitany NA, Hegazy S, El-Desoky K: Evidences for antiosteoporotic and selective estrogen receptor modulator activity of silymarin compared with ethinylestradiol in ovariectomized rats. Phytomedicine 17:116-125, 2010. 13. Adverse Drug Reactions Advisory Committee: An adverse reaction to the herbal medication milk thistle (Silybum marianum). Med J Aust 170:218-219, 1999. 14. Shakeel M, Trinidade A, McCluney N, et al: Complementary and alternative medicine in epistaxis: A point worth considering during the patient’s history. Eur J

Emerg Med 17:17-19, 2010. 15. Flaig TW, Gustafson DL, Su LJ, et al: A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Invest New Drugs 25:139-146, 2007. 16. Venkataramanan R, Ramachandran V, Komoroski BJ, et al: Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucoronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 28:1270-1273, 2000. 17. Gurley B, Hubbard MA, Williams KD, et al: Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: Comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol 46:201-213, 2006. 18. Fuhr U, Beckmann-Knopp S, Jetter A, et al: The effect of silymarin on oral nifedipine pharmacokinetics. Planta Med 73:1429-1435, 2007. 19. Kawaguchi-Suzuki M, Frye RF, Zhu HJ, et al: The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. Drug Metab Dispos 42:16111616, 2014. 20. Mohamed ME, Frye RF: Effects of herbal supplements on drug glucuronidation. Review of clinical, animal, and in vitro studies. Planta Med 77:311-321, 2011.

Save the Date

by Authors at Memorial Sloan Kettering Cancer Center

Bookmark Author: Barrie Cassileth, PhD Format: Paperback ISBN: 978-1-938170-35-5 Pages: 216 Publication Date: April 1, 2014 Dimensions: 5.5 × 8.5 Also Available: eBook

Bookmark Title: Lighter as We Go: Virtues, Character Strengths, and Aging Authors: Mindy Greenstein, PhD, and Jimmie Holland, MD Publisher: Oxford University Press Publication date: September 2014 Price: $27.95; Hardcover, 320 pages

11th International Conference of the Society for Integrative Oncology October 26–October 28, 2014, Houston The 11th International Conference of the Society for Integrative Oncology will be held in Houston, Texas at the Omni Houston Galleria Hotel October 26-28, 2014. The conference theme is “Personalized Integrative Oncology: Targeted Approaches for Optimal Outcomes.” 2014 Conference Co-Chairs Richard Lee, MD Peiying Yang, MS, PhD The University of Texas MD Anderson Cancer Center. For more information, visit integrativeonc.org

ASCOPost.com | OCTOBER 15, 2014

PAGE 173

Book Review

Integrative Oncology: Mind, Body, and More By Ronald Piana

n 1990, David Eisenberg, MD, from the Harvard School of Public Health, conducted a survey that found a growing percentage of American cancer patients were using treatments outside of mainstream oncology, without conferring with their oncologists. Dr. Eisenberg’s work would garner attention from freethinkers in the oncology community who saw potential benefit in evidence-based “complementary” therapies.

Andrew T. Weil, MD

oncology can be defined as the rational, evidence-based combination of conventional therapy with complementary interventions into an individualized therapeutic regimen that addresses the whole person living with and beyond cancer—body, mind, and spirit.” So what can a reader expect in Integrative Oncology? First off, it is a large, heavily referenced book, running 848 pages with 29 chapters and 44 contributors. To manage this large volume of content in a reader-friendly way, the authors begin each chapter with a bulleted list of key concepts and boxed highlights. The tables and figures interspersed throughout the book have an equally readable design. Further, to make for easy retrieval of information from source documents, the editors provide the reader with a bibliography in each chapter.

Big Statements

Donald I. Abrams, MD

Continued effort and curiosity in merging complementary approaches with standard cancer care would eventually evolve into a new discipline known as integrative oncology. This discipline has become an integral part of oncology care, as evidenced by the recently released second edition of Integrative Oncology, edited by best-selling author and television personality Andrew T. Weil, MD, and well-known integrative medicine specialist Donald I. Abrams, MD.

In chapter 1, titled “Why Integrative Oncology?” Dr. Weil opens by explaining that integrative medicine is an established movement in North America and China, and growing in acceptance in most other regions of the globe. He writes, “I am confident that it is the direction medicine and health care must take to address the demands from patients, dissatisfaction of practitioners, and the worsening economics of health care worldwide.” That’s a big statement to make in the first paragraph of a book. Challenging the status quo is admirable, and much needed if we are indeed going to improve our health-care system. But Dr. Weil also wades into some deep water as he closes chapter 1, by discussing hormonally driven cancers, primarily cancer of the breast and prostate.

This is a book tailored to pull the oncologist out of his or her comfort zone, and it succeeds. Reader-Friendly Design Integrative oncology’s road to acceptance into standard oncologic care has had its rough patches, one of which was determining a name and definition that would separate it from alternative medicine, whose practitioners have plagued vulnerable cancer patients with spurious therapies. In the preface to the first edition, Dr. Abrams wrote, “Integrative

He writes, “There is good evidence that moderate, regular consumption of whole soy food, beginning early in life, affects the development of the female breast in ways that make it resistant to malignant growth.” He continues by contending that soy products offer significant protection against prostate cancer. Then he takes on the U.S. dairy industry, asserting, “there

is growing evidence that the hormonal content of cow’s milk in North America (and products made from it) add to other hormonal pressures, both exogenous and endogenous, that increase the possibility of malignant growth in both the breast and prostate.” Again, these are big statements, and he says they are backed by “good evidence.” Oncology is evidence-driven, so from the onset, Dr. Weil will be challenged by much of The ASCO Post’s readership on the quality of his “good evidence.” One more point about the opening chapter: Dr. Weil believes that the first generation of integrative oncologists will probably find themselves most in demand as consultants, helping patients with difficult decisions about conventional treatments and advising them about various risks/benefits and dietary strategies. For this evolution to begin, it’s important that integrative oncologists work in concert with the physicians delivering chemotherapy or radiation. This will require a lot of organization and all of these clinicians getting on the same evidence-based page. Partnering with establishments such as ASCO, which has sophisticated integrated communication systems in place, will go a long way toward unifying the goals set out in this book.

Provocative Postulates Dr. Abrams and Manuel Guzman, MD, are the authors of chapter 8, “Cannabinoids and Cancer.” Given the recent legalization of marijuana for recreational use in Colorado, this chapter takes on more popular interest. Appetite stimulation and antiemetic properties have long been established in cannabis; however, Drs. Abrams and Guzman drill much deeper into the issue than symptom control. Both are experts in cannabinoids, having researched the subject for decades. They lead off with a brief and informative history of cannabis as medicine and then delve into the drug’s pharmacology. However, this chapter also includes one of the book’s more provocative postulates: “A growing body of preclinical evidence suggests that cannabis may not only be effective for symptom management, but may have a direct antitumor effect as well.” Drs. Abrams and Guzman boldly

Bookmark Title: Integrative Oncology (Second Edition) Editors: Donald I. Abrams, MD, and Andrew T. Weil, MD Publisher: Oxford University Press Publication date: September 3, 2014 Price: $65.00; Paperback, 848 pages; also available as eBook

Caveat Emptor Integrative Oncology, second edition, is presumably geared to oncologists and other physicians. It is important to note, however, that many patients with cancer and their family members may also buy the book. Oncologists should be cognizant of some of the undocumented messages in the book, which members of the general public, including patients with cancer, may pursue in desperation. This should be borne in mind when speaking to your patients about the role of evidencebased integrative oncology in their treatment plan.

write that evidence from cell culture systems and animal models have suggested that tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, and other cannacontinued on page 174

The ASCO Post | OCTOBER 15, 2014

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Book Review Mind, Body, and More continued from page 173

binoids “may inhibit growth of some tumors by the modulation of signaling pathways that lead to growth arrest and cell death as well as inhibition of angiogenesis and metastasis.” The exploration of possible antitumorigenic properties in cannabinoids is intriguing, and it illustrates the dichot-

formation about assuaging symptoms such as hot flashes, nausea and vomiting, and xerostomia. The editors are correct in stressing the need for investigators to continue to study these complementary therapies for efficacy and safety. However, the book also veers into the outer reaches of complementary oncology, some of which may test the patience of more conservative physi-

Integrative oncology is an exciting new discipline that offers best-practice methods to prevent cancer and support those affected by it on all levels. omy within the book. The editors offer the reader a good deal of proven methodologies that the integrative oncologist can add to the symptom management and palliative care armamentarium. The best of these sections give spot-on in-

cians—for example, chapter 15, “Energy Medicine and Cancer.” This medicine is described as a complementary modality whose practitioners purport to restore the flow of energy fields associated with the human body for

symptom relief or disease prevention. Other chapters explore the use of similar alternative therapies as primary cancer treatments or anthroposophic medicine (a holistic approach integrating conventional tumor therapy and plant or mineral medications). These are speculative journeys into the future about strategies that will require much research before being accepted by the broader oncology community.

Closing Thoughts That said, all of the narrative is well written and thought provoking. This is a book tailored to pull the oncologist out of his or her comfort zone, and it succeeds. Integrative oncology is an exciting new discipline that offers best-practice methods to prevent cancer and support those affected by it on all levels: body, mind, and spirit. This comprehensive

book provides meticulous, well-written chapters on proven and yet-to-be-proven methods for enhancing cancer care with integrative oncology. Here’s a tip: instead of reading this in linear fashion from page 1 on, try reading selectively, picking out and mixing chapters on established methods with those that remain controversial, such as chapter 10, “The Antioxidant Debate.” It will make for a more fun way to digest this mountain of information. The editors were wise to end the book with the chapter titled, “A Patient’s Perspective.” After all, the patient is what this is all about. And the second edition of Integrative Oncology gives clinicians more knowledge and skills to deliver high-quality care to their patients. This book is highly recommended, especially for students and fellows whose practice philosophy on the science and art of oncology is still emerging. n

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Poetry in Oncology

The Audacity of Courage

(and the Conditional Fallacies in Statistics) By Parvez Dara, MD, FACP We have tools We have ghouls But nowhere are there more fools Than in the rules from those who govern the tools! In the bias That climbs on the shoulders To bring plausibility Through implied causality, Where is ignorance? Where is reality? Where are all the tools of Reason? When did justification Fill the void And intellect Become Treason? In the name of Progress! For every season What is it that drives this madness? What is it that foments this fear? What is it that stokes this fire? Of Ignorance laid bare!

When did this tall sap Spawned by the spray of illogic Blown through the aperture Of a fat tail Confined to the deviation of two Become logic? I see Before me The making of a genie Devoid of Bayesian food That cannot answer a wish But bloats and floats Hovers and covers Behind the mask of We! Frailty thy name is true Pseudo in your thought Mocking in your action You always fall from grace But never too far From the sap Where your existence Remains tethered in place!

Oh humanity how foolish Oh reason how devoid Of life how gray Of living how perilous What is to become? What is to remain? What is in the end? But emptiness and blame! The logic of a strain That grows viral each day From this to this And that to that From tools from ghouls That manifest! The impoverished spirit that makes us less! Should we not complain? Should we hide our feelings? Should we live in disdain? Should we marshal thoughts Float them into life’s vein And continue our effaced reeling?

Or forge the audacity Of courage Not crying for fear Nor living in rear And use the limits Of Common Sense To force life Into the future tense! When love of virtue Integrity of knowledge Wisdom of time And governance of province Will bring ceremony To Logic And free of treason Life will be whole And True Once again Matched to Reason!

Dr. Parvez Dara is an oncologist in private practice in Toms River, New Jersey.

