TAP Vol 6 Issue 22 by Harborside Press LLC

Metastatic Breast Cancer 1, 70 | Newly Approved Oncology Drugs

1, 19, 33, 50

| Refractory Hairy Cell Leukemia

VOLUME 6, ISSUE 22

28, 34, 35

DECEMBER 10, 2015

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

FDA Update

November Yields Record Number of FDA Approvals for New Oncology Drugs and Drug Indications By Jo Cavallo

By Chandrakanth Are, MBBS, MBA, FRCS, FACS

n 2014, the U.S. Food and Drug Administration (FDA) approved 9 new drugs and biologics in the treatment of cancer and added 10 notable new indications or formulations to existing drug labels, marking a year of significant progress in improving the quality of cancer care in the United States. So far this year, the FDA’s Center for Drug Evaluation and Research has already surpassed that number, with 13 new drug approvals—6 in November alone—plus 13 new drug indications or formulations and 1 expanded indication for lenalidomide (Revlimid) in combination with dexamethasone for newly diagnosed patients with multiple myeloma.1 (See related reports from JADPRO Live at APSHO [page 19], for FDA Update [pages 21, 33, and 50], and for In the Clinic [pages 40, 120, 123, and 124].)

Among the list of anticancer therapies approved this year are a number of FDA-approval firsts, including ixazomib (Ninlaro), the first approved oral proteasome inhibitor in the treatment of multiple myeloma; panobinostat (Farydak), the Richard Pazdur, MD first-ever histone deacetylase inhibitor to receive FDA approval, also for multiple myeloma; and palbociclib (Ibrance), the first drug in a new class of cyclin-dependent kinase (CDK) 4 and CDK 6 selective inhibitors, in the treatment of metastatic breast cancer. Among the new drug indications approved by the FDA so far this year are pembrolizumab (Keytruda) for patients with metastatic non–small cell lung cancer (NSCLC) whose tumors express p rogrammed cell death ligand 1 continued on page 42

Perspective

ASCO Guideline on the Use of Biomarkers in Treatment Decisions in Metastatic Breast Cancer: Shedding Light on an Often Mysterious Art By Elizabeth Reed, MD

Filial Gaze at Our Noble Profession

s summarized in this issue of The ASCO Post (see page 70), Van Poznak and colleagues recently published an ASCO clinical practice guideline on the use of biomarkers for decisions regarding systemic therapy in women with metastatic breast cancer.1 This new guideline updates the previous ASCO biomarker

guideline, which addressed all indications in breast cancer for biomarker assays.2 The newest guideline builds upon the ASCO and the College of American Pathologists two guidelines on testing for human epidermal growth factor receptor 2 (HER2) and endocrine receptors for estrogen and progesterone.3-5 Van Poznak et al addressed the use of biomarkThe panel should be commended ers in selecting treatment for gleaning the data from a limited for metastatic breast cancer on the basis of estrogen number of trials and lending its receptor, progesterone regreat clinical experience to publish ceptor, and HER2 status, as well as considering evaluaa guideline that enlightens the tion of response to therapy often mysterious art of managing using assays for carcinoembryonic antigen, cancer metastatic breast cancer. antigen 15-3 (CA 15-3), —Elizabeth Reed, MD

Send your comments to editor@ASCOPost.com

s we stood outside patient X’s room going over the vitals, from a distance, I saw the father of the patient by the side of her bed. I saw him standing there and looking down at his child conveying what I guess were words of reassurance and reinforcing the pillars of strength needed for her recovery. It appeared like he was not saying much, but his silence, punctuated by a few words and combined with that affectionate and elegiac gaze, was enough to make her look comfortable. It is difficult for patient X to do anything on her own due to the severity of her illness. Even continued on page 164

Dr. Are is Jerald L & Carolynn J Varner Professor of Surgical Oncology & Global Health; Vice Chair of Education; and Program Director, General Surgery Residency, University of Nebraska Medical Center, Omaha. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage Lynn Sage Breast Cancer Symposium �� 3, 4 Palliative Care Symposium �� 5, 10–14 Breast Cancer Symposium �� 15–16 JADPRO Live at APSHO ��18–20 Society of Integrative Oncology ��22–23 Geriatrics for the Oncologist ��27 Direct From ASCO �� 85–88 Global Cancer Burden: Argentina ��92–93 Barry R. Meisenberg, MD, on Costs, Outcomes, and Expectations �� 99 Foot Care in Oncology �� 106 Liver Mets in Colon Cancer �� 148 In Memoriam: Mary Pazdur, RN, MSN ��162–163

continued on page 71

A Harborside Press® Publication

The ASCO Post | DECEMBER 10, 2015

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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

George W. Sledge, MD Stanford University School of Medicine

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com

Associate Editors

Alison Freifeld, MD University of Nebraska Medical Center

Jame Abraham, MD Cleveland Clinic

Louis B. Harrison, MD Moffitt Cancer Center

Syed A. Abutalib, MD Cancer Treatment Centers of America

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

Clifford A. Hudis, MD, FACP Memorial Sloan Kettering Cancer Center

Chandrakanth Are, MD University of Nebraska Medical Center

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Joseph S. Bailes, MD Texas Oncology

Hagop M. Kantarjian, MD MD Anderson Cancer Center

Laurence H. Baker, DO University of Michigan Health System

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Jamie Von Roenn, MD American Society of Clinical Oncology Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

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Richard Boxer, MD University of Wisconsin School of Medicine

Michael P. Link, MD Stanford University Medical Center

Harold J. Burstein, MD Dana-Farber Cancer Institute

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January by Harborside Press®, LLC, 94 North Woodhull Road, Huntington NY 11743, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Huntington, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, LLC, 151 Fairchild Avenue, Ste. 2, Plainview, NY 11803-1709. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@ asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email subscriptions@harborsidepress.com or fax (631) 692-0805. Copyright ©2015 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

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Lynn Sage Breast Cancer Symposium Breast Cancer

Combining Molecular-Driven Approach and Immunotherapy to Improve Treatment for Patients With Inflammatory Breast Cancer By Charlotte Bath

“W

e have a responsibility to develop better treatment for inflammatory breast cancer,” Massimo Cristofanilli, MD, FACP, told participants at the 17th Annual Lynn Sage Breast Cancer Symposium in Chicago. As recently appointed Associate Director of Translational Research and Precision Medicine at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Dr. Cristofanilli is overseeing efforts there to develop a molecular pattern– driven therapeutic approach to improve treatment for patients with inflammatory breast cancer and other malignancies. Inflammatory breast cancer is “the most aggressive and lethal form of the disease,” Dr. Cristofanilli said, with a large proportion of patients experiencing early recurrence and surviving less than 5 years. “These patients do not survive as long as they should because chemotherapy is very ineffective. There are a number of reasons for that, but chemoresistance is one of the hallmarks of this disease, so we need to find a way to combine biologic therapy with immunotherapy,” Dr. Cristofanilli elaborated in an interview with The ASCO Post.

Distinct but Not Rare Disease It is a misconception that inflammatory breast cancer is a rare disease. “It is distinct but not a rare type of breast cancer,” Dr. Cristofanilli said. This misconception about inflammatory breast cancer is “related to the fact that it is frequently misdiagnosed and underdiagnosed,” Dr. Cristofanilli said, “and that is a major problem.” As a clinicopathologic entity, inflammatory breast cancer is “defined by rapid onset of diffuse erythema” and “edema of the breast without underlying mass.” According to Dr. Cristofanilli, 95% of women presenting with erythema first receive antibiotics, sometimes for up to 6 months. “These are not women who go to a tertiary center or see a specialist right away. They may go to the family physician, then to their obstetrician/ gynecologist. So they go through a number of steps,” he said. Some women who have a delayed diagnosis have been breastfeeding. “If you are breastfeeding and have swollen and red breasts, your first impression is it must be an infection. But if after a week your infection has not improved, there

must be a reason for that.” Other women who present with swollen breasts report that it happened over a very short period of time and that a mammogram was negative just months ago.

No Conservative Surgery Treatment for inflammatory breast cancer requires multimodality therapy, with chemotherapy, mastectomy, and radiation therapy. “There is no conservative surgery, no skin-sparing mastectomy, no lumpectomy” for patients with inflammatory breast cancer, Dr. Cristofanilli noted. Even with this treatment, a large proportion of patients experience early recurrence (within the first 2 years). Many patients do not reach 5-year

A Role for Immunity “It is well established that the molecular subtypes are represented in both inflammatory and noninflammatory disease, but there is an immune signature that appears in inflammatory patients,” Dr. Cristofanilli said. “In the search for a multigene predictor of pathologic complete response in [inflammatory breast cancer] using DNA microarrays, a 107-gene signature was found that distinguished between responders and nonresponders.1 This signature was enriched for immunityrelated genes, showing that in [inflammatory breast cancer], as in [other types of breast cancer], response to neoadjuvant chemotherapy is associated with immunity-related processes,”

These patients do not survive as long as they should because chemotherapy is very ineffective. There are a number of reasons for that, but chemoresistance is one of the hallmarks of this disease, so we need to find a way to combine biologic therapy with immunotherapy. —Massimo Cristofanilli, MD, FACP

survival. “Even in the latest statistics,” Dr. Cristofanilli said, “overall survival is only around 36 months.” Prognosis is worse than for other types of breast cancer, even when matched for standard biomarkers—estrogen receptor, progesterone receptor, and HER2. “So what can we do to improve on this modality of treatment, and what can we add? First of all, we can certainly look at the possibility of improving the neoadjuvant systemic therapy,” Dr. Cristofanilli said. That could involve combining chemotherapy and radiation therapy upfront “in patients who are refractory and not able to achieve tumor response with chemotherapy before mastectomy,” he said. “Another question that remains open is: What type of adjuvant chemotherapy can we use in patients for whom chemotherapy has failed, who have extensive disease, and who have a high chance of recurrence, where standard endocrine therapy may not be enough?” he added.

Dr. Cristofanilli reported, “clearly suggesting there is a role for immunity in this particular disease.” The same group of researchers also looked at the expression of programmed cell death protein ligand 1 (PD-L1) “to see if checkpoint inhibition would be important for predicting and eventually reducing the chance of recurrence in these patients,” Dr. Cristofanilli said. “They found that PD-L1 expression was actually associated with recurrence, although the small numbers do not lead to evidence of any disease survival difference. These results were just published this year.”2

Genomic Profiling Study Genomic analysis has identified novel drivers and targetable pathways in inflammatory breast cancer. In a genomic profiling study reported just this November by Dr. Cristofanilli and colleagues,3 “the most important information is that mutations were detected pretty much in every patient,” Dr. Cristofanilli said.

Comprehensive genetic profiling was done on 53 formalin-fixed paraffinembedded specimens of inflammatory breast cancer. The median number of mutations was five. Clinically relevant genomic alterations, defined as genomic alterations “associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials” were present in 96% of the cases. The most frequently altered genes were TP53 (62%), MYC (32%), PIK3CA (28%), ERBB2 (26%), FGFR1 (17%), BRCA2 (15%), and PTEN (15%). In the triple-negative breast cancer subset (39% of the patients), 8 (42%) of 19 showed MYC amplification vs 9 (28%) of 32 in non–triplenegative inflammatory breast cancer. “There are clearly three major pathways: the cell cycle and apoptosis pathway, the PI3K pathway, and the RTK/ RAS pathway,” Dr. Cristofanilli reported. “These are now guides for us to look at what type of specific treatment—either standard or investigational treatments in clinical trials—we can use for selected patients with inflammatory breast cancer.” He noted the high proportions of mutations in the cell cycle and apoptosis pathway, “suggesting that underlying genomic instability will be important to target and consider in the selection of treatment.”