THE SIDE OF CANCER YOU’RE NOT SEEING

The Oncotype DX® assay reveals the unique biology of a tumor, presenting a more complete and individualized picture of the patient’s cancer. It is essential information that can fundamentally change decisions about treatment. With over 440,000 patients tested worldwide, the Oncotype DX portfolio—assays for breast, colon, and prostate—is a world leader in applying genomic science to cancer treatment planning. For more information on using the Oncotype DX assay with appropriate patients, visit OncotypeDX.com/portfolio.

breast | colon | prostate

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2014-2015 Oncology Meetings October 18th SIS World Congress on Breast Healthcare October 16-19 • Orlando, Florida For more information: www2.kenes.com/sis/Pages/Home. aspx 2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org Atlanta Lung Cancer Symposium October 18 • Atlanta, Georgia For more information: www.phillipsgilmore.com/alcs2014 16th World Congress of Psycho-Oncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com

11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

14th Annual Conference of SIOG October 23-25 • Lisbon, Portugal For more information: www.siog.org

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: www.cutaneousmalignancies.com

11th Annual Meeting of the International Society of Gastrointestinal Oncology (ISGIO) October 23-24 • Arlington, Virginia For more information: www.isgio.org

20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/ home/programs/physicians

ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston, Massachusetts For more information: www.palliative.asco.org

2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org

SAVE THE DATE NPs

FO R

YO UR

AN D

PA s

October 30TH – November 2ND Loews Royal Pacific Hotel at Universal Orlando, FL

A CE/CME/CEU Conference for Advanced Practitioners in Oncology

apsho.org/jadprolive

2014-2015

3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail. aspx/80028747 CNS Anticancer Drug Discovery/ Development Conference November 12-13 • Miami Beach, Florida For more information: www.soc-neuro-onc.org Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: www.mayo.edu/cme/surgicalspecialties-2014s306 19th Annual Meeting of the Society for Neuro-Oncology November 13-16 • Miami Beach, Florida For more information: www.soc-neuro-onc.org/

European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl RSNA 2014: Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

December American Association for Cancer Research: Tumor Immunology December 1-4 • Orlando, Florida For more information: www.aacr.org Society of Urologic Oncology 15th Annual Meeting December 3-5 • Bethesda, Maryland For more information: http://suonet. org/meetings/2014/default.aspx UICC World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org 24th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists December 5-7 • Vienna, Austria For more information: iasgo2014.org ASH Annual Meeting and Exposition December 6-9 • San Francisco, California For more information: hematology.org

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org ESMO Symposium on Immuno-Oncology November 21-22 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ Immuno-Oncology-2014

37th Annual San Antonio Breast Cancer Symposium December 9-13 • San Antonio, Texas For more information: www.sabcs.org

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2014-2015 Oncology Meetings January 2015 Melanoma 2015: 25th Annual Cutaneous Malignancy Update January 10-11 • San Diego, California For more information: www.scripps.org/events/melanomaannual-cutaneous-malignancyupdate-january-10-2015 Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org 11th Annual Clinical Breakthroughs and Challenges in Hematologic Malignancies January 17 • Lake Buena Vista, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

February 2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11-15 • San Diego, California For more information: www.asbmt.org 5th International Conference on Innovative Approaches in Head & Neck Oncology February 12-14 • Nice, France For more information: www.estro.org/congressesmeetings/items/5th-ichno The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 19-21 • San Diego, California For more information: www.imedex.com/antiangiogenesis-and-immunetherapies/

Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org

2014-2015

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

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

NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp

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

6th Current Concepts in the Management of Thyroid and Parathyroid Neoplasms February 26-28 • Houston, Texas For more information: www.mdanderson.org 32nd Annual Miami Breast Cancer Conference® February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/32nd-AnnualMiami-Breast-Cancer-Conference

March 13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers March 5-8 • Orlando, Florida For more information: www.aacr. org 16th European Congress: Perspectives in Lung Cancer March 6-7 • Torino, Italy For more information: www.imedex.com/lung-cancercongress-europe/index.asp Advances in the Management of Multiple Myeloma March 6-7 • Saint Petersburg, Florida For more information: http:// moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial Sloan-Kettering Cancer Center March 6-9 • New York, New York For more information: www.mskcc.org/ hemoncreviewcourse

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 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 State-of-the-Art Neuro-Oncology Conference: 3rd Annual Meeting March 19-20 • Clearwater Beach, Florida For more information: http://moffitt. org/for-physicians-healthcareprofessionals/conferences/ conferences 21st Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 19-21 • Stevenson, Washington For more information: www.ohsu.edu/bbb Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/

April American Brachytherapy Society Annual Meeting April 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index.cfm 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 ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: http://www.esmo.org/Conferences/ ELCC-2015-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 179

ASCO Meetings ASCO Quality Care Symposium

quality.asco.org

October 17-18, 2014 | Boston, Massachusetts

Palliative Care in Oncology Symposium

pallonc.org

October 24-25, 2014 | Boston, Massachusetts Cosponsored with: American Academy of Hospice and Palliative Medicine, American Society for Radiation Oncology, and Multinational Association of Supportive Care in Cancer

Gastrointestinal Cancers Symposium

gicasym.org

January 15–17, 2015 | San Francisco, California Cosponsored with: American Gastroenterological Association Institute, American Society for Radiation Oncology, and Society of Surgical Oncology

Celebrating Ten Years

Genitourinary Cancers Symposium Celebrating Ten Years

gucasym.org

February 26–28, 2015 | Orlando, Florida Cosponsored with: American Society for Radiation Oncology and Society of Urologic Oncology

Annual Meeting

am.asco.org

May 29–June 2, 2015 | Chicago, Illinois

Best of ASCO Boston Meeting

boa.asco.org

July 31-August 1, 2015 | Boston, Massachusetts

Best of ASCO San Francisco Meeting

boa.asco.org

August 7-8, 2015 | San Francisco, California

Best of ASCO Chicago Meeting

boa.asco.org

August 28–29, 2015 | Chicago, Illinois

Breast Cancer Symposium September 25-27, 2015 | San Francisco, California

Celebrating Ten Years

breastcasym.org

ASCOPost.com | OCTOBER 15, 2014

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2014-2015 Oncology Meetings continued from page 177

May 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 American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.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 The International Society of Ocular Oncology (ISOO) Meeting June 16-19 • Paris, France For more information: http://www.isoo.org

June

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

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

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

2014-2015

July

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/ professionals/meetings-ed/ annualconference.aspx Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

August Best of ASCO - San Francisco August 7-8 • San Francisco, California For more information: http://boa.asco.org/

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.php2

Statement of Ownership, Management and Circulation (Requester Publication) 1. Publication Title: The ASCO Post. 2. Publication Number: 2154-3283. 3. Filing Date: 9/25/14. 4. Issue Frequency: Semimonthly, except in May. 5. Number of Issues Published Annually: 23. 6. Annual Subscription Price (if any) $300.00. 7. Complete Mailing Address of Known Office of Publication: Harborside Press LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. Contact Person: John Gentile. Telephone: 631-935-7655. 8. Complete Mailing Address of Headquarters or General Business Office of Publisher: Harborside Press LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. 9. Full Names and Complete Mailing Addresses of Publisher, Editor, and Managing Director: Publisher: John A. Gentile Jr, Harborside Press LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. Editor: James O. Armitage, MD, Harborside Press LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. Managing Editor: Cara Glynn, Harborside Press LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. 10. Owner: Full Name: Harborside Press LLC, John A Gentile Jr (Principal), Anthony Cutrone (Principal), Conor Lynch (Principal). Complete Mailing Address: 37 Main St, Cold Spring Harbor, NY 11724-1423. 11. Known Bondholders, Mortgagees, and Other Security Holders Owning or Holding 1 Percent or More of Total Amount of Bonds, Mortgages, or Other Securities: None. 12. Tax Status: N/A. 13. Publication Title: The ASCO Post. 14) Issue Date for Circulation Data Below: September 15, 2014. 15. Extent and Nature of Circulation - Average No. Copies Each Issue During Preceding 12 Months. a. Total Number of Copies (Net press run): 28,523. b. Legitimate Paid and/or Requested Distribution (By Mail and Outside the Mail) (1) Outside County Paid/Requested Mail Subscriptions stated on PS Form 3541: 14,576. (2) In-County Paid/Requested Mail Subscriptions stated on PS Form 3541: N/A. (3) Sales Through Dealers and Carriers, Street Vendors, Counter Sales, and other Paid or Requested Distribution Outside USPS®: N/A. (4) Requested Copies Distributed by Other Mail Classes Through the USPS (e.g. First-Class Mail®): 17. c. Total Paid and/or Requested Circulation (sum of 15b (1), (2,), (3), and (4): 14,593. d. Nonrequested Distribution (By Mail and Outside the Mail) (1) Outside County Nonrequested Copies Stated on PS Form 3541: 13,754. (2) In-County Nonrequested Copies Stated on PS Form 3541: N/A. (3) Nonrequested Copies Distributed Through the USPS by Other Classes of Mail: N/A. (4) Nonrequested Copies Distributed Outside the Mail: 107. e. Total Nonrequested Distribution (Sum of 15d (1), (2), (3) and (4)) 13,861. f. Total Distribution (Sum of 15c and e.): 28,454. g. Copies not Distributed: 69. h. Total (Sum of 15f and g) 28,523. i. Percent Paid and/or Requested Circulation: 51% 15) Extent and Nature of Circulation - No. Copies of Single Issue Published Nearest to Filing Date. a. Total Number of Copies (Net press run): 28,772. b. Legitimate Paid and/or Requested Distribtuion (By Mail and Outside the Mail) (1) Outside County Paid/Requested Mail Subscriptions stated on PS Form 3541: 14,542. (2) In-County Paid/Requested Mail Subscriptions stated on PS Form 3541: N/A. (3) Sales Through Dealers and Carriers, Street Vendors, Counter Sales, and other Paid or Requested Distribution Outside USPS®: N/A. (4) Requested Copies Distributed by Other Mail Classes Through the USPS (e.g. First-Class Mail®): 23. c. Total Paid and/or Requested Circulation (sum of 15b (1), (2,), (3), and (4): 14,565. d. Nonrequested Distribution (By Mail and Outside the Mail) (1) Outside County Nonrequested Copies Stated on PS Form 3541: 13,456. (2) In-County Nonrequested Copies Stated on PS Form 3541: N/A. (3) Nonrequested Copies Distributed Through the USPS by Other Classes of Mail: N/A. (4) Nonrequested Copies Distributed Outside the Mail: 15. e. Total Nonrequested Distribtuion (Sum of 15d (1), (2), (3) and (4)) 13,471. f. Total Distribution (Sum of 15c and e): 28,036. g. Copies not Distributed: 176. h. Total (Sum of 15f and g) 28,772. i. Percent Paid and/or Requested Circulation: 52% 16. Total circulation does not include electronic copies. 17. Publication of Statement of Ownership for a Requester Publication is required and will be printed in the October 15 2014 issue of this publication. 18. Signature and Title of Editor, Publisher, Business Manager, or Owner: John A Gentile Jr, Publisher. Date: 9/25/14. I certify that all information furnished on this form is true and complete. I understand that anyone who furnishes false or misleading information on this form or who omits material or information requested on the form may be subject to criminal sanctions (including fines and imprisonment) and/or civil sanctions (including civil penalties).

The ASCO Post | OCTOBER 15, 2014

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Announcements

Roswell Park Researchers Awarded Nearly $5 Million to Support Research Projects

everal faculty members at Roswell Park Cancer Institute have been awarded nearly $5 million in grant funding from public and private organizations to further their efforts to find new and better ways to detect and treat cancer and improve patients’ quality of life. The 13 awards, including two for more than $1 million each, will support projects ranging from an investigation of differences among e-cigarette devices to a study assessing the anti-cancer potential of a drug for amyotrophic lateral sclerosis, or Lou Gehrig’s disease. Maciej Goniewicz, PhD, PharmD, an Assistant Member of the Department of Health Behavior, has been awarded a 3-year, $1.38 million

Facility, received a 4-year, $1.35 million award from the National Cancer Institute (NCI) for a clinical study that aims to generate a potent “army” of immune cells from a patient’s own blood to

specifically and efficiently fight cancer by utilizing innovative gene-therapy techniques, such as TGF-beta blockade in Tcell-receptor-engineered immunotherapy, an approach developed in his lab.

This work may establish a new treatment paradigm based on immune-cell therapy for eradicating melanoma, sarcoma and ovarian cancer cells, and takes advantage of several state-of-the-art resources with-

Maciej Goniewicz, PhD, PharmD

grant from the National Institute on Drug Abuse to lead a multisite clinical research study, collaborating with the University at Buffalo and University of California–San Francisco, to analyze nicotine delivery from novel nontobacco electronic systems, or e-cigarettes. The researchers will look at variations among brands of e-cigarettes and what those differences mean for users, such as how much nicotine is delivered into the bloodstream and how flavorings affect the way smokers puff, as well as the amount of nicotine inhaled. The goal is to propose a standardized testing protocol for these devices that will aid future research and offer consumers a reliable way to compare risks and benefits. Richard Koya, MD, PhD, an Associate Professor of Oncology in the Center for Immunotherapy and Director of the Vector Development and Production

Richard Koya, MD, PhD

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ASCOPost.com | OCTOBER 15, 2014

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Announcements

in RPCI’s Center for Immunotherapy. Shahriar Koochekpour, MD, PhD, a Professor of Oncology in the Departments of Cancer Genetics, Medicine, and Urology, received a 2-year, $406,247 grant from the NCI for an investigation into the potential for treating prostate cancer with a drug that’s prescribed for amyotrophic lateral sclerosis. Dr. Kooch-

ekpour will evaluate the therapeutic efficacy of the U.S. Food and Drug Administration-approved oral drug riluzole and its association with fatty-acid synthase, a key enzyme that’s overexpressed in prostate cancer cells. Fengzhi Li, PhD, an Associate Professor of Oncology in the Department of Shahriar Koochekpour, MD, PhD

Fengzhi Li, PhD

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continued on page 182

The ASCO Post | OCTOBER 15, 2014

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Announcements Roswell Park continued from page 181

Pharmacology and Therapeutics, received a 2-year, $406,247 grant from the NCI for his study of a new anticancer agent, FL118, against pancreatic cancer. Survival rates for pancreatic cancer remain poor due to the cancerâ&#x20AC;&#x2122;s inherent resistance to existing chemotherapy and radiation

treatments. FL118 is designed to overcome multiple common mechanisms of treatment resistance, including increased expression of cancer-associated antiapoptotic proteins and loss of functional p53. Jianmin Zhang, PhD, an Assistant Professor in the Department of Genetics, received a 2-year, $406,247 grant from the NCI for a project that will compare how