Pathways Talk to Each Other An unpublished study of 20 pairmatched cases of inflammatory breast cancer revealed variations within and across tumors. Intratumor heterogeneity analysis found that the majority of genetic variants occurred at low frequencies in individual tumors, and intertumor heterogeneity analysis found that the majority of genes showed low levels of variation across tumor samples. Looking at genomic variation in core pathways and processes shared across inflammatory breast cancer cases, PI3K “seems to be extremely important for survival and proliferation,” whereas APC/WNT and NOTCH are more involved with cell fate. “This is very important for developing therapies to reduce the chance of recurrence,” Dr. Cristofanilli noted. Inflammatory breast cancers harbor frequent genomic alterations in ERBB (HER) and PI3K pathways and many continued on page 4

The ASCO Post | DECEMBER 10, 2015

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Lynn Sage Breast Cancer Symposium Inflammatory Breast Cancer continued from page 3

variants detected in the PI3K/ERBB pathway are predicted to functionally activate the pathway. “The ERBB pathway and the PI3 kinase pathway talk to each other,” Dr. Cristofanilli said, “and this is very important to targeted therapy.” Summarizing recent studies, Dr. Cristofanilli noted that next-generation sequencing analysis can identify multiple potentially targetable lesions in inflammatory breast cancer based on current therapies and drugs in development. The higher mutation rates in ERBB3 for inflammatory breast cancer than for other cancers may mean it is a new target in inflammatory breast cancer. “ERBB-targeted therapies for [inflammatory breast cancer] may be associated with resistance due to a high level of PI3K pathway variants. Combination therapy is important,” Dr. Cristofanilli reported. “Preliminary data,” he added, “suggest that [next-generation sequencing] can be used to predict the level of immune infiltrates in [inflammatory breast cancer] tumors.”

Ongoing Trial for Patients With Metastases Inflammatory breast cancer is characterized by cell aggregates de-

fined as “tumor emboli” that metastasize into the chest wall and skin and express e-cadherin. About 25% of patients with inflammatory breast cancer develop brain metastases because of this disease. A phase I/II study at Northwestern is testing romidepsin (Istodax) in combination with nab-paclitaxel (Abraxane) in patients with metastatic inflammatory breast cancer. “Phase I has been completed,” Dr. Cristofanilli said, and the 10-mg dose is safe. “We have already seen evidence of a response very early on, suggesting that even in patients who are less heavily pretreated, there is a possibility that we can affect the metastatic process of this disease.” Continuing inflammatory breast cancer–directed research, including the use of preclinical models, is needed to better understand the disease and the patient, Dr. Cristofanilli advised. Future steps will involve “looking very deeply into germline analysis,” he said, as well as “investigating checkpoint inhibitors in immunotherapy, first in an advanced setting and maybe later in neoadjuvant therapy.” n Disclosure: Dr. Cristofanilli reported no potential conflicts of interest.

References 1. Bertucci F, Ueno NT, Finetti P, et al: Gene expression profiles of inflammatory breast cancer: Correlation with response to neoadjuvant chemotherapy and metastasis-free survival. Ann Oncol 25:358-365, 2014. 2. Bertucci F, Finetti P, Colpaert C, et al: PDL1 expression in inflammatory

breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget 6:13506-13519, 2015. 3. Ross JS, Ali SM, Wang K, et al: Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations. Breast Cancer Res Treat 154:155-162, 2015.

Lynn Sage Breast Cancer Symposium

The 17th Annual Lynn Sage Breast Cancer Symposium was held at the Fairmont Hotel, Chicago, October 29–November 1, 2015. The program was chaired by William Gradishar, MD, and co-chairs, Nora Hansen, MD, Monica Morrow, MD, and V. Craig Jordan, PhD.

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

Graham A. Colditz, MD, DrPh, (top) and Bobby Daly, MD, MBA, and Olufunmilayo I. Olopade, MD, FACP, OON, on Breast Cancer Incidence and Mortality Trends see pages 53, 54, and 61

Timothy J. Whelan, BM, BCh, and Philip M. Poortmans, PhD, on Regional Nodal Irradiation in Early Breast Cancer see page 76

Vivien D. Tsu, PhD, MPH, on Cancer Care in Low-Resource Areas see page 97

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | DECEMBER 10, 2015

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Palliative Care Symposium Supportive Care

Olanzapine Significantly Reduces Chemotherapy-Induced Nausea and Vomiting By Meg Barbor

he addition of olanzapine to standard antiemetics significantly reduced chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy, according to Rudolph M. Navari, MD, PhD, and colleagues. “As far as I know, this is the first trial that looked at no nausea as the primary

receptor antagonist (ie, palonosetron, ondansetron, or granisetron), and dexamethasone. The study included 192 patients in the olanzapine arm and 188 in the placebo arm. The two arms were well balanced in terms of age, gender, performance status, and diagnosis. Patients received 10 mg of oral olan-

The primary endpoint was no nausea; this is different [from past studies] because most of the antiemetic trials in the literature use complete response as the primary endpoint and look at nausea as a secondary endpoint. —Rudolph M. Navari, MD, PhD

endpoint,” said Dr. Navari, who presented the results of the phase III trial at the 2015 Palliative Care in Oncology Symposium in Boston.1 He is currently based in Geneva, Switzerland, serving as Director of the World Health Organization Cancer Care Program in Eastern Europe. Olanzapine is approved by the U.S. Food and Drug Administration (FDA) as an antipsychotic but does not have an FDA indication as an antiemetic.

Study Details Investigators sought to determine the additional efficacy of olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving their first course of highly emetogenic chemotherapy, with a primary endpoint of no nausea and a secondary endpoint of complete response (no emesis, no rescue). “The primary endpoint was no nausea; this is different [from past studies] because most of the antiemetic trials in the literature use complete response as the primary endpoint and look at nausea as a secondary endpoint,” said Dr. Navari. A randomized, double-blind, phase III trial was performed in chemotherapy-naive patients receiving cisplatin (≥ 70 mg/m2), or cyclophosphamide (600 mg/m2) plus an anthracycline (60 mg/m2), comparing olanzapine to placebo in combination with aprepitant, a 5-hydroxytryptamine 3 (5-HT3)

zapine or matching placebo, plus 125 mg of aprepitant, a 5-HT3 agent, and 12 mg of oral dexamethasone prior to chemotherapy on day 1, followed by 10 mg/d of oral olanzapine or matching placebo and 8 mg of dexamethasone on days 2 to 4 post chemotherapy, plus 80 mg of aprepitant on days 2 and 3 post chemotherapy. The pre- and postchemotherapy regimens of aprepitant, 5-HT3 agent, and dexamethasone were identical in the olanzapine and placebo arms. On day 1, fosaprepitant (Emend, 150 mg intravenously) was allowed as a substitute for the oral aprepitant. Nausea was measured on a 0-to-10 visual analog scale, with 0 being “no nausea at all” and 10 being “nausea as bad as it can be.” Measurements were taken in the acute (0–24 hours post chemotherapy), delayed (24–120 hours post chemotherapy), and overall (120 hours post chemotherapy) phases. Measurements of complete response were taken during the same time periods.

Key Findings “A very significant P value in favor of no nausea in the olanzapine arm was observed in all three phases,” said Dr. Navari. The proportion of patients who had no nausea was significantly greater for the olanzapine arm compared with the placebo arm for the acute period (74% vs 45%, P < .0001), delayed period (42% vs 25%, P = .0008), and overall period (37% vs 22%, P = .0015). Complete response was also significantly improved for olanzapine recipients compared to placebo recipients for all three phases: acute (86% vs 65%, P < .0001), delayed (67% vs 52%, P = .0073), and overall (64% vs 41%, P < .0001). “In previous studies where olanzapine was used, there was concern about toxicities, mainly short-term sedation and increased appetite,” Dr. Navari stated. Transient sedation was observed in the olanzapine arm on day 2, but this sedation resolved despite continued use of olanzapine on days 3 and 4. “The important issue is that no patient in the study on olanzapine discontinued the study or discontinued olanzapine, despite sedation,” he added. No difference in appetite was observed in either arm on days 2 to 6. Other than transient sedation, no significant adverse effects were observed with the use of olanzapine.

‘A Milestone in Antiemetics’ “As someone who’s been in the field of oncology for 40-plus years, I’ve come to realize that the elimination of cancer as a disease in our society is never going to happen,” said Lawrence H. Einhorn, MD, a medical oncologist and Distinguished Professor of Medicine at Indiana University School of Medicine in Indianapolis. “But what we can do is eliminate the fear from cancer. What are the two biggest fears that cancer patients have when they

Role of Olanzapine in Supportive Care ■■ In a 380-patient study, olanzapine, combined with a 5-HT3 receptor antagonist, aprepitant, and dexamethasone, significantly improved control of nausea and emesis in patients receiving highly emetogenic chemotherapy in the acute, delayed, and overall periods after chemotherapy. ■■ Transient sedation was seen on day 2 after chemotherapy in olanzapine recipients; no other significant adverse events were noted with the drug.

Lawrence H. Einhorn, MD

have metastatic disease? First is [chemotherapy-induced nausea and vomiting], and the second is pain.” “In this study, the primary endpoint of no nausea is a unique and appropriate endpoint,” said Dr. Einhorn. “I agree 100% with Dr. Navari that it’s far more important to have no nausea [as a primary endpoint] than to have a complete remission with no episodes of emesis.” The investigators concluded that olanzapine in combination with a 5-HT3 receptor antagonist, aprepitant, and dexamethasone significantly improves the control of nausea and emesis in the acute, delayed, and overall phases for patients receiving highly emetogenic chemotherapy. “There were many skeptics about the utility of this drug,” added Dr. E inhorn. “But olanzapine does represent a true milestone in antiemetic therapy.” The investigators noted that the study results were consistent with current guidelines from the National Comprehensive Cancer Network, which recommends the use of olanzapine with standard antiemetics as an option for preventing chemotherapy-induced nausea and vomiting in patients receiving emetogenic chemotherapy.2 n

Disclosure: Drs. Navari and Einhorn reported no potential conflicts of interest.

References 1. Navari R, Qin R, Ruddy J, et al: Olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC): Alliance A221301, a randomized, double-blind, placebo-controlled trial. 2015 Palliative Care in Oncology Symposium. Abstract 176. Presented October 9, 2015. 2. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Antiemesis, Version 2.2015. Available at nccn.org. Accessed November 20, 2015.

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Palliative Care Symposium Supportive Care

Anamorelin Improves Cachexia Symptoms in Patients With Advanced Non–Small Cell Lung Cancer By Meg Barbor

he investigational agent anamorelin significantly increased lean body mass, body weight, total body mass, and fat mass in patients with

advanced non–small cell lung cancer (NSCLC) and cachexia, according to Jennifer S. Temel, MD, who presented the results of two phase III studies at

the 2015 Palliative Care in Oncology Symposium in Boston.1 Cancer anorexia/cachexia syndrome develops in up to 70% of patients

with advanced cancer and is characterized by decreased appetite and food intake as well as loss of body weight and lean body mass. Patients with this con-

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Palliative Care Symposium dition frequently experience decreased quality of life, lower chemotherapy tolerance, reduced physical functioning, and worse survival. “Cachexia is a common condition, especially in patients with advanced NSCLC,” said Dr. Temel, Clinical Director of Thoracic Oncology at Massachusetts General Hospital in Boston.

“This condition significantly impacts patients, as well as family members; it is quite distressing for them when their loved one can’t participate in family meals and for them to witness the physical changes associated with cachexia.” Currently, there are few therapeutic options and no standard of care for the treatment of anorexia/cachexia. “Cur-

rent treatment options have limited efficacy and potential side effects, such as muscle wasting associated with prolonged use,” she said. Dr. Temel and her colleagues conducted two international, randomized, double-blind trials (ROMANA 1 and ROMANA 2) evaluating the effect of anamorelin, an orally active,

highly selective ghrelin receptor agonist, on cachexia in patients with advanced NSCLC.

Study Design Patients with inoperable stage III or IV NSCLC and cachexia (≥ 5% weight loss within the prior 6 months or body

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Palliative Care Symposium Anamorelin for Cachexia continued from page 11

mass index < 20 kg/m2) were randomly assigned to ROMANA 1 (484 patients) or ROMANA 2 (495 patients). Patients were randomized in a 2:1 fashion to receive 100 mg of anamorelin or matching placebo, administered orally once daily for 12 weeks. All par-

ticipants were followed for 1 year to assess overall survival. Coprimary efficacy endpoints were the change in lean body mass and handgrip strength from baseline over 12 weeks. Secondary endpoints included change in body weight, anorexia/cachexia symptoms and fatigue over 12 weeks, and pooled overall survival at

1 year. Exploratory analyses evaluated change in total body mass and fat mass from baseline to 12 weeks. The majority of study participants had stage IV disease. “The most common NSCLC histology was squamous cell carcinoma, reflecting the fact that this was an internationally conducted trial,” added Dr. Temel.