Jianmin Zhang, PhD

Hippo signaling pathway components are expressed in African-American and European-American breast cancer patients. This translational approach will help to identify women at high risk for aggressive breast cancer toward the goal of eliminating breast cancer racial disparities. Hans Minderman, PhD, an Assistant Professor of Oncology in the De-

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Announcements

Hans Minderman, PhD

partment of Experimental Therapeutics and Assistant Director of the Flow and Image Cytometry Facility, received a 1-year, $399,500 shared-instrument grant from the NIH for the purchase of an imaging flow cytometer. RPCIâ&#x20AC;&#x2122;s Flow and Image Facility is recognized as a leader in applications of imaging flow cytometry, and the implementa-

tion of this technology at Roswell Park has increased demand by RPCI teams and researchers for this cutting-edge analysis. The instrument will allow the facility to meet increased demand for flow-cytometry analysis. Scott Abrams, PhD, a Professor of Oncology in the Department of ImmuScott Abrams, PhD

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continued on page 184

The ASCO Post | OCTOBER 15, 2014

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Announcements Roswell Park continued from page 183

nology, received a 2-year, $125,935 research supplement to promote diversity in health-related research from the NCI. This grant supplements his ongoing R01 project, which explores IRF-8 as a negative regulator of CD11b+Gr-1+ myeloid production function. This new

award supports the work of doctoral student Danielle Twum in Dr. Abramsâ&#x20AC;&#x2122; laboratory. The research project continues to focus on the broad questions of how cancer corrupts host-defense mechanisms, a process ordinarily critical in the fight against these diseases. The work aims to find new ways to track or treat cancer patients in whom tumor-

induced immune defects are thought to play a role in the disease process. Yasmin Thanavala, PhD, a Professor and Member of the Department of Immunology, received a 1-year, $108,500 award from the Flight Attendant Medical Research Institute Inc. (FAMRI) to explore how second-hand tobacco smoke contributes to immune suppres-

Yasmin Thanavala, PhD

sion and chronic inflammation, both of which lead to bacterial and viral respiratory infections. These infections further increase inflammation, contributing to a vicious cycle. Dr. Thanavala hopes to develop novel therapies to restore normal immune function and break the cycle. The mission of FAMRI is to sponsor scientific and medical research for the early detection and cure of diseases and medical conditions caused from exposure to tobacco smoke. Sergei Kurenov, MS, Director of Surgical Simulation in the Department of Surgical Oncology, received a fouryear, $69,010 subcontract award from

Sergei Kurenov, MS

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the University of Florida (UF), part of a larger R01 award to UF from the National Institute of Biomedical Imaging and Bioengineering. Dr. Kurenov will help develop software for simulationbased virtual-reality modules used to train physicians in laparoscopic surgery and assess their expertise. Denise Rokitka, MD, an Assistant Professor in the Department of Pediatric Oncology, received a Hyundai Hope Grant, a 2-year, $250,000 award from the Kaleida/Hyundai Hope Foundation, to explore executive functioning, such as reasoning, problem-solving, organization, planning and behavior control among young adult survivors of childhood and adolescent cancer and how these factors relate to quality of life

Denise Rokitka, MD

ASCOPost.com | OCTOBER 15, 2014

PAGE 185

Reflections

Fear By Michael Feinstein, MD The following essay by Michael Feinstein, MD, is excerpted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was co-edited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon.com and thebigcasino.org.

ancer, often referred to uneasily as “The Big C,” is a word we are brought up to dread. Cancer is associated with pain, suffering, and death. A diagnosis of cancer causes a range of emotions: shock, anger, disappointment, frustration, and, of course, fear. “Why me?” is a prevalent response. It’s normal to think about dying, but the intense fear of doing so can be debilitating. Responses differ from person to person, but the fear and the anxiety of the outcome remain. Unfortunately, most people equate cancer with death. They don’t know that some cancers have a better prognosis than others and that some can-

cers do better than other diseases. The survival of cancer varies substantially, not only based on the type of malignancy, but also on the individual patient. Today, nearly 14 million people are living with cancer or have survived the disease. Cancer is all around us—in our families, our friends, our heroes, and our enemies. What is it like to be told that you have cancer? How do people cope with the disease? An adjustment period is essential. Patients need time to reflect on what is most important in their lives. It takes time to understand the diagnosis, the treatment options, and what it means to individuals and their families. Support is critical. The days and weeks after a diagnosis is made are emotionally trying. A lot of mental energy can be used up, making it hard to take in and process all of the medical information seemingly coming from all directions.

How Fear Affects Life One negative feeling may dominate and dictate. This frightful state can prevent an individual patient from moving forward in an appropriate manner. The

back pain of several months’ duration without other symptoms. He had no significant prior medical history. After a thorough evaluation by his primary care physician, he was found to have a suspicious lesion on his T12 vertebra. The location was such that it was felt

Michael Feinstein, MD

to be the source of the patient’s back pain. He was referred to the Barrow Neurological Institute in Phoenix, Arizona, where a needle biopsy was taken [of the lesion] on the T12 vertebra under CT scan guidance. The biopsy was read as showing nonspecific fibrous tissue without histologic evidence of malignancy. The patient was told, or it was inferred, that he had a malignancy involving his 10th thoracic vertebra based on the CT scan result. Imme-

The survival of cancer varies substantially, not only based on the type of malignancy, but also on the individual patient. following case demonstrates the very dramatic impact of uncontrolled fear on an individual’s life. JS, a 60-year-old man, had mid-

diately, the patient became fixated on a fear of dying, sold his business, and rushed to get his affairs in order. The patient was subsequently re-

Cell Stress Biology, received a 1-year, $50,000 grant from the Roswell Park and depression. Information learned Alliance Foundation for an investigafrom this study will help identify pro- tion that targets proteins important for cancer cell metabolism (guanylate metabolism) as a way to suppress melanoma metastases, ultimately resulting in the generation of novel anti-melanoma agents. Nuo Yang, PhD, a Postdoctoral Research Affiliate in the Department of Cancer Genetics, received a 3-month, $3,000 grant from the American Brain Tumor Association for an investigaMikhail Nikiforov, PhD tion that aims to identify the specific grams to benefit long-term survivors. T-cell receptor that plays a key role Mikhail Nikiforov, PhD, a Profes- in killing glioma tumor cells, and to sor of Oncology in the Department of compare important marker changes

following treatment with survivin vaccine therapy, contributing to the successful application of this cancer vac-

Roswell Park

continued from page 184

ferred to me for further evaluation and recommendations for management. He was totally convinced that he had a malignant disease and that he would succumb to it in a short period of time. Based on a clinical diagnosis of malignancy, a full evaluation was carried out looking for a primary tumor. Nothing was revealed. With much coaxing on my part, a neurosurgeon carried out an open vertebral biopsy. A diagnosis of coccidiomycosis was obtained. Coccidiomycosis is a fungal infection commonly known as “Valley Fever,” which is endemic to the Southwest. An infectious disease consultation was obtained and the patient was appropriately treated with antifungal therapy. This patient may have always feared cancer, but when fear threatened to become reality, he found himself literally vulnerable, powerless, and helpless. Although in the end the patient didn’t have cancer, this overwhelming fear led him to change his life dramatically, and, as it turned out, unnecessarily. n Dr. Feinstein is a medical oncologist/ hematologist who served on the faculty of several medical schools, including Cornell University College of Medicine (now Weill Medical College-Cornell University) and New York University School of Medicine in New York City. Dr. Feinstein lives in Scottsdale, Arizona. “Fear” is excerpted from The Big Casino with permission from the book’s publishers, Stan Winokur, MD, and Vincent Coppola. Additional essays from The Big Casino will be published in future issues of The ASCO Post.

Theresa Hahn, PhD

Nuo Yang, PhD

cine in glioma patients. Theresa Hahn, PhD, an Associate Professor of Oncology in the Departments of Medicine and Epidemiology,

received a 1-year, $27,329 subcontract award from Dana-Farber Cancer Institute in Boston, part of a larger grant to Dana-Farber from the NCI to assess the financial impact, including employment, benefits and direct costs, to patients undergoing a blood or marrow transplant. n

The ASCO Post | OCTOBER 15, 2014

PAGE 186

Patient’s Corner Sarcoma

Social Media Is Helping Me Cope With Cancer

Facebook provided me with information to find treatment for my spindle cell sarcoma. Now it is providing me with support as I struggle with recurrence. By Larry Slavens, as told to Jo Cavallo

espite a diagnosis in August 2013 of stage III high-grade spindle cell sarcoma and subsequent disease recurrence, I’m mindful of how fortunate I am that my cancer was found before widespread metastases could take hold, making treatment futile. It was just happenstance, 2 months before, on a long drive from my home near Des Moines, Iowa, to Lawrence, Kansas, that I reached under my left knee and felt a flat, small lump about the size of a nickel. Thinking I must have bruised my leg, I initially dismissed the bump. But when the mass grew in size over the next few weeks I decided to see a doctor. The combination of rarely getting sick and having a high deductible on my health insurance discouraged me from seeking regular medical checkups. Since I didn’t have a primary care physician, I went to a local walk-in clinic where I was referred for ultrasound and MRI testing. I was told the scans suggested a soft-tissue sarcoma and that an appointment was being made with a surgical oncologist for a biopsy of the tumor.

Finding Medical Information Online Concerned about a possible diagnosis of cancer, I wanted to learn everything I could about soft-tissue sarcoma before I met with the oncologist, and I went online looking for information. What I found convinced me that I needed to seek the opinion of a specialist in this rare cancer. Not knowing where to

find one in my area, I again turned to the Internet for help. I posted a message on the Facebook page of the Iowa Chapter of the Sarcoma Foundation of America looking for recommendations for an oncologist and was given the Twitter

rence. Unfortunately, the most recent CT scan found two small nodules, one 8 mm and one 4 mm, on my right lung. Although I have not yet had a biopsy to confirm a metastasis, the lesions are very likely malignant. My doctor had

An online community I found on the Sarcoma Alliance Facebook page is providing me with comfort and support as I go through this next phase of my cancer journey. —Larry Slavens

addresses of several specialists. Within hours after contacting them, I was sent a message to call the office of one of the specialists for an appointment. Several days later, a biopsy of the suspicious mass confirmed high-grade spindle cell sarcoma. While the tumor was stage III, additional imaging tests showed the cancer was confined to the tumor and had not spread. Although the malignant mass was still relatively small, 5 cm, because it was so close to the femoral artery, my oncologist recommended a 5-week course of radiation to shrink the tumor before surgically removing it.

Cautiously Optimistic For the last year, follow-up imaging tests showed no sign of cancer recur-

warned me that I had a 40% chance of the cancer recurring in my lungs, so the finding doesn’t come as a complete surprise. Still, the news is disappointing and frightening. And once again, social media is helping me cope with my cancer. An online community I found on the Sarcoma Alliance Facebook page is providing me with comfort and support as I go through this next phase of my cancer journey, and I’m grateful for their prayers, virtual hugs, and positive comments.

Facing the Future Even before this latest setback, my experience with cancer had left me with the realization that I probably won’t live into very old age. I’ve started

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

rethinking my priorities, and reaching out to friends and relatives who have drifted away. I’ve also started to downsize my life, getting rid of possessions I no longer want or need, and it feels liberating. Although it sounds perverse to talk about having good fortune when discussing cancer, in my case it is true. I was lucky to have found the primary cancer while it was small enough to be easily treated. I was lucky to have a resource like social media to find specialists in my rare cancer. And, I am lucky now to have found an online support community that is giving me the courage to face the future, whatever it may bring. The one thing I know for sure is I intend to fight this cancer every step of the way. n Larry Slavens is a software engineer in Des Moines, Iowa.

Resources for Sarcoma Sarcoma Alliance http://sarcomaalliance.org http://sarcomaalliance.org/chatroom/ www.facebook.com/sarcomaalliance

Sarcoma Foundation of America www.curesarcoma.org www.facebook.com/curesarcoma

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

ASCOPost.com | OCTOBER 15, 2014

PAGE 187

Journal Spotlight Gynecologic Oncology

Nine-Valent HPV Vaccine May Prevent Nearly 90% of Cervical Cancers

ecause nine human papillomavirus (HPV) subtypes were found to cause the majority of cervical precancers, a nine-valent HPV vaccine currently being investigated may be able to prevent more cervical cancers than current vaccines, according to research published in Cancer Epidemiology, Biomarkers & Prevention.1 “We wanted to study how many cervical precancers could potentially be prevented by an investigational nine-valent HPV vaccine that provides protection against the HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58,” said Elmar A. Joura, MD, Associate Professor of Gynecology at the Medical University of Vienna, Austria. “Approximately 85% or more of precancerous lesions of the cervix were attributed to the nine HPV types covered in the vaccine; therefore, if nine-valent HPV vaccination programs are effectively implemented, the majority of these lesions could be prevented.”

ber of precancers harboring the HPV types included in an investigational nine-valent HPV vaccine being developed by Merck. After adjusting for the presence of multiple HPV subtypes in a single lesion, they found that seven high-risk HPV types included in the nine-valent

vaccine were present in about 55% of CIN 1, about 78% of CIN 2, about 91% of CIN 3, and nearly 100% of adenocarcinoma in situ lesions. n Disclosure: This study was funded by Merck. Dr. Joura received grant support paid to his institution by Merck and GlaxoSmithKline

TELL YOUR ADVANCED PRACTICE COLLEAGUES TO

PLC, advisory board fees from Merck and GlaxoSmithKline PLC, and lecture fees from Sanofi Pasteur MSD, Merck, and Roche.

Reference 1. Joura EA, et al: Cancer Epidemiol Biomarkers Prev 23:1997-2008, 2014.

Despite the clear safety profile of the currently disseminated HPV vaccines, uptake in the United States and other resource-rich countries has been inadequate. —Elmar A. Joura, MD

“Given the high vaccine efficacy that was observed in a large phase III clinical trial testing the nine-valent HPV vaccine, if vaccination programs with this newgeneration vaccine are effectively implemented, approximately 90% of invasive cervical cancer cases worldwide could be prevented, in addition to the majority of precancerous lesions,” he added. “Despite the clear safety profile of the currently disseminated HPV vaccines, uptake in the United States and other resource-rich countries has been inadequate,” said Dr. Joura. “To achieve the population-level potential of the HPV vaccine to reduce cancer, vaccine uptake must increase.”

Study Details Dr. Joura and colleagues used data from 12,514 women, ages 15 to 45, enrolled in the placebo arms of three clinical trials testing a quadrivalent HPV vaccine. Among these women, 2,507 were diagnosed with CIN1, CIN2, CIN3, or adenocarcinoma in situ. The researchers estimated the num-

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The ASCO Post | OCTOBER 15, 2014

PAGE 188

In the News Genitourinary Oncology

Moderate Form of Male Pattern Baldness Associated With Increased Risk of Aggressive Prostate Cancer By Charlotte Bath

en with moderate pattern baldness on the front and the crown of the head at age 45 had a 40% increased risk, compared to men with no baldness at that age, of developing prostate cancer later in life, according to a study led by researchers from the National Cancer Institute (NCI) and published in the Journal of Clinical Oncology.1 The study’s senior author, Michael B. Cook, PhD, of the NCI’s Hormonal and Reproductive Epidemiology Branch, and other experts not involved in the study have commented in press statements and reports that the study presents strong evidence for a link between pattern baldness and aggressive prostate cancer, but say that these results are not yet practice-changing. “Previous research linking baldness and prostate cancer has been inconclusive, but this large study suggests a significant link between high risk prostate cancer and hair loss—and suggests that men with hair loss may need to be followed more closely. More evidence is needed, however, before we can rou-

The study is suggestive, not definitive. It doesn’t alter how we approach screening at this point, and it doesn’t alter how we approach the active disease at this point. It just raises some interesting questions in the population. —Charles J. Ryan, MD

tinely consider baldness in prostate cancer screening recommendations,” said Charles J. Ryan, MD, Professor of Clinical Medicine and Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, in a statement released by ASCO.2 In a follow-up interview with The ASCO Post, Dr. Ryan stressed, “The study is suggestive, not definitive. It doesn’t alter how we approach screening at this point, and it doesn’t alter how we approach the active disease at

this point. It just raises some interesting questions in the population.” Among those interesting questions are: what roles do hormones and genetics play in baldness and increased risk of prostate cancer, and why do men with moderate, but not severe, pattern baldness have an increased risk of prostate cancer?

The Balding Question The study looked at data from a cohort of men aged 55 to 74 years at the time they enrolled in the prospective Prostate, Lung, Colorectal and Ovar-

Expect Questions From Patients

he study finding1 that men with moderate pattern baldness on the front and the crown of the head at age 45 had a 40% increased risk, compared to men with no baldness at

Michael B. Cook, PhD

that age, of developing prostate cancer later in life has received coverage by diverse media, from USA Today2 to TIME3 to the Wall Street Journal.4 USA Today even accompanied its article with a photograph of a balding George from the Seinfeld television series. With all this attention, physicians can expect questions from patients about the study and what it means for men. “Our study found an increased risk

for aggressive prostate cancer only in men with a very specific pattern of hair loss, baldness at the front and moderate hair-thinning on the crown of the head, at the age of 45. But we saw no increased risk for any form of prostate cancer in men with other hair-loss patterns,” explained senior study author Michael B. Cook, PhD, an investigator in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute in Bethesda, Maryland. “While our data show a strong possibility for a link between the development of baldness and aggressive prostate cancer, it’s too soon to apply these findings to patient care.” According to Charles J. Ryan, MD, Professor of Clinical Medicine and Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, the study is not definitive and merely raises interesting questions in the population. Those questions involve hormonal, genetic, and other factors that will need to answered by additional studies.

In the meantime, since the current study did show that moderate pattern baldness at age 45 preceded the diagnosis of prostate cancer, Dr. Ryan suggested that information about pattern baldness be considered for inclusion in the patient’s medical record. n

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

References 1. Zhou CK, Pfeiffer RM, Cleary SD, et al: Relationship between male pattern baldness and the risk of aggressive prostate cancer: An analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. J Clin Oncol, September 15, 2014 (early release online). 2. Szabo L: Does the state of man’s pate reveal his cancer risk? USA Today, September 15, 2014. 3. Oaklander M: Male pattern baldness linked to aggressive prostate cancer. TIME, September 15, 2014. 4. Loftus P: Certain bald men have a higher risk of developing aggressive prostate cancer. Wall Street Journal, September 15, 2014.

ian (PLCO) Cancer Screening Trial, between 1993 and 2001. To be eligible, men could have no history of prostate, lung, or colorectal cancer, or be receiving treatment for any kind of cancer, except nonmelanoma skin cancer. Eligible men were randomly assigned to screening with prostate-specific antigen (PSA) for the first 6 years and annual digital rectal examination for the first 4 years, or to usual care. The men received a baseline questionnaire at the time of randomization, and from 2006 to 2008, those who remained under active follow-up received a supplemental questionnaire. On that questionnaire, men were asked to recall their hair loss patterns at age 45 and given a number of options, from no baldness to frontal and severe vertex baldness. The questionnaire included illustrations of the different patterns, which are reprinted in the JCO article.1 The 39,070 men “who responded to the balding question,” the article noted, were included in the analytic cohort. Information on cancer diagnoses and deaths was obtained from updated questionnaires, as confirmed by death certificates and medical documents. Male pattern baldness at age 45 years was reported by 53.4%, and among those, 46.4% reported frontal baldness only, 23.5% frontal plus mild vertex baldness, 18.1% frontal plus moderate vertex baldness, and 12.0% frontal plus severe vertex baldness. During a median follow-up of 2.78 years, 1,138 incident prostate cancer cases were diagnosed, including 571 aggressive cases. Compared with no baldness, frontal plus moderate vertex baldness was significantly associated with an increased risk of aggressive prostate cancer (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.07–1.80), but not overall or nonaggressive prostate cancer. None of the other classes of baldness were associated with prostate cancer.

Risk Is Not Linear Dr. Ryan noted that the finding that the risk of aggressive prostate cancer didn’t increase with severe baldness represents “one of the potential gaps in these data. It doesn’t quite follow a linear course. You would expect,” he said, that if the risk of aggressive prostate cancer is higher in men with moderate than

ASCOPost.com | OCTOBER 15, 2014

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In the News

in those with mild pattern baldness, the risk would be even higher with severe than with moderate pattern baldness, but that is not what the study showed. The study authors proposed a number of possible explanations for why they found no significant association between the highest class of male pattern baldness (frontal plus severe vertex baldness) and prostate cancer risk. These included measurement errors of recalled hair loss and different biologic mechanisms of balding patterns or extent. Dr. Cook has reported that his research team is currently conducting two additional cohort analyses exploring the relationship between male pattern baldness and the risk of developing and dying from prostate cancer. One of these studies is using a baseline dermatologic assessment of male pattern baldness, which would eliminate any recall errors.

make every man who is losing his hair panic, but certainly there is that potential in some patients,” he added. “With respect to prostate cancer, there is a link biologically between the two processes,” Dr. Ryan said. “Essentially, think of it as a chronic exposure to testosterone or a chronic exposure to androgens and that when that is happening in the scalp or in the skin, it leads to hair loss, but when that is happening in the prostate, it can actually promote the progression of the cancer.” “Besides androgenic action, circulating insulin-like growth factors and hyperinsulinemia may also play roles in prostate carcinogenesis and baldness either directly or via interactions with androgen,” the study authors wrote. “That is one of the other issues,” Dr. Ryan agreed. “Baldness is actually associated with heart disease and with diabetes.”

Underlying Health Issues

Different Genetic Predispositions

“Male pattern baldness of various different types has been associated with a variety of health conditions, including cardiac disease and prostate cancer,” Dr. Ryan said, so there is “the potential for there to be underlying health issues in some of these patients, but not all patients. The last thing we want to do is

“Baldness is highly variable among men of different genetic predispositions,” Dr. Ryan said. “It is very relatively rare among Asians, for example. It is very common—about 50%—among men of European descent.” The study cohort was predominantly

white (89.3%). In the discussion portion of the JCO article, the authors noted that “the paradox that black men are less likely to have male pattern baldness than their white counterparts but have higher risk for prostate cancer requires further elucidation.”

Risk Down the Road “The other key point is that this finding had to do with baldness at the age of 45, and the diagnosis of the prostate cancer was occurring at about the age of 70, so it was about 20 years or more later. The baldness is actually something that preceded the prostate cancer,” Dr. Ryan said. “We have a dilemma about whether PSA screening is useful for the population as a whole, and now we have a situation where there is a physical finding that is present in one’s mid-40s that might be a red flag for risk down the road. It is possible that those individuals could be identified for screening and one could test whether screening is effective in that group. That is a big process to undertake, and I don’t know if anyone is actually advocating that.” A smaller, incremental step that might be considered, Dr. Ryan said, is to integrate that physical finding of baldness into the patient’s medical record.

Dr. Ryan stated that he is not advocating general PSA screening for men in their 40s with the type of pattern baldness identified in the study. “I am asking the question whether or not that is a reasonable response to these data. I think you have to look at the magnitude of the risk. This is something that epidemiologists would have to do, look at the magnitude of the risk associated with baldness.” “To take this to the next level, you would have to do a prospective study, where you identify people at the age of 45, follow them for 20 years. That would cost multiple millions of dollars, and the question is, would that be worth our tax dollars and our research money? I don’t know.” n

Disclosure: Drs. Cook and Ryan reported no potential conflicts of interest.

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

Virginia LeBaron, PhD, APRN, on Global Crisis in Untreated Cancer Pain see page 78

Brad S. Kahl, MD, on the RESORT Trial in Lymphoma With Commentary From Richard I. Fisher, MD see pages 90 and 91

Visit The ASCO Post online at ASCOPost.com

Sri Komanduri, MD, and Al B. Benson III, MD, FACP, FASCO, on Colonoscopic Polypectomy and Cancer Risk see page 85

Jennifer R. Brown, MD, PhD, and Matthew S. Davids, MD, MMSC, on the Mentor-Mentee Relationship see pages 126-127

The ASCO Post | OCTOBER 15, 2014

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Announcements

LIVESTRONG Narrows Finalists in ‘Big C’ Competition: Winner to Be Announced This Month

ewly launched in 2014 by LIVESTRONG, “The Big C” is a one-of-a-kind global competition to generate innovations that improve the daily quality of life for the 32.5 million people around the world living with cancer now. The competition was open to entrepreneurs, trailblazers, technology whizzes, and anyone with a product, service, or innovation that helps those facing cancer today. Ventures are competing for $140,000 in seed funding, mentoring, and global exposure to a community of potential customers and investors to develop programs, services, new technology, and inventions that improve cancer patients’ and survivors’ daily quality of life.

own cells to recreate the tissue. • unCancer India is designed to give cancer patients and survivors in India navigation services that provide information on diagnoses and sur-

vivorship, emotional support, and a connection to much-needed, timely S:6.75”patients are not resources that those currently receiving. Overall, 60 ventures will receive a to-

tal of $140,000 in seed funding, based on their innovation’s utility, ingenuity and benefits to cancer patients and survivors. In addition, the grand prize winner will receive $25,000. n

Five Finalists The LIVESTRONG Foundation’s inaugural Big C competition has reached its final stage, choosing 5 final ventures from more than 750 entries from around the world. The finalists are presenting their ventures to a panel of seven judges on October 17; the grand prize winner will be announced at the finale event at the Austin Music Hall in Texas. The five finalists (in alphabetical order) are: • Adhere Tech created smart pill bottles to send patient dosage behavior that is analyzed in real-time, allowing patients to receive dosage reminders via text message. The pill bottle itself lights up and chimes to remind patients about their medication, as well. The bottles are currently in a pilot stage. • Decisive Health’s Treatment Explorer support tool matches cancer patients’ lifestyle preferences with the best possible treatment option to match the two. The tool is customized for each patient and shared with health-care providers so that individual patients can receive optimal patient-centered care. • Restwise’s app helps cancer patients and survivors understand the importance of resting and managing fatigue to rehabilitate themselves from treatment and get the most out of their exercise programs. The program began with a pilot at the LIVESTRONG at the YMCA program in Boise, Idaho. • TeVido BioDevices uses threedimensional printing technology to create real-life breast tissue to be used in breast reconstruction surgeries following mastectomies. The Austin-based company uses a patient’s

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

Attack from multiple angles COMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro • These tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

• Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®treated patients. Discontinue COMETRIQ in patients with perforation or fistula. • Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

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Journal Spotlight

Expert Consensus Recommends Echocardiograph as Cornerstone to Protecting Cancer Patients’ Heart Health

atients with cancer and survivors of cancer are living longer than ever before as a result of significant advances made over the past decade. Importantly, however, cardiovascular

complications of their cancer treatment may present a life-threatening issue after theirS:6.75” cancer treatment has ended. Significant numbers of patients who have been treated with chemo-

therapy drugs are at risk to have weakened hearts. Adult survivors of childhood cancer are 15 times as likely to have congestive heart failure and 10 times as likely to have coronary artery

disease as their healthy siblings. To help clinicians monitor and minimize the cardiotoxic effects of various cancer therapies, the American Society continued on page 192

Statistically significant efficacy in patients with progressive, metastatic MTC • COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within 14 months prior to study entry PROD

• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001) • Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)

• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the planned interim analysis

PFS

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Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%). Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. Please see accompanying brief summary of Prescribing Information, including Boxed Warnings. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088. Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

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of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) have released a comprehensive Expert Consensus on multimodality imaging evaluation of adult patients during and after can-

cer therapy. The paper was published recently in Journal of the American Society of Echocardiography.