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Statistically Significant Improvements Patients assigned to anamorelin experienced an increase in lean body mass compared with those assigned to placebo in ROMANA 1 (1.10 of kilogram gain vs –0.44 kg lost, P < .001) and ROMANA 2 (0.75 vs –0.96 kg, P < .001), but no difference in handgrip strength was observed. Patients assigned to anamorelin had a significant increase in body weight (2.2 vs 0.14 kg, P < .001) and (0.95 vs –0.57 kg, P < .001) and improvement in their anorexia/cachexia symptoms (4.12 vs 1.92, P < .001) and (3.48 vs 1.34, P = .002) in ROMANA 1 and 2, respectively (higher scores are consistent with a lower symptom burden for both of these symptom scales). “In both ROMANA 1 and 2, even as early as the 3-week time point, there was a statistically significant difference favoring anamorelin in respect to changes in body weight and anorexia/cachexia symptoms,” said Dr. Temel. “These differences were sustained and dramatic throughout the study period.” Exploratory analysis demonstrated an increase in total body mass (2.87 vs 0.07 kg, P < .001) and (2.04 vs –0.59 kg, P < .001), and fat mass (1.21 vs –0.13 kg, P < .001) and (0.77 vs 0.09 kg, P = .01) for anamorelin vs placebo in ROMANA 1 and 2, respectively. “At the 9- and 12-week time points in ROMANA 1, there were statisticontinued on page 13

In both ROMANA 1 and 2, even as early as the 3-week time point, there was a statistically significant difference favoring anamorelin in respect to changes in body weight and anorexia/cachexia symptoms. —Jennifer S. Temel, MD

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Palliative Care Symposium Supportive Care

Cancer Care Through Nonpharmacologic Symptom Management By Meg Barbor

onpharmacologic approaches to managing pain have a fairly robust base of science and research supporting their use but are not as widely accepted and understood as drug therapy in the realm of cancer care. In a breakout session at the 2015 Palliative Care in Oncology Symposium in Boston, experts in acupuncture, massage therapy, and music therapy addressed the benefits of nonpharmacologic therapies in alleviating pain and other effects of cancer and its treatments.1

Acupuncture “At MD Anderson, we have a formal integrative medicine program with a focus on clinical care, research, and education,” said Lorenzo Cohen, PhD, Professor and Director of the Integrative Medicine Program at the University of Texas MD Anderson Cancer Center in Houston. “And it is clearly important to have these integrative medicine treatment modalities alongside conventional care.” A component of traditional Chinese medicine, acupuncture has been used to treat 200 million people in at least 78 countries annually. According to Dr. Cohen, it is safe, cost-effective, minimally invasive, and can be used to treat individuals of all ages.

Acupuncture is integrated into patient care at MD Anderson, “because there is a good evidence base for chemotherapy-induced nausea and emerging data for many other cancer treatment– related symptoms.” But the mechanisms of action remain elusive,” explained Dr. Cohen, “and when it comes to these nonconventional modalities, if we don’t know the mechanism, even when we have the placebo-controlled randomized controlled trial evidence, it’s hard for the skeptics to believe.” However, numerous studies have shown that acupuncture offers benefits for uncontrolled nausea and vomiting, hot flashes, noncancer- and cancerrelated chronic pain, chemotherapyinduced peripheral neuropathy, and radiation-induced xerostomia.2-4 Dr. Cohen stated that acupuncture therapy is “worth trying” for uncontrolled nausea, vomiting, or pain. He also endorsed its utility when conventional treatment and palliative care have failed to improve symptoms and for dealing with side effects of treatment or medications.

Massage Therapy “If somebody near you hurts, there’s an impulse to touch them,” said Janet

Anamorelin for Cachexia

Disclosure: Dr. Temel has received research funding and travel expenses from Helsinn Therapeutics.

—Lorenzo Cohen, PhD

It is our belief that there is always some kind of touch that is safe and effective to offer a person with cancer. —Janet Kahn, PhD, LMT

Kahn, PhD, LMT, Research Assistant Professor at the University of Vermont’s College of Medicine in Burlington. “In fact, some form of massage has existed in virtually every kind of medicine that humans have ever developed.” Massage has a robust literature base, indicating a wide range of benefits for people at all stages of life, and has been

harles Loprinzi, MD, Regis Professor of Breast Cancer Research, Mayo Clinic, Rochester, Minnesota, commented on these study findings to The ASCO Post: “This is a clinical application of the ghrelin agonist story that’s been brewing

continued on page 14

clots, like megestrol acetate does.” Anamorelin was well tolerated, with no notable differences in toxicity between the study arms; nausea, hyperglycemia, and diabetes were the most frequent drug-related adverse events. Median 1-year survival was

Is it [anamorelin] better than megestrol acetate…? It might be, and also doesn’t increase the risk of blood clots, like megestrol acetate does. —Charles Loprinzi, MD

Reference 1. Temel J, Currow D, Fearon K, et al: Anamorelin in patients with advanced non-small cell lung cancer and cachexia: Results from the phase III studies ROMANA 1 and 2. 2015 Palliative Care in Oncology Symposium. Abstract 175. Presented October 9, 2015.

shown to relieve pain and stress and induce relaxation. “Massage is a fairly popular form of care in the United States,” said Dr. Kahn. Data from the 2007 National Health Interview Survey revealed that in that year, Americans collectively made over 95 million visits to massage therapists

EXPERT POINT OF VIEW

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cally significant differences favoring patients assigned to anamorelin in respect to lower rates of fatigue, but there were no such differences for patients in ROMANA 2,” she added. The investigators concluded that anamorelin was effective in improving anorexia/cachexia symptoms in patients with advanced NSCLC. Patients experienced significant increases in lean body mass, body weight, total body mass and fat mass, indicating increased anabolic activity and renewed energy balance. n

When it comes to these nonconventional modalities, if we don’t know the mechanism, even when we have the placebo-controlled randomized controlled trial, it’s hard for the skeptics to believe.

for maybe a decade. Is it better than megestrol acetate, the drug that’s out there and stimulates appetite and leads to weight gain? It might be, and also doesn’t increase the risk of blood

not different between the study arms. “Cachexia is a vexing symptom,” added Susan McClement, PhD, RN, Professor, College of Nursing, Faculty of Health Sciences, University of

Susan McClement, PhD, RN

Manitoba, and Research Associate, Manitoba Palliative Care Research Unit, CancerCare Manitoba. “If there’s something we can identify for patients that can help truly reverse cachexia so the weight gain that we see is not just fat and water but lean muscle mass and all the other important outcome indicators that Dr. Temel talked about, then that’s exciting,” stated Dr. McClement. n Disclosure: Drs. LoPrinzi and McClement reported no potential conflicts of interest.

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Palliative Care Symposium Nonpharmacologic Therapy continued from page 13

and paid over $4 billion dollars for them. “Most of those 4 billion dollars were paid for out of pocket,” she added. “So you can imagine these numbers would be larger if this were covered care; we just don’t know by what magnitude.” Dr. Kahn and her colleagues developed a program called Touch Caring and Cancer, “which is designed to teach family members and friends of people with cancer how to offer safe

depression, and nausea were rated before and after the session. “For each of these symptoms, the magnitude of change was greater among the massage group than it was among the reading group,” said Dr. Kahn. The reading group had anywhere from 12% to 28% improvement (reduction in troublesome symptoms), whereas the massage group had a 29% to 44% improvement. The investigators also noted significant improvement in the levels of caregiver

Music therapy reduces physical pain, brings joy to patients and teams, and helps to bring about the resolution of existential pain. —Kathy Jo Gutgsell, RN, MT-BC

and effective touch and touch that can actually decrease nausea, pain, or anxiety,” she explained. Designed to be low cost and easily accessible, the program is available as a 78-minute DVD and a 68-page (largely pictorial) manual. In addition to teaching simple touch techniques for comfort and relaxation, it addresses communication in massage and each person’s responsibility for that communication, as well as safety precautions related to the side effects of cancer and its treatments. A randomized controlled trial testing the efficacy of the program was conducted in 97 New England households.5 Patients were randomized to receive either massage or reading therapy for a study period of 4 weeks, and symptoms such as pain, fatigue,

comfort and confidence in delivering effective touch. “One of the hardest things is feeling like you don’t know what to do for a loved one,” said Dr. Kahn. “But it is our belief that there is always some kind of touch that is safe and effective to offer a person with cancer.”

Music Therapy “Music therapy reduces physical pain, brings joy to patients and teams, and helps to bring about the resolution of existential pain,” said Kathy Jo Gutgsell, RN, MT-BC, a music therapist at the University Hospitals Seidman Cancer Center in Cleveland. Ms. Gutgsell was the principal investigator of a randomized controlled trial conducted at University Hospitals Case Medical Center.6 The study sought to determine the efficacy of a single music therapy session to reduce pain in palliative care patients. A total of 200 inpatients were enrolled in the study from 2009–2011 and were randomly assigned to standard care with music therapy (live, music therapist–led autogenic relaxation followed by live ocean drum and harp music) or standard care alone. Blinded clinical nurse specialists assessed pain before and after the intervention, evaluating the primary outcome of pain measured by the Numeric Rating Scale (NRS) and the secondary outcomes of Functional Pain Scale (FPS) and Face, Legs, Activity, Cry, Consolability (FLACC) scale measurements. Significantly greater decreases in the NRS and FPS were observed in

Nonpharmacologic Symptom Management ■■ Numerous studies have shown that acupuncture offers benefits for uncontrolled nausea and vomiting, hot flashes, noncancer- and cancerrelated chronic pain, chemotherapy-induced peripheral neuropathy, and radiation-induced xerostomia. ■■ Massage has a robust literature base, indicating a wide range of benefits for people at all stages of life, and has been shown to relieve pain and stress and induce relaxation. ■■ A randomized controlled trial demonstrated the efficacy of a single music therapy session to reduce pain in palliative care patients.

the music therapy group, although no significant difference in FLACC scores was found between the study groups. “We had wonderful results,” said Ms. Gutgsell. The trial demonstrated that music therapy does indeed lower pain. “Music therapy helps to bring about a resolution of existential pain,” said Ms. Gutgsell. “And we all know that is the hardest part of pain— when we get into the existential issues. Interventions such as songwriting enable our patients to express their emotions and leave a legacy for loved ones.” n Disclosure: Dr. Cohen, Dr. Kahn, and Ms. Gutgsell reported no potential conflicts of interest.

References 1. Cohen L, Kahn J, Gutgsell KJ: Nonpharmacologic symptom management. 2015 Palliative Care in Oncology Symposium. Breakout Session. Presented October 9, 2015. 2. Garcia MK, Graham-Getty L, Haddad R, et al: Systematic review of acupuncture to control hot flashes in cancer patients. Cancer 121:3948-3958, 2015. 3. Garcia M, McQuade J, Haddad R, et al: Systematic review of acupuncture in cancer care: A synthesis of the evidence. J Clin Oncol 31:952-960, 2013. 4. Garcia MK, McQuade J, Lee R, et al: Acupuncture for symptom management in cancer care: An update. Curr Oncol Rep 16:418, 2014. 5. Collinge W, Kahn J, Walton T, et al: Touch, caring, and cancer: Randomized controlled trial of a multimedia caregiver education program. Support Care Cancer 21:1405-1414, 2013. 6. Gutgsell KJ, Schluchter M, Margevicius S, et al: Music therapy reduces pain in palliative care patients: A randomized controlled trial. J Pain Symptom Manage 45:822-831, 2013.

U-M Cancer Center Names Bhramar Mukherjee, PhD, Associate Director for Population Science Research

he University of Michigan (U-M) Comprehensive Cancer Center has appointed Bhramar Mukherjee, PhD, as Associate Director for Population Science Research. Dr. Mukherjee is John D. Kalbfleisch Collegiate Professor of Biostatistics and Professor of Epidemiology at the U-M School of Public Health. She also serves as the Associate Chair for Biostatistics. In her new role, she will oversee the Cancer Center’s research on cancer screening, detection, and prevention,

Bhramar Mukherjee, PhD

as well as research on cancer outcomes, disparities, and new models of cancer care delivery. Dr. Mukherjee’s predecessor in this position was Stephen B.

ruber, MD, PhD, MPH, who is now G the Director of the University of Southern California Norris Comprehensive Cancer Center. Dr. Mukherjee’s appointment is effective January 15. Dr. Mukherjee’s cancer research has focused on how the interaction between genes and the environment impacts cancer risk. She has studied the roles of diet, physical activity, and lifestyle factors, and their interplay with the genetic architecture of an individual. Dr. Mukherjee plans to foster and

facilitate cross-collaboration within the Population Sciences Program in the Cancer Center and across various other units at the University of Michigan. Her goal will be to support the outstanding biomedical prevention and sociobehavioral programs at the Cancer Center, as well as help with new recruitments and initiatives that advance population sciences. Dr. Mukherjee joined the University of Michigan faculty in 2006. She received her doctorate in statistics from Purdue University. n

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Breast Cancer Symposium Molecular Biomarkers

Tumor Profiling of Breast Tumors in Older Patients Reveals Differences From Those of Younger Patients By Chase Doyle

sing multiplatform profiling, researchers have identified potentially targetable biomarker aberrations in a large cohort of geriatric breast tumors.1 According to the study, presented at the 2015 Breast Cancer Symposium, these data may help researchers to design clinical trials focusing on geriatric patient populations in the future. “The triple-negative breast group showed the most differences when

cancer from 2009 to 2015. All samples underwent local pathology and central review and were tested using multiplatform profiling at Caris Life Sciences: that included immunohistochemistry (IHC), fluorescent or chromogenic in situ hybridization (FISH/CISH), and DNA sequencing for somatic mutations. Of the 8,720 breast cancer tumors initially identified, researchers separated tumors from patients younger than 70

The triple-negative breast group showed the most differences when comparing younger and elderly patients. ERBB2 abnormalities in older patients may also warrant further evaluation. —Paula R. Pohlmann, MD

EXPERT POINT OF VIEW

lthough the study clearly showed statistically significant differences, discussant Charles E. Geyer, Jr, MD, FACP, Associate Director of Clinical Research at the Massey Cancer Center in Richmond, Virginia, indicated that it’s unclear whether these are “clinically relevant differences,” adding that, overall, there were more similarities than differences between the geriatric and younger populations. “The most interesting data for me were the high Charles E. Geyer, Jr, MD, FACP percentage of PD-1 and PD-L1 markers in staining,” said Dr. Geyer. “I think these are much higher numbers than what we’ve seen reported, particularly in the hormone receptor–positive/HER2-negative patients.” “I would differ with Dr. Pohlmann’s conclusions that the study provides relevant information for the design of clinical trials focusing on geriatric patient population,” Dr. Geyer remarked. “Rather, the data suggest the focus needs to be on inclusion of geriatric patients in our targeted therapy trials. I think it would be a mistake to peel these patients off and attempt to evaluate them in separate studies.” n Disclosure: Dr. Geyer reported no potential conflicts of interest.

comparing younger and elderly patients,” said Paula R. Pohlmann, MD, of Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington DC. “ERBB2 abnormalities in older patients may also warrant further evaluation.” The study also found that staining for the programmed cell death protein 1 and its ligand (PD-1/PD-L1) was positive in all breast cancer subtypes—not just triple-negative tumors (estrogen receptor–/progesterone receptor–/ HER2-negative)—the group that has been the focus of immunotherapy trials with PD-1/PD-L1 inhibitors. As Dr. Pohlmann reported, geriatric patients are often excluded from clinical trials and are underrepresented in biomarker literature. Because breast cancer is a disease of aging and the number of geriatric patients is rising in the United States, studying older populations of patients with breast cancer may be necessary for the refinement of treatmentselection strategies. “Our aims were to describe molecular characteristics of breast cancer in geriatric patients,” said Dr. Pohlmann,” and to compare molecular characteristics of tumor samples from geriatric patients with those from younger patients.”

Study Design This was a cross-sectional retrospective study of biomarker data obtained from samples of patients with breast

years and excluded tumors taken from male patients with breast cancer. The final cohort consisted of 1,189 samples taken from patients older than 70 years (the “geriatric” patients). The remaining 7,531 samples were taken from patients younger than 70 years (the “younger” patients). Tumors came from both primary and metastatic sites.

Molecular Differences With IHC staining, ER, PR, AR, TOP01, TLE3, Ki67, PTEN, and TOP2A were all detected positive more than 50% of the time. Ki67 was more often positive in younger patient samples, Dr. Pohlmann noted. The most frequently mutated genes were TP53 and PIK3CA, which were found in greater than 2% of samples. TP53 was more often mutated in younger patients, and PIK3CA was more often mutated in geriatric patients.

TOP2A was more frequently positive among younger patients, although amplification was low overall in both age groups and was almost exclusive to HER2-positive patients. EGFR was significantly elevated in the triple-negative subgroup, whereas TLE3 was more often elevated in the estrogen receptor–positive/progesterone receptor–positive/HER2-negative group. ERBB2 was mutated in 12 cases of geriatric breast cancer and in 38 cases among younger patients. “It’s important to mention that we had HER2 positivity in only four of these cases,” Dr. Pohlmann reported. For HER2-positive patients, although most of the abnormalities were equivalent when comparing younger and geriatric population samples, ERBB2 mutations were more frequent

A Molecular Look at Geriatric vs Younger Breast Tumors ■■ Tumor profiling of 1,189 geriatric breast tumors revealed distinctions between geriatric and younger populations. ■■ Only 1 in 69 geriatric triple-negative breast cancer samples (1%) had BRCA1 mutations, vs 40 in 390 (10%) among younger patients with triple-negative disease. ■■ PD-L1 tumor cells tested positive in 8% of hormone receptor–positive tumors, 20% HER2-positive, and 19% of triple-negative geriatric patient samples. ■■ Tumor-infiltrating lymphocytes were PD-1 positive in 39% of hormone receptor–positive, 44% of HER2-positive, and 60% of triple-negative geriatric patient samples.

in the geriatric group (12% vs 3%), she indicated. “That being said, the enriched population has a small sample size, so we have to take these results with caution,” added Dr. Pohlmann. It was also noted that BRCA1 was rarely mutated in the older patient population of triple-negative breast cancer. PD-L1 tumor cells tested positive in 8% of hormone receptor–positive tumors, 20% of HER2-positive tumors, and 19% of triple-negative geriatric patient samples. Tumor-infiltrating lymphocytes were PD-1–positive in 39% of hormone receptor–positive, 44% of HER2-positive, and 60% of triple-negative geriatric patient samples. A lack of patient information about staging, previous treatments, subsequent treatments after molecular profiling, and outcomes was cited as a possible limitation to the study, as was the relatively small number of HER2-positive samples and the lack of definitive clinical validation of cutoff values for each test in breast cancer populations. n

Disclosure: Dr. Pohlmann owns stock in Immunonet Biosciences and has consulted for OncoPlex Diagnostics and Personalized Cancer Therapy.

Reference 1. Xiu J, Reddy SK, Pohlmann PR: Tumor profiling of 1189 geriatric breast tumors. 2015 Breast Cancer Symposium. Abstract 116. Presented September 25, 2015.

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Breast Cancer Symposium Systemic Therapy

Neoadjuvant Chemotherapy Appears to Have No Effect on Short-Term Outcomes in Breast Cancer Surgery By Chase Doyle

atients who received neoadjuvant chemotherapy within 30 days prior to breast cancer surgery did not appear to be at increased risk for overall postoperative complications, according to a study presented at the 2015 Breast Cancer Symposium.1 “Although on unadjusted analysis there were more complications in the neoadjuvant-chemotherapy cohort, this difference was negated when controlling for baseline differences with a propensity-score adjusted multivariate model,” said Erin Cordeiro, MD, a surgeon at The Ottawa Hospital in Ontario, Canada. “There was no difference in the overall 30-day postoperative complication rate between patients treated with neoadjuvant chemotherapy vs not.” “Surgeons should not feel that they have to wait more than 4 weeks following chemotherapy to perform breast cancer surgery safely,” she added. Conventionally, neoadjuvant chemotherapy has been directed at advanced, inoperable breast cancers; however, in modern times, its use has expanded to include even small, earlystage cancers. “The indications for neoadjuvant chemotherapy are increasing,” Dr.

There was no difference in the overall 30-day postoperative complication rate between patients treated with neoadjuvant chemotherapy vs not. —Erin Cordeiro, MD

Cordeiro explained. “Patients with triple-negative disease as well as HER2positive disease have increased rates of pathologic complete response, and many clinicians are increasing their use of neoadjuvant chemotherapy to these populations.” A recent study of the National Cancer Database indicated that in 2011, 20% of all patients with breast cancer received neoadjuvant chemotherapy (up from 14% in 2006). And yet, as Dr. Cordeiro noted, there are still concerns among surgeons regarding the toxic side effects of chemotherapy. “Many surgeons feel that there may be an increase in postoperative complications when patients undergo surgery in the neoadjuvant chemotherapy setting,” said Dr. Cordeiro. “For

EXPERT POINT OF VIEW

iscussant Charles E. Geyer, Jr, MD, FACP, Associate Director for Clinical Research at Virginia Commonwealth University Massey Cancer Center in Richmond, Virginia, singled out the power of this study’s da-

I really feel this should put to rest any concerns that surgeons might have about neoadjuvant chemotherapy. —Charles E. Geyer, Jr, MD, FACP

taset. “In 2002,” he said, “the Institute of Medicine named NSQIP [National Surgical Quality Improvement Program] the ‘best in the nation’ for measuring and reporting surgical quality and outcomes…. To me, this elevates this study because the data are coming from a very strong, validated dataset.” Dr. Geyer also noted that although there were differences between groups in the unadjusted data, the 30-day morbidity rate for patients receiving neoadjuvant chemotherapy was still very positive. “You see low numbers of infections, low bleeding complications, and when you do the adjustments, you see that neoadjuvant chemotherapy does not increase risk,” concluded Dr. Geyer. “I really feel this should put to rest any concerns that surgeons might have about neoadjuvant chemotherapy.” n Disclosure: Dr. Geyer reported no potential conflicts of interest.

this reason, some surgeons are waiting 4 to 6 weeks following chemotherapy before performing surgery.”

Study Design To determine whether there is a difference in the proportion of overall 30-day postoperative complications, researchers analyzed data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), a large database incorporating over 600 hospitals in the United States, Canada, and Europe. All patients undergoing surgery for invasive breast cancer from 2005 to 2012 were included in the study, excluding those with high-risk comorbidities, metastatic disease, synchronous high-risk nonbreast surgery, or a missing neoadjuvant chemotherapy variable. After performing univariate and bivariate analyses, a propensity score was calculated based on the probability of the patient receiving neoadjuvant chemotherapy. Variables included in the propensity score were patient age; whether the patient had diabetes, chronic obstructive pulmonary disease, or hypertension; whether the patient underwent bilateral surgery; and the year of the surgery.

Results Of the 67,685 patients who underwent breast cancer surgery between

2005 and 2012 (and met inclusion criteria), 3,624 received neoadjuvant chemotherapy (5.4%). “Interestingly,” said Dr. Cordeiro, “a significant proportion of patients who received neoadjuvant chemotherapy had bilateral surgery, as compared to those who did not.” “It should also be noted,” she added, “that the utilization of neoadjuvant chemotherapy increased from just over 5% in 2005 to just over 10% in 2012.” Although an unadjusted analysis of overall postoperative complication rate revealed a significantly higher percentage of complications in patients receiving neoadjuvant chemotherapy compared with those who did not (5% vs 3.7%), this discrepancy was resolved after controlling for differences in initial baseline demographics. “When looking at the independent effect of neoadjuvant chemotherapy, there actually was no difference in the group that received neoadjuvant chemotherapy vs surgery upfront,” Dr. Cordeiro concluded. “Neoadjuvant chemotherapy did not turn out to be an independent predictor of postoperative complications.” However, other well-known predictors of postoperative complications were statistically significant, such as having a higher body mass index, being a smoker, having a higher American Society of Anesthesiologists classification, having a bleeding disorder, and having a longer operative time. n Disclosure: Dr. Cordeiro reported no potential conflicts of interest.

Reference 1. Cordeiro E, Arnaout A, Cil T: The effect of neoadjuvant chemotherapy on short-term outcomes in breast cancer surgery: A propensity score adjusted analysis of NSQIP data. 2015 Breast Cancer Symposium. Abstract 115. Presented September 25, 2015.

Breast Cancer Surgery and Neoadjuvant Chemotherapy ■■ Neoadjuvant chemotherapy does not appear to increase the risk of postoperative complications among patients with breast cancer, according to a recent study. ■■ In a propensity score-matched analysis, complication rates were comparable between surgical patients who underwent neoadjuvant chemotherapy and those who did not.

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The ASCO Post | DECEMBER 10, 2015

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JADPRO Live at APSHO Gynecologic Oncology

Ovarian Cancer: Current Treatment and Patient Management By Susan Reckling

ough initial treatment decisions have “long-lasting ramifications and affect the entire treatment paradigm” for women with ovarian cancer, according to Bradley J. Monk, MD, FACS, FACOG, of the University of Arizona Cancer Center, Phoenix. In a true collaborative presentation at the Annual JADPRO (Journal of the Advanced Practitioner in Oncology) Live at APSHO (Advanced

ing from the CHORUS trial.2,3 According to Dr. Monk, “neoadjuvant chemotherapy in these patients who are full of cancer has at least as good of an outcome [as primary surgery followed by chemotherapy] and may be a little better.” He continued: “After three cycles of chemotherapy, the surgery is easier and less morbid. This is done at least half of the time for advanced ovarian cancer patients.”