Detecting and Monitoring Damage to the Heart This consensus paper is the result of several years’ work to outline the specific effects of the many different

cancer therapies that exist, and details the strengths and challenges of various forms of imaging in detecting and monitoring damage to the heart as early as possible. The paper confirms that echocardiography is the modern method of choice for the evaluation of S:6.75” patients before, during, and after cancer therapy. Perhaps most importantly, the

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140-mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100-mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60-mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None. 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

consensus statement also strongly recommends an early baseline echocardiogram for all patients undergoing cancer therapy, and provides recommended time intervals for follow-up specific to each form of therapy used. Juan Carlos Plana, MD, FASE, was Chair of the writing group for the Consensus Statement.. Dr. Plana is former

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation. 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia. 4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain. 5 Palmar-plantar erythrodysesthesia syndrome. 1

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Reference 1. Plana JC, Galderisi M, Barac A, et al: Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: A report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiography 27:911-939, 2014.

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Disclosure: Dr. Plana reported no potential conflicts of interest. For full disclosures of all study authors, visit www.onlinejase.com. T:10.25”

dimensional] echo is not possible, [twodimensional] echo still provides excellent information to the clinician and allows for early detection of any cardiac issues, which is the most important consideration.” If cardiac dysfunction is detected early, cardioprotective medications can be prescribed to mitigate damage, or treatment can be modified when necessary. n B:11.25”

—Juan Carlos Plana, MD, FASE

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Even when [threedimensional] echo is not possible, [twodimensional] echo still provides excellent information to the clinician and allows for early detection of any cardiac issues.

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ HYPERTENSION, JNC1 STAGE N=2113 (%) Normal: Grade 0: Systolic 4 <120 mmHg and Diastolic <80 mmHg Pre-hypertension: Systolic 34 ≥120 mmHg or Diastolic ≥80 mmHg Stage 1: Systolic ≥140 mmHg or 46 Diastolic ≥90 mmHg

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are 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 COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. 17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ. • COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash. • COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking. • COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss. • To contact their healthcare provider before any planned surgeries, including dental procedures. • COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking. • Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ. • Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water. • Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment. Reference ID: 3223542 Distributed by Exelixis, Inc. 11/2012

The Consensus Statement also outlines the various innovative tools that echocardiography offers, such as three-dimensional echocardiography, myocardial deformation or “strain” imaging, contrast echocardiography, and stress echo. Notes Dr. Plana, “While [three-dimensional] echo is the preferred echo technique for monitoring cardio-toxicity, it may not always be available. But even when [three-

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Malignant: Diastolic 0 0 ≥120 mmHg 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose.

field of cardio-oncology has emerged as a result of better understanding and tools for early diagnosis of these adverse effects and aims to provide an integrated and holistic approach to patient care. Dr. Plana said that “once patients have survived cancer, they don’t die from cancer, they die from heart disease. Cardio-oncology is about making sure that doesn’t happen.”

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade 3-4 All Grades Grade 3-4 Grades CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

changes during the cancer treatment.” The size of the cardiotoxicity problem is significant, as there are currently over 12 million people in the United States living with active cancer or with a history of the disease, and this number is expected to grow as screening tests become more wideS:6.75” ly available, cancer treatment improves, and the United States population ages. The

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Co-Director of the Cardio-Oncology Clinic at the Cleveland Clinic and now a Professor of Medicine at Baylor College of Medicine. Dr. Plana said “This proactive imaging protocol is extremely helpful as it provides an accurate starting point for the patient’s normal cardiovascular health and offers the clinician early detection and warning should there be any adverse

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Ongoing Molecular Research in the Science of Oncology BIOMARKERS Tumor PD-L1 mRNA Expression Associated With Improved Outcome in Breast Cancer Inhibition of the PD-1/PD-ligand1 (PD-L1) axis has shown considerable therapeutic promise in several cancers. Tumor PD-L1 protein expression may predict response to drugs targeting this pathway, but its measurement has been limited by the lack of standardized immunohistochemical methods and variable antibody performance. In a study reported in Clinical Cancer Research, Schalper and colleagues observed consistent measurements of in situ PD-L1 mRNA levels in 636 stage I to III breast carcinomas using two different sets of tissue microarrays and found that increased PD-L1 mRNA expression was associated with increased numbers of tumor-infiltrating lymphocytes and prolonged recurrence-free survival. The two microarrays showed PD-L1 mRNA expression in 55.7% and 59.5% of cases, with higher PD-L1 mRNA expression being significantly associated with increased tumor-infiltrating lymphocytes (P = .04) but not with other clinical variables. Elevated tumor-infiltrating lymphocytes were found in 16.5% and 14.8% of samples with the two microarrays and were associated with estrogen receptor–negative status (P = .01 and P = .0001). PD-L1 mRNA expression was significantly associated with longer recurrence-free survival (P = .01), with the significant association persisting on multivariate analysis including age, tumor size, histologic grade, nodal metastasis, hormone receptor status, HER2 status, and extent of tumor-infiltrating lymphocytes (hazard ratio = 0.268, P = .009). The investigators concluded, “PD-L1 mRNA expression is identified in nearly 60% of breast tumors and it is associated with increased [tumor-infiltrating lymphocytes] and improved recurrence-free survival. These observations support the evaluation of PD-1/PD-L1-targeted therapies in breast cancer.” Schalper KA, et al: Clin Cancer Res 20:1-10, 2014.

TP53 Mutation Associated With Chromosome 3p Loss in Head and Neck Squamous Cell Carcinoma In an analysis of molecular and clinical features associated with survival in head and neck squamous cell carcino-

ma reported in Nature Genetics, Gross and colleagues found that the TP53 mutation is frequently accompanied by loss of chromosome 3p; the combination of these alterations was associated with median overall survival of 1.9 years, compared with > 5 years in patients with the TP53 mutation alone. The interaction with TP53 was found to be specific to chromosome 3p and was identified in head and neck cancer and other cancer cohorts. Human papillomavirus (HPV) inactivates TP53, and chromosome 3p deletion was found to be common and associated with poor outcome in HPVpositive head and neck tumors. The TP53-3p interaction was found to be modified by microRNA548k expression; this modification was associated with a further reduction in survival and was found to occur mutually exclusively with mutations affecting RAS signaling. The investigators concluded, “Together, the identified markers underscore the molecular heterogeneity of [head and neck squamous cell carcinoma] and enable a new multi-tiered classification of this disease.” Gross AM, et al: Nat Genet. August 3, 2014 (early release online).

pendent growth associated with CD44positive cells. Analysis of tumor samples from patients receiving chemotherapy with or without vismodegib for advanced gastric cancer showed that high CD44 expression was associated with reduced survival in patients receiving chemotherapy alone, but improved survival in those also receiving vismodegib. The investigators concluded, “[Hedgehog] signaling maintains [cancer stem cell] phenotypes and malignant transformation phenotypes in CD44[-positive] gastric cancer cells, and [hedgehog] inhibition can reverse chemotherapy resistance in CD44[positive] cells. Gastric cancer is a heterogeneous disease, and the strategy of combining chemotherapy with [hedgehog] inhibition may only be effective in tumors with high CD44 levels.” Yoon C, et al: Clin Cancer Res 20:3974-3988, 2014.

CD44 Expression a Marker for Chemotherapy Resistance in Gastric Cancer, Overcome by Hedgehog Inhibition

Studies in vitro have suggested that sub-millisecond pulses of radiation produce less genomic instability than continuous prolonged irradiation at the same total dose. In a study reported in Science Translational Medicine, Favaudon and colleagues assessed the effects of ultrahigh dose-rate irradiation (FLASH) in mouse models. In C57BL/6J mice exposed to short pulses (≤ 500 ms) of radiation at ultrahigh dose rate (FLASH at ≥ 40 Gy/s) or to conventional dose-rate irradiation (≤ 0.03 Gy/s) in single doses, conventional treatment at 15 Gy resulted in lung fibrosis associated with activation of the transforming growth factor-β cascade, whereas no complications were observed after FLASH doses < 20 Gy for > 36 weeks after irradiation. FLASH irradiation was also not associated with acute radiation-induced apoptosis in normal smooth muscle and epithelial cells; apoptosis could be reinduced by treatment with systemic tumor necrosis factor-α prior to irradiation. FLASH was as effective as conventional irradiation in suppressing growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc–positive orthotopic

CD44 is a gastric cancer stem cell marker, and the hedgehog signaling pathway can be dysregulated by cancer stem cells during tumorigenesis. In a study reported in Clinical Cancer Research, Yoon and colleagues found that high CD44 expression was associated with chemotherapy resistance and poorer survival in gastric cancer and that hedgehog inhibition could reverse resistance and improve survival. Gastric cancer cell lines (AGS, MKN45, and NCI-N87) grown as spheroids or sorted for CD44-positivity exhibited upregulation of hedgehog pathway proteins. Inhibition of the hedgehog pathway by Smoothened shRNA or vismodegib (Erivedge) resulted in reduced spheroid and colony formation. Resistance to fluorouracil and cisplatin treatment was observed in CD44-positive cells compared with unselected cells; resistance was reversed in vitro and in xenograft models by Smoothened shRNA or vismodegib treatment. Hedgehog inhibition also prevented migration, invasion, and anchorage-inde-

NOVEL STRATEGIES Potential for Improved Effectiveness and Reduced Toxicity of Radiotherapy With Ultrahigh Dose-Rate FLASH Irradiation

lung tumors in C57BL/6J mice. The authors concluded, “Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.” Favaudon V, et al: Sci Transl Med 6:245ra93, 2014.

MECHANISMS OF ACTION Dissemination of Glioblastoma Multiforme Outside Brain Is Common The finding of extracranial metastases after organ transplantation from glioblastoma multiforme donors raised issues with the notion that disease spread is restricted to the brain. In a study reported in Science Translational Medicine, Müller and colleagues found that hematogenous spread of glioblastoma multiforme is a common feature of the disease. Immunostaining of enriched mononuclear cells with antibodies directed against glial fibrillary acidic protein identified glioblastoma multiforme circulating tumor cells in peripheral blood in 29 (21%) of 141 glioblastoma patients. Surgical intervention did not appear to markedly enhance tumor cell dissemination. The absence of glial fibrillary acidic protein-positive cells in healthy volunteers and the presence of such tumorspecific alterations as EGFR amplification and gains and losses in genomic regions of chromosomes 7 and 10 in the patient samples support the identification of glioblastoma multiforme tumor as the source of the circulating cells. The spread of the cells was associated with EGFR amplification, indicating that the cells have growth potential. The investigators concluded, “We demonstrate that hematogenous [glioblastoma multiforme] spread is an intrinsic feature of [glioblastoma multiforme] biology.” Müller C, et al: Sci Transl Med 247:247ra101, 2014.

MSH6 Mutations May Influence Temozolomide Resistance in Treatment-Naive Gliomas Independent of MGMT Methylation Resistance to temozolomide in glioblastoma has been thought to be largely mediated by expression of the DNA repair enzyme MGMT, although there are data suggesting a role for inactivation of MSH6

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Lab Notes

and other mismatch repair proteins. In a study reported in Clinical Cancer Research, Nguyen and colleagues identified 11 previously unreported mutations in MSH6 in 9 different glioma samples and 6 paired brain tumor–initiating cell lines from adult patients; MSH6 mutations were also identified in 3 oligodendrogliomas and 2 treatment-naive gliomas, both representing previously unreported findings, according to the investigators. Evaluation of the effect of MGMT and MSH6 status on sensitivity to temozolomide using intracranial brain tumor initiating cell line xenografts showed that the mutations influenced temozolomide sensitivity both in vitro and in vivo in a manner independent of MGMT promoter methylation status. The investigators concluded, “These data demonstrate that endogenous MSH6 mutations may be present prior to alkylator therapy and occur in at least two histological subtypes of adult glial neoplasms, with this being the first report of these mutations in oligodendroglioma. These findings broaden our understanding of clinical response to [temozolomide] in gliomas.” Nguyen SA, et al: Clin Cancer Res. July 30, 2014 (early release online).