You have to keep a score card on what the platinum-free interval is. If the disease recurs in less than 6 months, then the patient can get bevacizumab on label second and third line. —Bradley J. Monk, MD, FACS, FACOG

Practitioner Society for Hematology and Oncology) conference, Dr. Monk joined Paula J. Anastasia, RN, MN, AOCN®, of Cedars-Sinai Medical Center in Los Angeles, to discuss the rationale behind front-line treatment decisions in advanced ovarian cancer, address qualityof-life concerns, and emphasize the importance of genetic testing.1

Front-Line Strategies One size most definitely does not fit all when it comes to initial treatment options for women with advanced ovarian cancer. Among the array of therapies are surgical resection, neoadjuvant chemotherapy, weekly chemotherapy, intraperitoneal chemotherapy, and consideration of targeted therapies. Deciding which one is right for which patient in which order is certainly a challenge that requires the performance of personalized medicine, agreed Dr. Monk and Ms. Anastasia. Further complicating the clinical picture are the array of cell types of ovarian cancer and the diverse molecular abnormalities found in these tumors (such as KRAS mutations in mucinous tumors and BRCA1/2 deficiencies in high-grade serous tumors). Turning first to surgery for newly diagnosed advanced ovarian cancer, Dr. Monk explained: “The goal of primary surgery is complete resection; if you don’t resect all the cancer, it really doesn’t have any benefit.” In some cases, he added, the best choice may be neoadjuvant chemotherapy and interval debulking after three cycles of chemotherapy, with supportive data com-

Ms. Anastasia emphasized the importance of guiding patients through a discussion of the different treatment strategies. She mentioned her preference for taking these conversations a step at a time and not bombarding a newly diagnosed patient with a host of complicated decisions. For her, the tone of these talks centers on survival, hope, and realistic goals. “There is a high probability of achieving a remission, not a cure, with optimal surgical debulking, and with chemotherapy,” remarked Ms. Anastasia. The presenters turned briefly to the use of weekly chemotherapy, citing supportive data from the JGOG 3016 trial of dose-dense weekly paclitaxel with carboplatin.4 Although Dr. Monk said this treatment improved progression-free survival with the possibility of a survival advantage, he acknowledged its hematologic toxicity profile. Ms. Anastasia agreed, noting several related patient concerns: the inconvenience of weekly treatment, the dose-limiting side effects of anemia and fatigue with the possibility of blood transfusions, and psychosocial issues such as decreased energy for intimacy and sexuality.

What of Intraperitoneal Chemotherapy? Much attention has been focused on the use of intraperitoneal chemotherapy for advanced ovarian cancer, with a recent long-term update showing its advantage over intravenous chemotherapy extending beyond 10 years.5 According to Dr. Monk, intraperitoneal chemo-

therapy is not a good choice for those with inadequate surgical resection, but best used for patients who have been debulked to < 1 cm of disease. As intraperitoneal chemotherapy is a highly toxic and time-consuming regimen, Ms. Anastasia mentioned that quality-of-life issues are key. She added: “Studies show that only 42% of women were able to complete this therapy. It is right for some people, but they have to be optimally debulked.”

Targeted Therapies One of the most promising targets in clinical trials for advanced ovarian cancer is angiogenesis, declared Dr. Monk. Although adding bevacizumab (Avastin) to the front-line setting is controversial in the United States, it has been approved in Europe, with the supporting clinical data from the GOG 218 and ICON-7 trials.6,7 Dr. Monk commented on the findings of GOG 218, which included bevacizumab in combination with carboplatin and paclitaxel: “There was a progressionfree survival advantage in patients who had a lot of disease but not a big enough advantage in overall survival to lead to regulatory approval.” Ms. Anastasia revealed that she does not use bevacizumab off label in the front-

-resistant disease, defined as progression during or within 6 months of last chemotherapy, nonplatinum single-agent therapy with or without bevacizumab is indicated. For those with platinum-sensitive disease or recurrence beyond 6 months, a platinum based doublet with or without bevacizumab is indicated. Dr. Monk added: “You have to keep a score card on what the platinum-free interval is. If the disease recurs in less than 6 months, then the patient can get bevacizumab on label second and third line.” Monotherapy with the PARP inhibitor olaparib (Lynparza) in advanced ovarian cancer with a BRCA mutation has been approved by the U.S. Food and Drug Administration for deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer after three or more lines of chemotherapy. According to Dr. Monk, “every patient needs to be BRCA tested and have the opportunity to get olaparib.” “It is imperative now that all women with high-grade serous epithelial cancer should have genetic testing,” stated Ms. Anastasia.

Additional Considerations “Palliation of symptom management is very important from day 1,” declared Dr. Monk. Ms. Anastasia agreed, urging ongoing discussion with patients “to get

We know our ladies with advanced ovarian cancer are going to have multiple recurrences. At one time in their treatment arsenal, they will be receiving it [bevacizumab]. —Paula J. Anastasia, RN, MN, AOCN®

line setting. “One of the reasons that we don’t,” she explained, “is we know our ladies with advanced ovarian cancer are going to have multiple recurrences. At one time in their treatment arsenal, they will be receiving it.” Dr. Monk concurred: “I would argue that every patient probably needs to get bevacizumab at some point.” For recurrent ovarian cancer, treatment considerations include the platinum-free interval, existing toxicities from first-line treatment, the volume of disease at the time of relapse, and serologic relapse (CA-125 measurement). In addition to participating in a clinical trial and re-treating with a platinum, integrating targeted therapies should be considered. For those with platinum-refractory or

them through today.” In fact, the National Comprehensive Cancer Network, the American Society of Clinical Oncology, and the Society of Gynecologic Oncologists recommend genetic testing for all women with ovarian, fallopian tube, and peritoneal carcinoma. Palliation of symptom management is very important from day 1, declared Dr Monk. Ms Anastasia agreed, urging ongoing discussion with patient to get them through today. Although most women with advanced ovarian cancer will not be cured, many will live 5-10 years, even while receiving multiple lines of chemotherapy. Reassessing patients goals and initiating palliative and supportive care services can assist with imcontinued on page 19

ASCOPost.com | DECEMBER 10, 2015

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JADPRO Live at APSHO Novel Therapies

2015 Review of Newly Approved Oncologic Therapies By Susan Reckling

ver the past year or so, a host of new agents were approved for the treatment of patients with various types of cancer (see related article on page 1). Patrick Medina, PharmD, of the University of Oklahoma College of Pharmacy, Oklahoma City, and Monique Giordana, PharmD, BCOP, of Regions Hospital, St. Paul, Minnesota, brought listeners up to date on many of these newly approved agents at the 3rd Annual JADPRO (Journal of the Advanced Practitioner in Oncology) Live at APSHO (Advanced Practitioner Society for Hematology and Oncology) conference.1 Approximately 700 nurse practitioners, physician assistants, pharmacists, clinical nurse specialists, and other health-care professionals assembled in Phoenix, Arizona, to attend this conference.

Pathway Inhibitors Two molecular pathway inhibitors were among the agents featured: sonidegib (Odomzo) and olaparib (Lynparza). Approved in July 2015 for adults with locally advanced basal cell carcinoma that has recurred after surgery or radiation therapy or for those who are not candidates for surgery or radiation therapy, sonidegib is a hedgehog signaling pathway inhibitor and the second agent in this class of drugs. Supporting data for this indication are from the randomized phase II BOLT trial.2 Among the adverse events reported with this oral agent are muscle spasms, fatigue, musculoskeletal pain, decreased weight and appetite, abdominal pain, and pruritus. “The majority of patients that you put on this drug will get this muscle pain,” stated Dr. Medina. The drug should be withheld for severe or intolerable musculoskeletal adverse reactions, so serum creatinine kinase elevation should be checked periodically. Dr. Medina continued: “This is a fairly unique side effect for this class of drugs, so there

Ovarian Cancer continued from page 18

proving quality of life and length of life. n Disclosure: Dr. Monk has served as an advisor or consultant for Advaxis, Amgen, AstraZeneca, Cerulean, Genentech, GlaxoSmithKline, Gradalis, Merck, Roche, Tesaro, and Verastem. He has served as a speaker for AstraZeneca, Genentech, and Roche and his institution has received grants for clinical research from Amgen, Array BioPharma, Genentech, Janssen/Johnson & Johnson, Lilly, Novartis, and Tesaro. Ms. Anastasia has served

definitely is some difference in side effects between this and vismodegib [Erivedge], which is not associated with this big increase in creatinine kinase.” Approved in December 2014, the PARP inhibitor olaparib is indicated for monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. According to the clinical trial on which this indication is based,3 responses to olaparib were observed across different tumor types with these mutations. With few active agents for ovarian cancer, Dr. Giordana called this an “exciting” drug for this patient population. Among the adverse events associated with olaparib are anemia, nausea, vomiting, dyspepsia, upper respiratory infection, arthralgia, and rash. “Although anemia is the biggest side effect, arthralgia can be troublesome for patients,” remarked Dr. Giordana.

Immunotherapies In late 2014, two anti–programmed cell death protein 1 (anti–PD-1) agents—nivolumab (Opdivo) and pembrolizumab (Keytruda)—changed the therapeutic landscape for those with unresectable or metastatic melanoma; and as of late 2015, both agents have expanded their indication to use in the treatment of non–small cell lung cancer (NSCLC). The original indication for nivolumab is for unresectable or metastatic melanoma and disease progression after ipilimumab (Yervoy) and if BRAF V600 mutation–positive, a BRAF inhibitor, based on the findings of the CheckMate-037 trial.4 Expanded indications now include both squamous5 and nonsquamous6 NSCLC, based on data from CheckMate-017 and CheckMate-057, respectively. In addition, on speakers bureaus for Amgen, Genentech, and ProStrakan.

References 1. Monk B, Anastasia P: Ovarian cancer: Current treatment and patient management. JADPRO Live at APSHO. Track: Solid Tumor Session. Presented November 7, 2015. 2. Kehoe S, Hook J, Nankivell M, et al: Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: Results from the MRC CHORUS trial. 2013

There definitely is some difference in side effects between [sonidegib] and vismodegib, which does not have this big increase in creatinine kinase. —Patrick Medina, PharmD

This is quite remarkable improvement [in response rate with nivolumab]. We have never seen these types of response rates in melanoma. —Monique Giordana, PharmD, BCOP

the most common immune-therapy adverse events reported with these agents are fatigue, diarrhea, and skin toxicity with rash. Dr. Giordana focused on the 32% objective response rate with nivolumab in the CheckMate-037 trial. “Back when ipilimumab was approved a few years back,” she remarked, “the response rate was around 11%. This is quite remarkable improvement. We have never seen these types of response rates in melanoma.” Furthermore, Dr. Giordana hinted at the “super exciting data” emerging with the combination of nivolumab and ipilimumab. The original indication for pembrolizumab was unresectable or metastatic melanoma and disease progression following ipilimumab and if BRAF V600 mutation–positive, a BRAF inhibitor, based on data from the Keynote-001 trial.7 As with nivolumab, more recent data now support its use for squamous and nonsquamous NSCLC.8 According

to more recent phase III study data with the combination of nivolumab and ipilimumab in unresectable or metastatic melanoma, Dr. Giordana noted that “we are seeing response rates of 60%.”

ASCO Annual Meeting. Abstract 5500. 3. Kehoe S, Hook J, Nankivell M, et al: Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS). Lancet 386:249-257, 2015. 4. Katsumata N, Yasuda M, Isonishi S, et al: Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016). Lancet Oncol 14:1020-1026, 2013.

5. Tewari D, Java JJ, Salani R, et al: Longterm survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer. J Clin Oncol 33:1460-1466, 2015. 6. Burger RA, Brady MF, Bookman MA, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473-2483, 2011. 7. Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:2484-2496, 2011.