Different Transcriptional Responses to Fulvestrant and Estrogen Deprivation in ER-Positive Breast Cancer In a study reported in Clinical Cancer Research, Patani and colleagues investigated whether distinct transcriptional responses were associated with the reported increased effectiveness of the estrogen receptor (ER) antagonist fulvestrant (Faslodex) over the aromatase inhibitor anastrozole in ER-positive breast cancer. Global gene-expression profiles from ERα-positive breast cancers before and during neoadjuvant treatment with fulvestrant (n = 22) or anastrozole (n = 81) and corresponding in vitro models were compared. The overall transcriptional response to fulvestrant and estrogen deprivation with anastrozole was correlated (r = .61 in presurgical studies, r = .87 in vitro), with the response involving downregulation of genes associated with estrogen regulation and proliferation. The transcriptional response to fulvestrant was of greater magnitude (slope = 0.62 in presurgical studies, 0.63 in vitro). The investigators identified 28 genes and 40 Gene Ontology consortium categories affected differentially by fulvestrant vs anastrozole. These included 17 fulvestrant-specific genes, including CAV1/2, SNAI2, and NRP1, that were associated

with ERα, androgen receptor, and TP53 in a network regulating cell cycle, death, survival, and tumor morphology. In addition, 18 genes responding differently to fulvestrant predicted antiproliferative response to fulvestrant but not anastrozole. The transcriptional effects of lower-dose fulvestrant treatment were correlated with those of higher-dose treatment but oc-

curred at a lesser magnitude (ratio = 0.29). The investigators concluded, “The transcriptional response to fulvestrant has much in common with estrogen deprivation, but is stronger with distinctions potentially attributable to arrest of estrogen-independent ERα activity and involvement of [androgen receptor] signaling. Genes responding differently to

2015

fulvestrant may have predictive utility. These data are consistent with the clinical efficacy of fulvestrant versus anastrozole and higher dosing regimens.” n Patani N, et al: Clin Cancer Res 20:3962-3973, 2014. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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Emerging Clinical Data on Cancer Management CANCER SCREENING Overscreening for Prostate, Breast, Colorectal, and Cervical Cancer Can Raise Costs and Harm Patients Analyses of data from 27,404 people aged 65 and older participating in the National Health Interview Survey (NHIS) from 2000 through 2010 suggest that overscreening for prostate, breast, cervical, and colorectal cancer screening “is common in both men and women, which not only increases health care expenditure but can lead to net patient harm.” The study by Trevor J. Royce, MD, MS, and colleagues at the University of North Carolina at Chapel Hill, was published in JAMA Internal Medicine.

Screening Reconsidered “There is general agreement that routine cancer screening has little likelihood to result in a net benefit for individuals with limited life expectancy, as reflected in the consistency in existing guidelines,” the authors wrote. As an example, they cited ASCO’s Choosing Wisely Campaign and its recommendation to avoid prostatespecific antigen (PSA) screening in men with less than a 10-year life expectancy, as well as similar recommendations from the American Cancer Society and the American Urological Association. Recommendations against screening for breast, cervical, and colorectal cancer are also based on age and limited life expectancy. Using a validated mortality index specific for NHIS, participants were grouped into those with low (< 25%), intermediate (25%–49%), high (50%–74%), and very high (≥ 75%) risks of 9-year mortality. While groups of individuals with very high risks or mortality (lower life expectancy) had lower rates of screening, a large proportion of the U.S. population with less than a 9-year life expectancy (≥ 75% mortality risk) received cancer screening, including 55% in the group who received prostate cancer screening, the investigators noted. “For women who had a hysterectomy for benign reasons, 34% to 56% had a Papanicolaou test within the past 3 years,” they added. Overall, 31% to 55% of participants with very high mortality risk received recent cancer screening. Screening for prostate and cervical cancers occurred less frequently in more recent years compared with 2000. Data on screening came from self-reporting by study participants. The authors commented: Our results highlight the challenges to

implementing evidence-based screening guidelines on a population level. While the lack of net benefit from cancer screening in individuals with limited life expectancy is widely recognized and publicized in clinical practice guidelines, important obstacles exist to reliably applying these guidelines clinically. One such obstacle is the lack of a readily available and easy-to-use clinical tool to accurately assess life expectancy for each patient. Without simple and reliable ways to assess 10-year life expectancy in the clinic, guidelines may be impractical for clinical adherence, which may partially explain the findings of this study. Furthermore, even when limited life expectancy is recognized, the physician may have difficulty communicating this prognosis and/or the patient may have difficulty accepting a limited life expectancy or cessation of screening. The practice of defensive medicine and fear of litigation may further contribute to overscreening.

A related study in the same issue of JAMA Internal Medicine used microsimulation modeling to determine whether colonoscopy screening at 5 or 3 years, rather than 10, for Medicare beneficiaries who had a negative result at age 55, or continuing screening until 85 or 95 years results in net benefit to individuals at average risk of colorectal cancer and average life expectancy. The answer was no. In almost all cases, more intensive screening resulted in a loss of quality-adjusted life-years, a net harm, according to Frank van Hees, MSc, of Erasmus University in Rotterdam, the Netherlands, and colleagues. “Screening Medicare beneficiaries more intensively than recommended is not only inefficient from a societal perspective; often it is also unfavorable for those being screened. This study provides evidence and a clear rationale for clinicians and policy makers to actively discourage this practice,” the investigators stated.

Three Recommendations In an editorial commenting on both articles, Cary P. Gross, MD, of Yale University School of Medicine, New Haven, stated that it “is particularly important to question screening strategies for older persons,” not only because of their shorter life expectancies, but because of higher risk of complications from procedures such as colonoscopy. Dr. Gross offered three steps “that can help to allay skepticism about cancer screening tests for old-

er persons, so that we can have confidence that these efforts are benefiting patients and not causing harm.” He continued, “First, clinicians should alter their approach to discussing cancer screening with older persons.” Decisions about screening should take into account individual differences in life expectancy. “Clinicians and patients should work together to design and evaluate informational tools that can help inform patients about anticipated benefits and harms given their individual risk.” “Second, Medicare payment policies warrant closer scrutiny.” Clinicians and patient advocates could help the Centers for Medicare & Medicaid Services (CMS) “identify clinical scenarios in which screening is neither reasonable nor necessary.” In addition, CMS should adhere to its own screening-related reimbursement policies and not pay for screening at shorter than recommended intervals. “Third, quality measures should address overscreening, including for cancer care,” after years of focusing on increasing screening use. “It truly will be a new era when providers will be evaluated, in part, by their ability to refrain from ordering cancer screening tests for some of their patients,” Dr. Gross concluded. Royce TJ, et al: JAMA Intern Med. August 18, 2014 (early release online). Van Hees F, et al: JAMA Intern Med. August 18, 2014 (early release online). Gross CP: JAMA Intern Med. August 18, 2014 (early release online).

COLORECTAL CANCER Enhanced Benefit Shown With FOLFIRI/Ziv-Aflibercept in Subset of Patients With Metastatic Colorectal Cancer The survival benefit demonstrated in the VELOUR study for FOLFIRI (irinotecan, fluorouracil [5-FU], leucovorin) plus ziv-aflibercept (Zaltrap) vs FOLFIRI plus placebo in metastatic colorectal cancer patients who progressed on oxaliplatin-based chemotherapy persisted beyond median survival times for some patients. This “suggested subpopulations might have different magnitudes of survival gain,” Ian Chau, MD, of the Royal Marsden Hospital in London, and colleagues noted in BMC Cancer. To determine which patients received the greatest benefit from FOLFIRI with ziv-aflibercept, the investigators conducted a posthoc multivariate analysis of the

VELOUR intent-to-treat population. The posthoc subset–the better-efficacy subgroup—excluded the 124 patients (approximately 10%) who had recurrence within 6 months of completing oxaliplatin-based adjuvant therapy (adjuvant fast relapsers). The better-efficacy subgroup included 404 patients (66%) from the FOLFIRI/ ziv-alflibercept investigational arm of the VELOUR trial and 406 patients (66%) from the ziv-alflibercept/placebo investigational arm. All had performance status of 0 with any number of metastatic sites or performance status of 1 with more than two metastatic sites.

Survival Outcomes “A significant improvement in efficacy outcome was observed with [ziv-]aflibercept in this better efficacy subgroup,” the authors wrote. Median overall survival for patients receiving FOLFIRI/ziv-aflibercept was 16.2 months vs 13.1 months for patients receiving FOLFIRI/placebo (adjusted hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.61–0.86). “Over time, the magnitude of survival differences between the 2 treatment groups continued to increase in the better efficacy subgroup with the absolute [overall survival] rate differences increased from 5% at 6 months to 15% at 30 months,” the researchers added. A significant improvement was also observed for progression free survival. Median progression-free survival was 7.2 months in the FOLFIRI/ziv-aflibercept group vs 4.8 months in the FOLFIRI/ placebo group. “The absolute difference in 6-month [progression-free survival] rates was 25%,” the researchers reported. Objective response rates were 23.7% with ziv-aflibercept vs 11% with placebo. No benefit was derived from zivaflibercept for patients in the poorerefficacy subgroup, which was comprised of adjuvant fast relapsers or patients with performance status of 2 or performance status of 1 with two or more metastatic sites. For these patients, median overall survival was 10.4 months for FOLFIRI/ ziv-aflibercept and 9.6 months for FOLFIRI/placebo (adjusted HR = 0.97, 95% CI = 0.78–1.21). No improvements were observed for progression-free survival or overall response rate in this subgroup. “The efficacy outcome benefits in the better efficacy subgroup were obtained without any compromise to safety,” the investigators stated. Adverse events “in the better efficacy subgroup closely mirrored those in the overall safety population. The

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toxicity profile is in line with expectations for the anti-VEGF plus chemotherapy class effect seen in other studies.” The authors concluded that identifying prognostic criteria for second-line patients with metastatic colorectal cancer “may help to guide practitioners toward targeted use of biologicals for maximal survival gains in clinically relevant patient populations.” Chau I, et al: BMC Cancer, 14:605, 2014.

Comorbidity Burden The older Americans questionnaire “captures data on 14 comorbid conditions and the degree to which each interferes with daily activities. A comorbidity burden score was computed by multiplying the total number of conditions by each condition’s level of interference with function,” the investigators explained. With

these data, the researchers then evaluated associations among comorbidity, toxicity, time to relapse, and overall survival. The number of comorbidities ranged from 0 to 10 (median 2) and the comorbidity burden score ranged from 0 to 25 (median 3). The most common conditions were arthritis, occurring in 58% of patients, and hypertension, affecting

55%. At least one grade 3 to 5 adverse event occurred in 52% of patients, with the total number of events ranging from 0 to 28. “Of these, 28% were hematologic, 12% gastrointestinal, and 3% neurologic. Only one person died of treatment-related toxicity,” the researchers wrote. At a median 5.2-years follow-up, continued on page 198

BREAST CANCER Comorbidity Associated With Shorter Overall Survival but Not With Time to Relapse or Toxicity in Older Women on Adjuvant Chemotherapy In the Cancer and Leukemia Group B (CALGB) 70103 study, comorbidity was associated with shorter overall survival among older women with earlystage breast cancer and good functional status receiving adjuvant chemotherapy. “The presence of four or more conditions appeared to be a threshold for shorter survival in this cohort,” Heidi D. Klepin, MD, MS, of Wake Forest School of Medicine, Winston-Salem, North Carolina, and colleagues reported in the Journal of Oncology Practice. Comorbidity was not associated with toxicity or time to relapse.

CALGB 70103 CALGB 70103 is a quality-of-life companion study to the CALGB 49907 (Alliance) trial, which found that women aged ≥ 65 years old treated with standard adjuvant chemotherapy (either doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/fluorouracil [5-FU]) had a lower risk of breast cancer recurrence and death than those treated with capecitabine. For the companion study, investigators collected survey data regarding comorbidity, social support, stressful life events, toxicity, physical function, adherence, and neurobehavioral symptoms before, during, and after completion of adjuvant therapy. The 329 participants also completed the Physical Health Subscale of the Older American Resources and Services Questionnaire. Slightly more than half of the patients (171) had received standard chemotherapy, 99 with doxorubicin/cyclophosphamide and 72 with cyclophosphamide/methotrexate/5-FU], and 158 patient had received capecitabine. The median age of the patients was 71 (range, 65–89), and most patients (68%) had stage II disease.

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the overall mortality rate was 25%, and the breast cancer–specific mortality rate was 11%. Sixteen percent of patients relapsed during follow-up. After adjusting for age, tumor size, treatment, node, and receptor status, the risk of death increased by 18% for each comorbidity (hazard ratio [HR] = 1.18, 95% confidence interval [CI] = 1.06–1.33). There was a similar association between comorbidity burden and overall survival (HR =1.08, 95% CI = 1.03–1.14). Comorbidity burden does adversely affect life expectancy and “should be included in treatment decision-making regarding expected benefit of adjuvant therapy,” the authors concluded. Klepin HD et al: J Oncol Pract 10:e285e292, 2014.