Other Agents Drs. Medina and Giordana featured several other agents during their presentation, a few of which are briefly mentioned here: • Gefitinib (Iressa): Reapproved in July 2015, this epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor is indicated only for firstline treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. • Dinutuximab (Unituxin): Approved in March 2015, this chimeric GD2 antibody is indicated in combination with granulocyte-macrophage colony-stimulating factor (Leukine), continued on page 20

The ASCO Post | DECEMBER 10, 2015

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JADPRO Live at APSHO Newly Approved Therapies continued from page 19

interleukin 2 (Proleukin), and 13-cisretinoic acid for treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line therapy. Dr. Medina called this “huge news in the pediatric world,” although she admitted it is an “inpatient nightmare” to deliver, as it causes severe neuropathic pain for patients. • Lenvatinib (Lenvima): Approved in February 2015, this inhibitor of vascular endothelial growth factor receptor is indicated for treatment of locally recurrent or metastatic progressive, radioactive iodine–refractory differentiated thyroid cancer. According to Dr. Medina, “it appears to be a drug that is highly efficacious in this somewhat niche population.”

• Palbociclib (Ibrance): Approved in February 2015, this cyclin-dependent kinase 4 and 6 inhibitor is indicated in combination with letrozole for treatment of postmenopausal women with estrogen receptor– positive, HER2-negative metastatic breast cancer as initial endocrinebased therapy. Although Dr. Medina admitted this treatment was associated with a “pretty high rate of neutropenia,” he added, “this drug has implications in a lot of tumors, not just breast cancer.” n

Disclosure: Drs. Medina and Giordana reported no potential conflicts of interest.

References 1. Medina P, Giordana M: Review of newly approved oncologic therapies: 2014– 2015. JADPRO Live at APSHO. General Session. Presented November 6, 2015.

2. Migden MR, Guminski A, Gutzmer R, et al: Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): A multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 16:716-728, 2015. 3. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al: Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33:244-250, 2015. 4. Weber JS, D’Angelo SP, Minor D, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375-384, 2015. 5. Spigel DR, Reckamp KL, Rizvi NA, et al: A phase III study (CheckMate 017) of nivolumab (anti-programmed death-1

[PD-1]) vs docetaxel in previously treated advanced or metastatic squamous cell non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract 8009. Presented May 29, 2015. 6. Paz-Ares L, Horn L, Borghaei H, et al: Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous cell non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract LBA109. Presented May 29, 2015. 7. Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109-1117, 2014. 8. Bustamante Alvarez JG, GonzálezCao M, Karachaliou N, et al: Advances in immunotherapy for treatment of lung cancer. Cancer Biol Med 12:209-222, 2015.

JADPRO Live at APSHO, 2015, Phoenix APSHO Membership Committee: The membership committee of the Advanced Practitioner Society in Hematology and Oncology (APSHO) strives to increase awareness of the Society among advanced practitioners in oncology. The membership committee convened at the 2015 JADPRO Live at APSHO meeting held recently in Phoenix. Pictured left to right, top row, are Jessica Tamasi, APSHO; Michelle Camarda, FNB, CBPN; Laura Farrell, RN, MSN, ARNP; Anne Markham, DNP, CRNP, AOCN; Nancy Gerum, MSN, APN, ANP-BC; Christopher Campen, PharmD, BCPS, BCOP; Kirin Brigle, PhD, NP; Helena Iannaccone, RN, MSN, ANP, AOCNP; Melissa O’Neill, APRN; Rachel Cloutier, MSN, RN, ACNP-BC; Anthony Cutrone, Harborside Press; Bottom row, left to right, Phyllis Everett, MSN, RN, AOCN, NP-C, APNG; Paige Goforth, MMS, PA-C; Pamela Smith, DNP, RN, ACNP-BC, CCRN; Helen Foley, AOCNS, ACHPN; Nataya Francis, ARNP.

November 3-6, 2016 • Washington, DC Gaylord National Hotel | National Harbor, MD

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FDA Update

FDA Approves Elotuzumab in Combination With Lenalidomide and Dexamethasone for Multiple Myeloma

he U.S. Food and Drug Administration (FDA) has granted approval for elotuzumab (Empliciti) in combination with two other therapies to treat patients with multiple myeloma who have received one to three prior medications.

gression-free survival of 19.4 months compared to participants taking only lenalidomide and dexamethasone (14.9 months). Additionally, the overall response rate of those taking

elotuzumab with lenalidomide and dexamethasone was 78.5%, compared to 65.5% in those taking only lenalidomide/dexamethasone. The most common side effects of

elotuzumab are fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, and pneumonia. n

In EGFRm+ advanced NSCLC,

“We are continuing to learn about the ways the immune system interacts with different types of cancer, including multiple myeloma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “[The recent] approval is the second monoclonal antibody approved to treat patients with multiple myeloma and works with another approved therapy to provide additional benefit.” Daratumumab (Darzalex), approved earlier in November, is the only other FDA-approved monoclonal antibody for the treatment of patients with multiple myeloma. Elotuzumab activates the body’s immune system to attack and kill multiple myeloma cells. It is approved in combination with another FDAapproved treatment for multiple myeloma, lenalidomide (Revlimid), and the corticosteroid dexamethasone.

ELOQUENT-2 The safety and efficacy of elotuzumab were tested in the ELOQUENT-2 trial, a randomized, openlabel clinical study of 646 participants with either relapsed disease or whose multiple myeloma had not responded to previous treatment. Those taking elotuzumab plus lenalidomide and dexamethasone experienced a pro-

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

NEARLY 2 OUT OF 3 CASES OF PROGRESSION WITH FIRSTGENERATION EGFR TKIs ARE RELATED TO THE T790M MUTATION1,2 Lung cancer is the leading cause of cancer-related deaths both in the US and worldwide.3,4 For NSCLC EGFRm+ patients, the recommended frst-line treatment is EGFR tyrosine kinase inhibitors (TKIs).5

The majority of tumors will acquire EGFR TKI–resistance mutations Despite initial high response rates with frst-generation EGFR TKIs, many tumors will develop new mutations and become resistant.6,7 A major barrier to disease control is resistance to treatment. Resistance to frst-generation therapy will develop in most patients with EGFRm+ advanced NSCLC on a currently approved EGFR TKI.7 After disease progression, clinical guidelines recommend subsequent treatments including either continuing with an EGFR TKI therapy or beginning platinum-based chemotherapy.5

Nearly 2 out of 3 cases of progression with ﬁrst-generation EGFR TKIs are related to the T790M mutation In patients with NSCLC who are EGFRm+, T790M is an acquired mutation and has been identifed as the most common mechanism of acquired resistance in nearly 2 out of 3 patients.1,2 Development of T790M mutation may confer resistance through several potential mechanisms, which may include8,9: - Steric hindrance, which reduces receptor binding of reversible EGFR TKIs - Increased binding affnity of EGFR for ATP, resulting in reduced TKI potency

T790M Is the Most Common Mechanism of Acquired Resistance to First-Generation EGFR TKI Therapy1

63%

T790M (98/155)

CI, (9555 –70 ) %

MET amplifcation (4/75)

5% (95% CI, 1%–13%)

HER2 amplifcation (3/24)

NEARLY 2 OUT OF 3

13% (95% CI, 3%–32%)

10% 20% 30% 40% 50% 60% 70%

Study of 155 patients with radiographic progression following a response or durable stable disease with frst-generation EGFR TKI therapy.

CASES ARE RELATED TO T790M

Other rare mechanisms of acquired resistance may include BRAF, FGFR, and PIK3CA mutations, and transformation to small-cell histology.10,11

Discovering the cause of resistance Patients should be monitored for radiologic or clinical progression. Tumors can also be assessed for molecular progression to uncover additional acquired mutations.1,12-16 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).5

AstraZeneca is a leader in lung cancer research AstraZeneca is conducting ongoing research to understand the science of the T790M mutation as a driver of resistance.

Find out more at EGFRevolution.com. References: 1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247. 2. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 3. American Cancer Society. Cancer Facts & Figures 2015. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed March 17, 2015. 4. GLOBOCAN 2012. http://globocan.iarc.fr. Accessed February 9, 2015. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Mok TS, Wu YL, Thongprasert S, et al. Geftinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957. 7. Sequist LV, Yang JCH, 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. 2013;31:3327-3334. 8. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to geftinib. N Engl J Med. 2005;352:786-792. 9. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affnity for ATP. Proc Natl Acad Sci U S A. 2008;105:2070-2075. 10. Cheng L, Alexander RE, MacLennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25:347-369. 11. Ware KE, Marshall ME, Heasley LY, et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One. 2010;5:e14117. doi:10.1371/journal.pone.0014117.12. Johnson KR, Ringland C, Stokes BJ, et al. Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis. Lancet. 2006;7:741-746. 13. Lussier YA, Khodarev NN, Regan K, et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specifc microRNAs. PLoS One. 2012;7:e50141. doi:10.1371/journal.pone.0050141. 14. Jackman DM, Miller VA, Cioffredi, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non–small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009;15:5267-5273. 15. Noronha V, Joshi A, Gokarn A, et al. The importance of brain metastasis in EGFR mutation positive NSCLC patients. Chemother Res Pract. doi:10.1155/2014/856156. 16. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. ©2015 AstraZeneca. All rights reserved. 3140404 6/15

The ASCO Post | DECEMBER 10, 2015

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SIO Conference Mind-Body Therapies Were the Focus at the 12th International Conference of the Society for Integrative Oncology By Jo Cavallo

mong the highlights at the 12th International Conference of the Society for Integrative Oncology (SIO) was a 1-day joint meeting on acupuncture, oncology, and fascia cosponsored by SIO, the Society for Acupuncture Research, the Fascia Research Society, and the Osher Center for Integrative Medicine. Held on the first day of the 3-day conference, the joint session drew more than 600 attendees and presented findings

tive Medicine Service at Memorial Sloan Kettering Cancer Center in New York. “That research, combined with the numerous clinical studies presented, really stimulated the scientific community to begin generating new hypotheses on how we can increase the mechanistic understanding of therapies such as yoga, massage, and acupuncture on cellular and tissue levels. [Hopefully, this will lead] to more targeted reduction in pain, lymphedema, and fibro-

We are beginning to develop and execute a plan to partner with other medical societies outside the United States to evaluate current clinical practices and the state of science in integrative oncology in other countries. —Jun J. Mao, MD, MSCE

from both basic and clinical research. The full conference was held November 14–16, 2015, at Harvard Medical School in collaboration with the Dana-Farber Cancer Institute in Boston.

Research Directions “A number of researchers investigating extracellular matrix connective tissue and lymphatics biology presented innovative data on how the host system may be amenable to manipulation by complementary therapies, such as massage and acupuncture, and lead to improved tissue healing, recovery, and symptom control in patients with cancer,” said Jun J. Mao, MD, MSCE, President of SIO and Chief of the Integra-

sis and contribute to better function, pushing our collective work forward.” The theme of the conference was Integrative Innovation, emphasizing the personalization of integrative medicine in the delivery of treatments to help patients with cancer achieve better outcomes with fewer treatment side effects. Among the studies presented was Dr. Mao’s randomized study assessing electroacupuncture or gabapentin in the treatment of hot flashes in breast cancer survivors.1 The study participants were randomly assigned to four interventions: electroacupuncture, sham electroacupuncture, gabapentin, or placebo. The study results showed that patients receiving electroacupuncture had

Jennifer Ligibel, MD

the greatest improvement, as measured by a hot flash composite score, followed by patients receiving the sham acupuncture therapy. “This study found that long-term acupuncture had more sustained benefit and fewer side effects than gabapentin in the treatment of hot flashes. These data can readily be used by patients and clinicians to make personalized decisions on whether to integrate acupuncture into the medical management of hot flashes,” said Dr. Mao. In all, the 2015 conference presented 137 scientific abstracts (see The Best of SIO on page 23) and attracted more than 350 oncologists, internal medicine physicians, researchers, nurses, integrative medicine practitioners, cancer survivors, and patient advocates from 19 countries. For a third year in a row, SIO received a National Cancer Institute conference grant to fund travel expenses for patient advocates and research trainees.

Countering the Effects of Cancer The keynote addresses were presented by Herbert Benson, MD, Director Emeritus of the Benson-Henry Institute for Mind Body Medicine and Professor of Mind Body Medicine at Harvard

Medical School; Jennifer Ligibel, MD, Assistant Professor in the Department of Medicine at Harvard Medical School and Attending Physician in Adult Oncology at Dana-Farber Cancer Institute; and Claudia Witt, MD, MBA, Chair of Complementary and Integrative Medicine at the University of Zurich. The speakers emphasized the importance of utilizing mind-body medicine, mind-

Herbert Benson, MD

Claudia Witt, MD, MBA

body exercise, and nutrition to counter the effects of cancer and its treatment and how approaches to mind-body medicine differ around the world. “It was interesting to hear the international perspective from Dr. Witt on how our conception of mind-body therapies is not consistent around the world due to the influence of diverse cultures and medical systems,” said Suzanna Zick, ND, MPH, Immediate Past President of SIO and Associate Research Professor in the Department of Family Medicine at the University of Michigan, Ann Arbor. “It is important for us to keep those differences in mind when we talk about these modalities and what they mean to patients as well as what these differences might mean when comparing study results.”

Growth of Integrative Oncology Now in its 13th year, the SIO is maturing along with the field of integrative medicine, according to Dr. Mao, although he concedes there are still difficulties that both the Society and the field have to overcome. “The studies and topcontinued on page 23

ASCOPost.com | DECEMBER 10, 2015

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SIO Conference The Best of SIO

he following five abstracts were chosen as the best studies presented at the 12th International Conference of the Society for Integrative Oncology (SIO) because of their quality and the impact they will have on the field of integrative medicine, according to Suzanna Zick, ND, MPH, Immediate Past President of SIO and Associate Research Professor in the Department of Family Medicine at the University of Michigan, Ann Arbor. “We think these five studies will change how integrative oncology moves forward in the future,” said Dr. Zick.

etary sugar induces tumorigenesis in mammary gland partially through 12lipoxygenase pathway. SIO 12th International Conference. Abstract 67. Presented November 15, 2015. This laboratory study investigated the effect of a sucrose-enriched diet in the development of primary and

undergoing 12 weekly taxane treatments. The women were randomly assigned to receive electroacupuncture or sham electroacupuncture. Forty-six of the patients completed the protocol. The study failed to find a significant difference in pain or neuropathy between the two groups at 12 weeks. However,

We think these five studies will change how integrative oncology moves forward in the future. —Suzanna Zick, ND, MPH

Seeking Consensus in Patient Outcomes Polley M, Frenkel M, Balneaves, et al: Developing guidelines for the collection of patient outcomes data in clinical integrative oncology settings. SIO 12th International Conference. Abstract 60. Presented November 15, 2015. This international project was developed to seek a consensus in patient outcomes to overcome barriers to efficient data collection. The researchers found that the challenges to data collection include lack of knowledge about which patient outcomes and outcome measures to use; how to analyze data; and lack of resources. They concluded that an international appetite exists for guidelines on efficiently capturing standardized patient outcomes data for integrative oncology practices and plan to draft guidelines for patient outcomes data collection in clinical integrative oncology settings.

Role of Sugar in Cancer Development Jiang Y, Pan Y, Rhea PR, et al: Di-

Mind-Body Therapies continued from page 22

ics presented at this year’s meeting really showed the growth and maturation of integrative oncology, but we still face many challenges, including how to develop a more sustainable program that benefits a large segment of patients, survivors, and caregivers,” said Dr. Mao. “For example, many of the integrative oncology services we provide are not covered by health insurance and require out-of-pocket payment,” he continued. “Cancer is a very expensive disease, so how do we develop inte-

metastatic breast cancer and a relevant molecular mechanism focusing on the 12-lipoxygenase pathway, which is known to be involved in inflammation and cancers. The researchers found evidence showing that added sugar in the diet accelerates the development of breast cancer partially through modulating inflammatory pathways, especially in upregulation of 12-lipoxygenase protein and in the production of 12-hydroxyeicosatetraenoic acid within tumor tissue.

Electroacupuncture to Prevent Peripheral Neuropathy Greenlee H, Awad D, Crew KD, et al: Randomized sham controlled pilot trial of weekly electroacupuncture for the prevention of taxane-induced peripheral neuropathy. SIO 12th International Conference. Abstract 74. Presented November 15, 2015. This randomized study included 63 women with stage I to III breast cancer

grative oncology services that are affordable for patients? It is a challenge we have yet to address, but SIO is prepared to meet this challenge.”

Goals for the Future To address affordability concerns and other challenges and ensure continued growth for SIO, Dr. Mao is focusing on two goals during his tenure as SIO President. One is to increase membership in the Society to advance research and education in integrative oncology. His second goal is to have greater global engagement to tackle the issue of cul-

the researchers noted that the patients on electroacupuncture had a slower recovery after they completed their taxane treatment than the women in the sham electroacupuncture arm of the study. They concluded that future studies should focus on electroacupuncture as a treatment for chemotherapy-induced peripheral neuropathy rather than as a preventive strategy for the condition.

Less Invasive Treatment for Anal Lesions Cohen M, Wilson C, Berry M, et al: Topical Chinese herbal AIJP ointment to treat anal high-grade squamous intraepithelial lesions (HSIL) in HIV-positive persons. SIO 12th International Conference. Abstract 82. Presented November 15, 2015. This phase II randomized trial compared a Chinese herbal cream known as AIJP (Arnebia Indigo Jade Pearl) to placebo in 70 HIV-positive

tural diversity and clinical care delivery among different countries. “The theme of next year’s conference is Advancing the Global Impact of Integrative Oncology,” said Dr. Mao. “We are beginning to develop and execute a plan to partner with other medical societies outside the United States to evaluate current clinical practices and the state of science in integrative oncology in other countries and to determine how we can collaborate with physicians and scientists around the globe to improve outcomes for patients with cancer. We currently have

men and women with anal high-grade squamous intraepithelial lesions, a precursor of anal cancer. The researchers found that the AIJP ointment appeared to be more effective than placebo and may successfully treat or reduce anal squamous intraepithelial lesions, allowing for less extensive ablative procedures.

Mind-Body Strategies to Help Prevent Recurrence Garland EL, Beck A, Hansen P, et al: Integrated mindfulness-oriented recovery enhancement and physical health intervention for obese cancer survivors: Preliminary results from a pilot randomized controlled trial. SIO 12th International Conference. Abstract 133. Presented November 15, 2015. The researchers recruited 17 obese (mean body mass index of 35.8) female patients with breast, colon, and endometrial cancers to investigate the efficacy of an integrated exercise and nutrition program with a mindfulness-oriented recovery enhancement (MORE) intervention, which uses techniques to enhance interoceptive awareness and cognitive control over automatic, compulsive eating behavior to control weight. The women were randomly assigned to receive an exercise and nutrition intervention alone or an exercise and nutrition intervention with MORE. The researchers found that integrating MORE with an exercise and nutrition training program appeared to enhance weight loss in these patients. They concluded that mindfulness training may strengthen cognitive control over appetitive and motivational reactions crucial to weight loss, promoting greater health in cancer survivors. n

450 members from 20 countries, and we are exploring the possibilities of developing chapters in specific countries so we can begin to have more effective collaboration both within specific regions and across regions.” n

Disclosure: Drs. Mao and Zick reported no potential conflicts of interest.

Reference 1. Mao JJ, Bowman MA, Xie SX, et al: Electroacupuncture versus gabapentin for hot flashes among breast cancer survivors: A randomized placebo-controlled trial. J Clin Oncol 33:3615-3620, 2015.

In patients 18 years and older...

DIFICID: Proven efficacy for treatment of Clostridium difficile–associated diarrhea (CDAD) Bactericidal therapy that targets C difficile Primarily active against species of clostridia, including C difficile, in vitro. The clinical significance of in vitro data is unknown.

DIFICID: Comparable initial clinical response rate vs vancomycin at end of 10-day treatment Clinical response rate

Hypothetical patient.

Patients (%)

Trial 1 (95% CI)a: 2.6% (-2.9%, 8.0%)

88%

86%

60 40 20

100 80 Patients (%)

100

Trial 2 (95% CI)a: 1.0% (-4.8%, 6.8%)

88%

87%

60 40 20 0

DIFICID 200 mg BID (n=289)

Vancomycin 125 mg QID (n=307)

DIFICID 200 mg BID (n=253)

Vancomycin 125 mg QID (n=256)

CI was derived using the Wilson score method.

Study description: Two Phase 3, randomized, double-blind, noninferiority studies (N=1,105) comparing the efficacy and safety of oral DIFICID 200 mg BID vs oral vancomycin 125 mg QID for 10 days for the treatment of adults (aged ≥18 years) with CDAD (defined by >3 unformed bowel movements or >200 mL of unformed stool for subjects having rectal collection devices in the 24 hours before randomization and presence of either C difficile toxin A or B in the stool within 48 hours of randomization). An additional efficacy end point was a sustained response 25 days after the end of treatment. Sustained response was evaluated only for patients who were clinical successes at the end of treatment. Sustained response was defined as clinical response at the end of treatment and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment.

Indication and Usage DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD). To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by C difficile.

Important Safety Information DIFICID is contraindicated in patients with hypersensitivity to fidaxomicin. DIFICID should not be used for systemic infections. Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted. Only use DIFICID for infection proven or strongly suspected to be caused by C difficile. Prescribing DIFICID in the absence of a proven or strongly suspected C difficile infection is unlikely to provide benefit to the patient and increases the risk of development of drugresistant bacteria. The most common adverse reactions reported in clinical trials are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%).

In the same studiesâ&#x20AC;Ś

Superior sustained response rate vs vancomycin through 25 days after end of treatment Sustained response rate Trial 1 (95% CI)b: 12.7% (4.4%, 20.9%)

100

70%

60 40

57%

Patients (%)

80 Patients (%)

Trial 2 (95% CI)b: 14.6% (5.8.%, 23.3%)

100

72%

60 40

57%

DIFICID 200 mg BID (n=289)

Vancomycin 125 mg QID

DIFICID 200 mg BID

Vancomycin 125 mg QID

(n=307)

(n=253)

(n=256)

CI was derived using the Wilson score method. Approximately 5% to 9% of the data in each trial and treatment arm were missing sustained response information and were imputed using the multiple imputation method.

Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained response were due to lower rates of proven or suspected CDAD during the follow-up period in DIFICID patients. In patients infected with a BI isolate, similar rates of clinical response at the end of treatment and during the follow-up period were seen in fidaxomicin-treated and vancomycin-treated patients. However, DIFICID did not demonstrate superiority in sustained response when compared with vancomycin in these patients. Initial C difficile group BI isolates

Trial 1

Non-BI isolates BI isolates

Trial 2

Non-BI isolates

DIFICID n/N (%)

Vancomycin n/N (%)

Difference (95% CI)c

44/76 (58%)

52/82 (63%)

-5.5% (-20.3%, 9.5%)

105/126 (83%)

87/131 (66%)

16.9% (6.3%, 27.0%)

42/65 (65%)

31/60 (52%)

12.9% (-4.2%, 29.2%)

109/131 (83%)

77/121 (64%)

19.6% (8.7%, 30.0%)

CI was derived using the Wilson score method. Interaction test between the effect on sustained response rate and BI vs non-BI isolates using logistic regression (P values: trial 1: 0.009; trial 2: 0.29). Approximately 25% of the mITT population were missing data for the REA group.

Important Safety Information (continued) Among patients receiving DIFICID, 33 (5.9%) withdrew from trials as a result of adverse reactions. Vomiting was the primary adverse reaction leading to discontinuation of dosing (incidence of 0.5% for both DIFICID and vancomycin patients). The safety and effectiveness of DIFICID in patients <18 years of age have not been established.

Please see the Brief Summary of Prescribing Information on adjacent page. BID=twice a day; mITT=modified intent to treat; QID=4 times a day; REA=restriction endonuclease analysis.

Product support and access for patients A program that provides patients with product support and access related to researching insurance benefits, information on co-pay assistance for eligible privately insured patients, product distribution questions, and alternate independent sources of funding.

For insurance coverage and reimbursement information, please visit www.accessdificid.com or call 1-844-282-4782 (M-F, 8 AM-8 PM; Sat, 9 AM-1 PM, ET). Eligibility restrictions apply for the Co-pay Assistance Program and the Patient Assistance Program. Please see Terms and Conditions for the Co-pay Assistance Program, available on the Enrollment Form.