Patients With DCIS Have Decreased Risk of Cardiovascular Death, Independent of Treatment Recent concerns about potential overdiagnosis and overtreatment of ductal carcinoma in situ of the breast (DCIS) led researchers in the Netherlands to study late effects of treatment, such as cardiovascular disease, morbidity, and mortality in a large population-based cohort of DCIS patients. “After a median follow-up of 10 years, we did not find an increased risk for cardiovascular morbidity or mortality after radiotherapy for DCIS when comparing surgery and radiotherapy vs surgery only, nor when comparing radiotherapy for left-sided vs right-sided DCIS,” the investigators reported in the Journal of the National Cancer Institute. Patients with

DCIS had a decreased risk of cardiovascular death, independent of treatment, when compared to the general population.

Study Details The researchers collected data on 10,468 women diagnosed with DCIS as their first neoplasia before the age of 75 years in the Netherlands between 1989 and 2004 and matched that data to cardiovascular disease data acquired through linkage with population-based registries. Patients were treated with surgery, either mastectomy or wide local excision. In the later years of the study, “wide excision [was frequently] followed by tangential breast field irradiation to a prescribed dose equivalent of 50 Gy in 25 fractions,” noted Naomi B. Boekel, MSc, of the Netherlands Cancer Institute, Amsterdam, and colleagues. “The percentage of DCIS patients treated with radiotherapy changed considerably during the study period, from 20% in 1989 to 46% in 2004.” The median follow-up time was 10 years, but 8 years when restricted to patients who had received radiation. A total of 1,319 patients died and 2,214 were diagnosed with a second neoplasm during follow-up. Although 950 patients experienced cardiovascular events, only 684 events occurred 5 or more years after diagnosis, and 204 of those events were cardiovascular deaths.

Findings When compared with the general population, 5-year survivors of DCIS had a similar all-cause mortality (standardized mortality ratio [SMR] = 1.04; 95% confidence interval [CI] =

0.97–1.11) but a lower risk of dying of cardiovascular disease (SMR = 0.77; 95% CI = 0.67–0.89). “No difference in [cardiovascular disease] risk was found when comparing 5-year survivors treated with radiotherapy with those treated with surgery only. Left-sided vs rightsided radiotherapy also did not increase this risk (hazard ratio [HR] = 0.94; 95% CI = 0.67–1.32),” the researchers reported. “Importantly, radiotherapy after breast-conserving surgery for DCIS approximately halves the rate of ipsilateral breast events during the subsequent decade with little effect on contralateral or distant events,” the investigators concluded. “Although our results are reassuring, studies with longer follow-up after breast irradiation are needed before definitive conclusions regarding [cardiovascular disease] risk can be drawn.” Boekel NB, et al: J Natl Cancer Inst 106(8):dju156, 2014.

LUNG CANCER FDG-PET Is Less Specific in Diagnosing Lung Cancer in Areas With Endemic Infectious Lung Disease Although positron-emission tomography (PET) combined with 18F–fluorodeoxyglucose (FDG) is recommended for the noninvasive diagnosis of pulmonary nodules suspicious for lung cancer, in populations with endemic infectious lung disease, FDG-PET may not accurately identify malignant lesions. An analysis of 70 studies reporting a total of 8,511 nodules, 5,105 (60%) of which were malignant, found that the “accuracy of FDG-PET for diagnosing lung nodules was extremely heterogeneous,” according to Stephen A. Deppen, PhD, of the Tennessee Valley Healthcare System and Vanderbilt University Medical Center, Nashville, and colleagues. “Use of FDG-PET combined with computed tomography [CT] was less specific in diagnosing malignancy in populations with endemic infectious lung disease compared with nonendemic regions. These data do not support the use of FDG-PET to diagnose lung cancer in endemic regions unless an institution achieves test performance accuracy similar to that found in nonendemic regions,” the researchers wrote in the Journal of the American Medical Association.

The studies, published from October

1, 2000, through April 28, 2014, were culled from MEDLINE, EMBASE, and the Web of Science databases. Included articles reported information from more than 10 participants with benign and malignant lesions and sufficient to calculate sensitivity and specificity of FDGPET to diagnose lung cancer. “Although the accuracy of FDG-PET/CT is superior to the accuracy of FDG-PET only, we included both modalities because they are still in use in the United States and elsewhere,” the authors explained. They did not find a significant difference in specificity between the modalities. In populations with endemic infectious lung disease, FDG-PET/CT specificity was estimated to be 16% lower than in nonendemic regions. “This lower specificity persisted at 14% even for rigorously conducted and wellcontrolled studies,” the investigators reported. The average adjusted estimate of specificity in regions with endemic disease was 61% (95% confidence interval [CI] = 49%-72%) vs 77% (95% CI = 73%-80%) in nonendemic regions. “For rigorously conducted and well-controlled studies, the estimates of specificity in endemic and nonendemic regions were 66% [95% CI = 51%-78%] and 80% [95% CI = 74%-85%], respectively,” the authors reported.

Clinical Implications “Histoplasmosis, coccidioidomycosis, and blastomycosis are the most prevalent fungal lung diseases in the United States, and are common etiologies of lung granulomas. Histoplasmosis and blastomycosis are endemic across much of the Mississippi, Ohio, and Missouri river valley regions through southern Ontario, Canada, whereas coccidioidomycosis is prevalent in the southwestern United States,” the researchers noted. Tuberculosis has been reported as the common etiology for granulomatous disease in China, Japan, and South Africa. Overestimates of the specificity in FDG-PET/CT in regions with endemic infectious lung disease “could lead to could lead to unnecessary biopsies or thoracotomies for indeterminate lung nodules,” the investigators stated. “Knowledge of this limitation in such regions is especially important if low-dose CT screening for lung cancer is widely adopted and should be reflected in current nodule management guidelines.” n Deppen SA, et al: JAMA 312:12271236, 2014. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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AACR 2014 Cancer Progress Report Call to Action: Prioritize Federal Funding for Biomedical Research By Jo Cavallo

ast month, the American Association for Cancer Research (AACR) released its 2014 Cancer Progress Report: Transforming Lives Through Research, which highlights the quickening pace of drug development and approval, especially in molecularly targeted agents, that are leading to increased numbers of cancer survivors—nearly 14.5 million in the United States today vs just 3 million in 1971, according to the report. However, the report also warns that research progress is being slowed due to years of budget cuts to the National Institutes of Health (NIH) and the National Cancer Institute (NCI) and calls for biomedical research in cancer to be made a national priority. “[Over] the last 25 years that I have been a cancer investigator I have witnessed tremendous progress across the spectrum of cancer research from bench to bedside,” said Carlos L. Arteaga, MD, President of AACR, and Director, Breast Cancer Program and Center for Cancer Targeted Therapies at Vanderbilt-Ingram Cancer Center in Nashville during a press conference announcing the report’s findings. “I have also seen extraordinary advances in the way patients are treated, and I think it’s fair to say that many of us who take care of patients with cancer are seeing responses to treatment that we have not seen before. We know that we are witnessing transformative change in the way we treat patients.”

of the progress against cancer and urges Congress to restore the $1.6 billion in NIH funding that was cut as a result

of sequestration. The AACR is also calling for increased funding to the NIH and NCI at a rate that is at least

comparable to biomedical inflation. According to the report, the NIH’s

JOIN US!

Funding Integral to Progress The report credits past federal support of the National Institutes of Health (NIH) and the National Cancer Institute (NCI) with fueling much

Letters to the Editor

am troubled by hypocrisy. An article in the July 25th edition of The ASCO Post on “Stakeholders Are Uniting Around Value in Cancer Care” ( July 25, 2014, page 1) tells us how we must “rein in” costs. The vast majority of the articles in this issue, however, trumpet the “new wonder drugs” that we have or will have shortly. n —Carl Singerman, MD Northridge, California Send Us Your Comments Write to editor@ASCOPOST.com

continued on page 200

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Announcements

ASCO 50th Anniversary Poll Names the Top 5 Advances From the Past 50 Years

SCO has announced the “Top 5 Advances in 50 Years of Modern Oncology,” based on results of worldwide voting on CancerProgress.Net— ASCO’s interactive website documenting the history of progress against cancer. The “Top 5 in 50” results identify pivotal discoveries in chemotherapy, prevention, molecularly targeted therapy, and supportive care that have stood the test of time, and upon which further discoveries have since been based.

‘Progress Builds on Progress’ Importantly, federal research funding played a role in many of these ad-

Cancer Progress Report continued from page 199

current funding is $3.5 billion less than where it would be today if it had grown at the same rate as biomedical inflation since 2010, which has translated into a loss of more than $5 billion in purchasing power over the last 4 years. The loss represents a disturbing trend, especially when compared with the growing health-care challenge and financial burden cancer has on individuals and society as a whole. The most current estimates from the NIH show that in 2009 the overall medical costs of cancer in the United States were

vances, which were announced a day ahead of the 2nd Annual Rally for Medical Research Hill Day on September 18, in Washington, DC. The goal of this event was to call attention to the real and meaningful progress that has been made because of the federal investment in medical research through the National Institutes of Health (NIH). Patients and advocates also joined in a call to Congress for greater funding for the NIH, which actually lost almost a quarter of its purchasing power in the last decade, adjusting for inflation. “Progress builds on progress. Over the past 5 decades, NIH-funded re-

search has transformed the outlook for people with cancer. These Top 5 in 50 highlight transformational discoveries that represent a shining sliver of what we have learned from a sustained investment in federally funded research,” said ASCO President Peter P. Yu, MD, FASCO. “However, without greater federal investment going forward, the pace of progress against cancer and other diseases will be far slower. We’re already seeing more high-quality research grants being turned down and a projected 40% cut to patient enrollment in NIH-funded cancer clinical trials, just since 2009.”

back on a path of predictable growth in funding, our ability to support cancer care for the benefit of current and future cancer patients will be jeopardized,” said Dr. Arteaga.

■ The report warns that research progress is being slowed due to years of budget cuts to the NIH and the NCI and calls for biomedical research in cancer to be made a national priority.

Highlights from AACR’s 2014 report showcasing progress against cancer in the last year include: • U.S. Food and Drug Administration (FDA) approval of six new anticancer therapeutics, five of which are molecularly targeted agents; and new uses for five previously approved anticancer

therapies. The number of new drugs approved between August 2013 and July 2014 represents the greatest number ever approved in 1 year. • “The pace of translating laboratory findings into drugs that are improving patients’ lives has accelerated,” said Jeffrey A. Engelman, MD, PhD, Director of the Center for Thoracic Cancers at Massachusetts General Hospital, and Associate Professor of Medicine at Harvard Medical School, at the AACR press briefing. “I think

continued on page 201

■ The AACR 2014 Cancer Progress Report highlights the quickening pace of drug development and approval, especially in molecularly targeted agents, that are leading to increased numbers of cancer survivors.

■ The report urges the Obama Administration and Congress to “prioritize the growth of the NIH and NCI budgets at a predictable, robust pace by providing annual budget increases at least comparable to the biomedical inflation rate.”

what we are all worried about is whether or not we are going to see a reversal of that increasing slope of progress [due to reduced funding for research].” Two imaging agents received new cancer-related FDA approvals, as did a previously approved screening test. Patients with some types of cancer now have three or more molecularly targeted treatment options, should their cancer recur or become resistant to the primary therapy. Cancer genomics research is the foundation for novel clinical trials designed to accelerate the pace at which new therapeutics are approved for patient care. Cancer immunotherapeutics are continuing to yield remarkable, long-lasting patient responses in several types of cancer. There now are an estimated 14.5 million cancer survivors in the U.S., and nearly 380,000 of these individuals received their cancer diagnosis as children or adolescents.

a higher quality of life than in any other time in history,” said Dr. Arteaga. “The lives of many cancer survivors have been transformed by research that has led to the development of new molecularly targeted therapeutics.” The AACR report concludes with a call to action to the Obama Administration and Congress to “prioritize the growth of the NIH and NCI budgets at a predictable, robust pace by providing annual budget increases at least comparable to the biomedical inflation rate.” If the Administration and Congress fail to act, warned Dr. Arteaga, the result could mean a loss of biomedical researchers to other fields. “Many young individuals who would be tremendous cancer investigators with good ideas are leaving cancer research or not joining cancer research because the signal is very clear: They are going to have a very hard time getting funding, so they might as well join other careers.” n

Lives Transformed by Research

A copy of the 2014 AACR Cancer Progress Report: Transforming Lives Through Research, may be downloaded from the AACR’s website at cancerprogressreport.org.

• •

•

— Carlos L. Arteaga, MD

$2l6.6 billion, including direct medical costs of $86.6 billion, and indirect mortality costs of $130 billion, making cancer among the most costliest of diseases in the nation. “When these costs are compared with the NIH and NCI budgets for fiscal years 2014, which are just $30 billion and $4.9 billion, respectively, it underscores the inadequacy in federal funding for cancer research that exists today,” according to the AACR report. “If policymakers fail to put the NIH

The “Top 5 in 50” vote was conducted between December 2013 and July 2014, as part of ASCO’s 50th anniversary celebration. The ballot consisted of 32 clinical research advances that occurred since ASCO’s founding in 1964 and are included in the Major Milestones Timeline of CancerProgress.Net. “All of these advances mark major turning points for cancer care and have improved and saved the lives of countless Americans,” said Dr. Yu. “Federally funded research answers questions that are

AACR 2014 Cancer Progress Report Highlights

Charting Progress Being Made in Cancer Care

Americans today are more likely to survive a cancer diagnosis and then enjoy a higher quality of life than in any other time in history.... Lives have been transformed by [biomedical] research that has led to the development of new molecularly targeted therapeutics.

Top 5 Advances in 50 Years of Modern Oncology

•

“As a result of advances like these, Americans today are more likely to survive a cancer diagnosis and then enjoy

ASCOPost.com | OCTOBER 15, 2014

PAGE 201

Announcements Top 5 Advances continued from page 200

critically important to patients, questions that would otherwise go unanswered— like comparing the effectiveness of two regimens, exploring new uses for generic drugs, finding new ways to improve patients’ quality of life, and testing truly novel approaches like many of those highlighted in the Top 5 in 50 announced today.”

ASCO’s proposed budget increases for NIH and NCI will help ensure that the nation’s clinical cancer research infrastructure is protected, help attract the nation’s brightest young minds to a career in medicine, and offer future patients access to more and better cures. —Peter P. Yu, MD, FASCO

search Hill Day, ASCO renewed its call for increased 2015 budgets for the NIH and the National Cancer Institute (NCI). ASCO is asking for a $5.26 billion budget for the NCI and at least a $32 billion budget for the NIH for the 2015 fiscal year—a request that will allow NIH to protect current projects and begin a plan for growth in future years.

“ASCO’s proposed budget increases for NIH and NCI will help ensure that the nation’s clinical cancer research infrastructure is protected, help attract the nation’s brightest young minds to a career in medicine, and offer future patients access to more and better cures,” said Dr. Yu. ASCO is co-sponsoring the Rally for

Medical Research, which includes meetings with Congressional leaders. Hundreds of medical research and advocacy groups and patients are expected to attend the event spearheaded by the American Association for Cancer Research, joining in a call to Congress for increased research funding for the NIH. n See sidebar on page 202

Quality Improvement: From Practical Training to Implementation ASCO invites you to apply for its Quality Training Program—a comprehensive course designed to lead your oncology team through quality improvement (QI) activities using proven experiential learning techniques. The 6-month program offers virtual sessions with in-person exercises and seminars led by expert faculty and coaches, maximizing learning opportunities for your team.

With more than 2,000 votes cast by physicians, patients, and the public, following are the “Top 5 Advances in Modern Oncology.” (See sidebar on page 202.) Each of these will be explored more fully in future issues of The ASCO Post. 1. Chemotherapy Cures Advanced Hodgkin Lymhoma 2. HPV Vaccine Approved to Prevent Cervical Cancer 3. Targeted Drug Transforms Treatment of Chronic Myelgenous Leukemia 4. Chemotherapy Cures Men With Testicular Cancer 5. Powerful Anti-nausea Drugs Dramatically Improve Patient’s Quality of Life

Clinical Cancer Advances Report Every year, ASCO tracks important advances in clinical cancer research with its Clinical Cancer Advances report, drawing from research published in scientific journals and presented at scientific meetings.

Need for Federal Research Funding Remains Critical During the Rally for Medical Re-

Results of the 2013-2014 Pilot Program: 97% of participants learned new QI concepts 95% of participants applied unfamiliar QI concepts “Quality improvement felt nebulous. What I did not know is how scientifically-based quality improvement work is, and this program gave me the roadmap and tools.” —Program Participant

For more information, or to apply, visit asco.org/qualitytraining Deadline: December 31, 2014 by 11:59 PM EST. CE credits and MOC Part IV points offered

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The ASCO Post | OCTOBER 15, 2014 AVASTIN® (bevacizumab)

Announcements

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

50th Anniversary Poll continued from page 201

Top 5 Advances in Modern Oncology 1. Chemotherapy Cures Advanced Hodgkin Lymphoma In the first chemotherapy breakthrough for advanced cancer in adults, a four-drug combination chemotherapy regimen, called MOPP (mustargen/ oncovin/procarbazine/prednisone), induced long-term remissions in over half of patients with aggressive Hodgkin lymphoma. The 1965 discovery sparked the first hope that advanced cancers could be cured with drug treatment, and paved the way for 90% cure rates for patients with this disease today. 2. HPV Vaccine Approved to Prevent Cervical Cancer The Food and Drug Administration’s 2006 approval of the first human papillomavirus (HPV) vaccine, Gardasil, protects against the two strains of HPV known to cause most cervical cancers. Widespread vaccination, if fully implemented, stands to drive dramatic reductions in cervical and other HPV-related cancers in the United States and worldwide. 3. Targeted Drug Transforms Treatment of Chronic Myelogenous Leukemia The rapid FDA review and approval of imatinib (Gleevec) in 2001 dramatically changed the treatment of patients with chronic myelogenous leukemia (CML). This easy-to-take daily pill, which targets a molecular defect present in nearly all patients with CML, turned a disease with almost no long-term survivors into one with 5-year survival rates of 90%. It also ushered in a new era of successful research on molecularly targeted treatments for many more cancers. 4. Chemotherapy Cures Men With Testicular Cancer A new three-drug combination chemotherapy regimen, called PVB (cisplatin/vinblastine/bleomycin), produced complete remissions and some cures for more than 70% of men with advanced testicular cancer. Earlier chemotherapy treatments worked in just 5% of men. This 1977 discovery, coupled with later surgery, radiation, and chemotherapy advances, made testicular cancer one of the most curable cancers and one of oncology’s biggest success stories. 5. Powerful Anti-nausea Drugs Dramatically Improve Many Patients’ Quality of Life The U.S. Food and Drug Administratin (FDA) approval of the antinausea drug, ondansetron (Zofran)—in 1991, as well as other supportive care drugs in the following years—dramatically changed the experience of cancer treatment, bringing unprecedented improvements to patients’ quality of life. These drugs not only bring relief from intense, treatment-induced nausea, but make it possible for patients to avoid once-routine hospital stays, complete their full course of treatment and live longer and better lives.

Cold Spring Harbor, NY, Fall 2014.

Photo by Catherine Glynn.

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 3.2%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occur up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidineoxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 1.5 Persistent, Recurrent, or Metastatic Carcinoma of the Cervix Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix. [See Clinical Studies (14.6).] 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations and Fistulae Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 3.2% across clinical studies. [See Adverse Reactions (6.1).] From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in <1% of Avastin-treated patients. The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin. Permanently discontinue Avastin in patients with gastrointestinal perforation. In Avastin clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer but were also reported less commonly in patients with other types of cancer. In a cervical cancer trial (Study 9), the incidence of gastrointestinal-vaginal fistulae was 8.2% in Avastin-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Non-Gastrointestinal Fistulae Serious and sometimes fatal fistula formation involving tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. Uncommon (<1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post-marketing experience. Most events occurred within the first 6 months of Avastin therapy. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), 1.8% of Avastin-treated patients and 1.4% of control patients were reported to have had non-gastrointestinal vaginal, vesical, or female genital tract fistulae. Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.3 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).] 5.4 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 0.4 to 6.9 %. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with nonsquamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

AVASTIN® (bevacizumab) In clinical studies in non−small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%−5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3−4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Venous Thromboembolic Events Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade ≥ 3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. Permanently discontinue Avastin in patients with life-threatening (Grade 4) VTE, including pulmonary embolism. [See Dosage and Administration (2.4), Adverse Reactions (6.1).] 5.7 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.8 Posterior Reversible Encephalopathy Syndrome (PRES) PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of PRES. Discontinue Avastin in patients developing PRES. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing PRES is not known. [See Dosage and Administration (2.4).] 5.9 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).] Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] 5.10 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.11 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations and Fistulae [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Non-Gastrointestinal Fistulae [See Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Venous Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Posterior Reversible Encephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.9).] • Infusion Reactions [See Dosage and Administration (2.4), Warnings and Precautions (5.10)] • Ovarian Failure [See Warnings and Precautions (5.11), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4817 patients with CRC, non-squamous NSCLC, glioblastoma, mRCC, or cervical cancer, including controlled (Studies 1, 2, 4, 5, 8 and 9) or uncontrolled, single arm trials (Study 6) treated at the recommended dose and schedule for a median of 6 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18-89 years (median 59 years), 44% male and 85% White. The population included 2184 first- and second-line mCRC patients who received a median of 10 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of

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Arm 1 IFL+ Placebo (n = 396) NCI-CTC Grade 3-4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra-Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

74%

87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

AVASTIN® (bevacizumab) and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN-α plus Avastin compared to the IFN-α plus placebo arm are presented in Table 3. Table 3 NCI-CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo) System Organ Class/ IFN-α + Placebo Preferred terma (n = 304) Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Arm 2 IFL+ Avastin (n = 392)

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued. Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5-FU/LV + Avastin (n = 98) (n = 102) (n = 109) 55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

39% 10% 15% 2%

47% 35% 26% 9%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

19%

40% 32% 25% 6%

Avastin in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine-Irinotecan or FluoropyrimidineOxaliplatin Based Chemotherapy in Second-line mCRC Patients who have Progressed on an Avastin Containing Regimen in First-line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 5. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/ embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin-related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and PRES (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Avastin compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension

IFN-α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Avastin arm compared to IFN-α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). Persistent, Recurrent, or Metastatic Carcinoma of the Cervix All grade adverse reactions were collected in Study 9. Grade 1-4 adverse reactions occurring where the incidence difference is ≥ 5% in patients receiving Avastin plus chemotherapy compared to chemotherapy alone are presented in Table 4. Table 4 NCI-CTC Grades 1-4 and 3-4 Adverse Reactions in Study 9 (Incidence Difference of ≥ 5% Between Treatment Arms in Chemo + Avastin vs. Chemo Alone) Grade 1-4 Grade 3-4 reactions reactions Chemo Chemo+ Chemo Chemo+ Alone Avastin Alone Avastin (n=222) (n=218) (n=222) (n=218) Metabolism and Nutrition Disorders Decreased Appetite 26% 34% Hyperglycemia 19% 26% Hypomagnesemia 15% 24% Hyponatremia 10% 19% Hypoalbuminemia 11% 16% General Disorders and Administration Site Conditions Fatigue 75% 80% Edema Peripheral 22% 15% Investigations Weight Decreased 7% 21% Blood Creatinine Increased 10% 16% Infections and Infestations Urinary Tract Infection 14% 22% Infection 5% 10% Vascular Disorders Hypertension 6% 29% 0.5% 11.5% Thrombosis 3% 10% 2.7% 8.3% Nervous System Disorders Headache 13% 22% Dysarthria 1% 8% Gastrointestinal Disorders Stomatitis 10% 15% Proctalgia 1% 6% Anal Fistula — 6% Blood and Lymphatic System Disorders Neutropenia 6% 12% Lymphopenia 5% 12% Psychiatric Disorders Anxiety 10% 17% Reproductive System and Breast Disorders Pelvic Pain 8% 14% Respiratory, Thoracic and Mediastinal Disorders Epistaxis 1% 17% Renal and Urinary Disorders Proteinuria 3% 10% Grade 3 or 4 adverse reactions occurring at a higher incidence ( ≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone were abdominal pain (11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%), proctalgia (2.8% vs. 0%), urinary tract infection 8.3% vs. 6.3%), cellulitis (3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%), hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8% vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic pain (5.5% vs. 1.4%). There were no Grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment-emergent anti-bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme-linked immunosorbent assay (ELISA). The clinical significance of these anti-product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, PRES, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort

AVASTIN® (bevacizumab) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin-treated patients. [See Warnings and Precautions (5.11), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients. 17 PATIENT COUNSELING INFORMATION Advise patients: • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated. • To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting. • Of increased risk of wound healing complications during and following Avastin. • Of increased risk of an arterial thromboembolic event. • Of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following last dose of Avastin. • Of the increased risk for ovarian failure following Avastin treatment.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990

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Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

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Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B-cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post-treatment period was demonstrated in 22% (7/32) of the Avastin-treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post-treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.11), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized,

AVASTIN® (bevacizumab) double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1. Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

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AVASTIN® (bevacizumab) 9 doses of Avastin, 337 mRCC patients who received a median of 16 doses of Avastin, and 218 cervical cancer patients who received a median of 6 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, and 403 previously untreated patients with diffuse large B-cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin as compared to 4% (1/25) of patients who received bolus-IFL alone. In Study 6, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra-abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone. In a second, randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. There were no patients with Grade 5 VTE. [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%. Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re-initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re-initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.9).]

To confront a threat in first-line metastatic non-squamous NSCLC…

Think Avastin

Because survival matters most

Percentage Surviving

Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991 100

1-year survival: 51% vs 44%2

2-year survival: 23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

OS (Months) Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68– 0.94], P=0.013).1 Clinically meaningful 1- and 2-year survival rates were demonstrated with Avastin plus PC (51% and 23%, respectively, vs 44% and 15% with PC alone).2

Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; OS=overall survival; HR=hazard ratio; CI=confidence interval.

Indication

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Most common adverse events

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)

AVA0000400603

Printed in USA.

Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/ pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. Avastin Prescribing Information. Genentech, Inc. March 2013. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

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