BRIEF SUMMARY OF PRESCRIBING INFORMATION DIFICID (fidaxomicin) tablets, for oral use INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID® and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile. Clostridium difficile-Associated Diarrhea DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD). CONTRAINDICATIONS Hypersensitivity to fidaxomicin. WARNINGS AND PRECAUTIONS Not for Systemic Infections Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections. Hypersensitivity Reactions Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted. Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides. Physicians prescribing DIFICID to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions. Development of Drug-Resistant Bacteria Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice. The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment. Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies. Table 1. Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID Patients in Controlled Trials DIFICID (N=564) n (%) Blood and Lymphatic System Disorders Anemia 14 (2%) Neutropenia 14 (2%) Gastrointestinal Disorders Nausea 62 (11%) Vomiting 41 (7%) Abdominal Pain 33 (6%) Gastrointestinal Hemorrhage 20 (4%) System Organ Class Preferred Term

Vancomycin (N=583) n (%) 12 (2%) 6 (1%) 66 (11%) 37 (6%) 23 (4%) 12 (2%)

The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials: Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon Investigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count Metabolism and Nutrition Disorders: hyperglycemia, metabolic acidosis Skin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash Post Marketing Experience Adverse reactions reported in the post marketing setting arise from a population of unknown size and are voluntary in nature. As such, reliability in estimating their frequency or in establishing a causal relationship to drug exposure is not always possible. Hypersensitivity reactions (dyspnea, angioedema, rash, and pruritus) have been reported. DRUG INTERACTIONS Fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract. Cyclosporine Cyclosporine is an inhibitor of multiple transporters, including P-gp. When cyclosporine was co-administered with DIFICID, plasma concentrations of fidaxomicin and OP-1118 were significantly increased but remained in the ng/mL range. Concentrations of fidaxomicin and OP-1118 may also be decreased at the site of action (i.e., gastrointestinal tract) via P-gp inhibition; however, concomitant P-gp inhibitor use had no attributable effect on safety or treatment outcome of fidaxomicin-treated patients in controlled clinical trials. Based on these results, fidaxomicin may be co-administered with P-gp inhibitors and no dose adjustment is recommended. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively. The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether fidaxomicin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DIFICID is administered to a nursing woman. Pediatric Use The safety and effectiveness of DIFICID in patients <18 years of age have not been established. Geriatric Use Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects. In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age). However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

Before prescribing DIFICID, please read the full Prescribing Information, available at dificid.com. 0500004-00 Revised: 04/2014 Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. AINF-1158143-0000 08/15

ASCOPost.com | DECEMBER 10, 2015

PAGE 27

Geriatrics for the Oncologist

Clinical Trial Design in Older Patients By Stuart M. Lichtman, MD

Geriatrics for the Oncologist is guest edited by Stuart Lichtman, MD, and developed in collaboration with the International Society of Geriatric Oncology (SIOG). Visit SIOG.org for more on geriatric oncology.

ncreasing age is directly associated with an increasing risk of cancer, and persons over age 65 constitute the fastest-growing group in the United States. Not only do older adults comprise the majority of cancer patients, at the same time, they have also been vastly underrepresented in clinical trials. As a result,

of treatment and survivorship as they pertain to older adults, including function, clinical benefit, quality of life, polypharmacy, toxicity, and comorbidity.

Largest Consumers of Chemotherapy Older cancer patients have traditionally not been the subject of clinical drug development. However, they are the largest consumers of chemotherapy, and their numbers are rising dramatically. Worldwide, 1 of every 10 persons is 60 years old or over. By 2050, one of every five persons will be 60 or older, and by 2150, this ratio will decrease to one of every three persons. By 2050, the actual number of people over the age of 60 will

To meet the needs of these vulnerable cancer patients, these clinical design considerations should be incorporated in studies as soon as possible. Reluctance to alter our standard designs must be overcome, or the progress that is urgently needed will never occur. —Stuart M. Lichtman, MD

little evidence-based data exist to guide their course of treatment. Alternative trial designs and expanded research evaluations are needed to guide cancer therapy in this population, which is estimated to account for 20% of all Americans by the year 2030. There have been proposals to correct the widespread underreporting and underrepresentation of older adults in cancer trials and to reduce the existing barriers to trial enrollment. There are also specific issues

be almost 2 billion, at which point the population of older persons will outnumber children up to 14 years old. Furthermore, the older population itself is aging. The United Nations Statistics on Population Aging in 2000 noted that the average life span increased by 26 years since 1950, and the proportion of people over 65 years old increased from 1 in 30 to about 1 in 6. Currently, the oldest old— aged 80 years and older—make up 12% of the population over 60, and this segment

Table 1: Barriers to Trial Participation by Older Adults Underlying assumptions • Perception of aggressive therapy as unacceptably toxic • Limited expectations based on lack of information General physical and psychological barriers • Comorbidity • Unsuitable endpoints (trial design) • Lack of information —Negative assumptions —Patient/physician mistrust Trial impediments • Few trials available • Designs exclude older adult issues • Exclusion of vulnerable older patients Key peripheral issues • Lack of social support • Lack of insurance coverage Competition from alternative and complementary therapy

is the fastest growing of the older population. By 2050, 21% of the older population is expected to be 80 years or older.

GUEST EDITOR

Underrepresented in Trials Increasing age is directly associated with increasing rates of cancer, corresponding to an 11-fold greater incidence in persons over the age of 65 years compared with those under age 65. Consequently, the older population comprises a majority of cancer patients. Despite the increasing incidence of cancer associated with aging and the aging of the U.S. population, only a relatively small number of older patients have been included in clinical trials. As a result, there is a lack of high-quality data on which to base meaningful decisions. Older adults have been underserved in the area of drug development, and they often go untreated, even when data exist for efficacious therapy.1 The needs of the older cancer patient are simply not being met. A number of barriers limit the participation of older patients in clinical trials (Table 1). For various reasons, clinicians often do not offer a clinical trial to eligible older patients. Cognitive dysfunction also interferes with patient understanding of complicated informed consent documents; such impairments affect as many as 36% of adults aged 85 and older, thus ruling out trial enrollment.

Need for Novel Trial Designs In addition, a number of clinical trial design issues need to be addressed. Specific issues that are particularly per-

Stuart M. Lichtman, MD

r. Lichtman is an Attending Physician at Memorial Sloan Kettering Cancer Center, Commack, New York, and Professor of Medicine, Weill Cornell Medical College, New York. He is also President Elect of the International Society of Geriatric Oncology (www.siog.org). tinent to older patients include function, comorbidity, and social supports. Clinical investigators and biostatisticians must develop novel trials to optimize the data derived from these studies (Table 2). Suggestions have been proposed to “geriatricize” the standard oncology drug design.2 For instance, we have to meld the standard oncology outcomes of disease-specific and overall survival with geriatric outcomes of evaluating function, cognition, toxicity, nutrition, and dependence (ie, quality vs quantity of life). ASCO has published a position pacontinued on page 28

Table 2: Reshaping Clinical Trials for Older Patients With Cancer Basic Design • • • •

Include a range of older patients Define population focus: Frailty, vulnerable, well Define age-specific outcomes Incorporate geriatric assessment —Functional status⎯“maintenance of active life expectancy” —Comorbidity: Liberalize requirements depending on drug being evaluated —Social support —Nutritional status —Cognitive function —Psychological state —Quality of life

Handling Polypharmacy and Concomitant Medications • Pharmacokinetic studies: Limit sampling strategies • Limit office visits and testing to facilitate compliance • Regularly assess adherence to oral medications

The ASCO Post | DECEMBER 10, 2015

PAGE 28

Journal Spotlight Hematology

BRAF Inhibition Successful in Relapsed/Refractory Hairy Cell Leukemia By Matthew Stenger

n two phase II studies reported in The New England Journal of Medicine, Enrico Tiacci, MD, of the University of Perugia, Italy, and colleagues found that the BRAF inhibitor vemurafenib (Zelboraf ) produced responses in nearly all patients with BRAF V600E–positive hairy cell leukemia that relapsed after treatment with a purine analog or who had disease refractory to purine analogs. It has been found that the BRAF V600E mutation, commonly found in solid tumors, is the key genetic lesion in hairy cell leukemia.

Study Details In two single-group multicenter studies, 26 evaluable patients in Italy and 24 in the United States received vemurafenib, 960 mg twice daily. The presence of the BRAF mutation was confirmed in all patients. Patents in both studies had received a median of three prior therapies, and 56% and 41% had been disease refractory to their most recent therapy; 29% and 19% had undergone splenectomy. Vemurafenib was given for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. The primary endpoints were complete response rate in the Italian study and overall response rate in the U.S. study.

Responses in Italian Study In the Italian study, the overall response rate was 96%, including complete hematologic response in 35%, after a median of 8 weeks. Median times to blood count recovery were 2 weeks for platelet

count, 4 weeks for neutrophil count, and 8 weeks for hemoglobin level. Reversion of symptomatic splenomegaly and clearance of leukemia cells from the blood usually occurred within 2 weeks after start of treatment. A marked reduction in bone marrow leukemic-cell infiltration was observed at 4 weeks, the earliest evaluation. However, in all patients with complete hematologic response, immunohistochemical testing showed minimal residual disease (≤ 10% of leukemic cells) at the end of treatment. After a median follow-up of 23

months, median relapse-free survival was 9 months, including 19 months in patients with complete hematologic response and 6 months in those with partial response (hazard ratio [HR] = 0.26, P = .006). Median treatment-free survival was 21.5 months, including 25 months in patients with complete hematologic response and 18 months in those with partial response (P = .21). Of 20 patients with relapse (5 after complete response and 15 after partial response), 7 did not require therapy at a median of 15 months (range = 4–18 months) after relapse, since cytopenias were mild and stable. Worsening cytopenia in the remaining 13 required antileukemic treatment. An exploratory analysis indicated no difference in relapse-free or treatment-

■■ Persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests that bypass reactivation of MEK and ERK could be a vemurafenib resistance mechanism.

per on the specific needs to enhance the evidence base to improve cancer care of older patients.3 To meet the needs of these vulnerable cancer patients, which will be the majority, these clinical design considerations should be incorporated in studies as soon as possible. Reluctance to alter our standard designs must be overcome, or the

In the U.S. study, the overall response rate was 100%, including complete hematologic response in 42%, after a median of 12 weeks. Most patients had recovery of neutrophil count, hemoglobin level, and platelet count by 28 days. Among survivors at the time of data cutoff, the median

—Enrico Tiacci, MD, and colleagues

■■ Vemurafenib treatment produced responses in nearly all patients.

continued from page 27

Responses in U.S. Study

A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy cell leukemia.

Vemurafenib in Hairy Cell Leukemia

Trials in Older Patients

free survival between 18 patients who received additional treatment after best response and 7 who received no additional treatment.

progress that is urgently needed will never occur.4-6 n

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

References 1. Hurria A, Dale W, Mooney M, et al: Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations. J Clin Oncol 32:2587-2594, 2014.

follow-up was 11.7 months. At 1 year, progression-free survival was 73% and overall survival was 91%. Progression occurred in 7 (29%) of 24 patients, including 3 who had complete hematologic response and 4 who had partial response. At 1 year after response, the cumulative incidence of relapse was 27%. In both trials, vemurafenib retreatment at the time of relapse produced responses in some patients.

Residual ERK Phosphorylation Among 13 patients in the Italian study who could be evaluated for phosphorylated ERK in marrow biopsy specimens from the day after completion of therapy, 6 (all with partial response) had residual hairy cells still expressing phosphorylated ERK and 7 (2 with complete hematologic response and 5 with partial response) did not. In an exploratory analysis, the median progression-free survival was 8 months (range = 5–13 months) in those with vs 13 months (range = 8–24 months) in those without residual phosphorylated ERK-positive 2. Wildiers H, Mauer M, Pallis A, et al: End points and trial design in geriatric oncology research: A joint European Organisation for Research and Treatment of Cancer—Alliance for Clinical Trials in Oncology—International Society of Geriatric Oncology position article. J Clin Oncol 31:3711-3718, 2013. 3. Lichtman SM: Clinical trial design in older adults with cancer—The need for new paradigms. J Geriatr Oncol 3:368-375, 2012. 4. Lichtman SM: Call for changes in

leukemic cells (HR = 10.33, P = .004). Residual disease, measured by the Hairy Cell Index, was higher in patients with persistent phosphorylated ERK in leukemic cells (P = .03). As noted by the investigators, “[P]ersistent ERK phosphorylation in residual hairy cells at the end of treatment may indicate a greater burden of residual disease and shorter progression-free survival, which suggests that reactivation of MEK and ERK is a resistance mechanism to vemurafenib.”

Adverse Events The most common drug-related adverse events of any grade were rash/erythema (46% and 62% in the two studies) and arthralgia/arthritis (43% and 31%). Secondary cutaneous tumors, which were treated with simple excision, occurred in 7 (14%) of the 50 patients. The most common treatment-related grade 3 events were rash/erythema (7%), arthralgia/arthritis (7%), and pancreatitis (7%) in the Italian study and rash/erythema (19%), photosensitivity reaction (8%), alkaline phosphatase elevation (8%), and asthenia (8%) in the U.S. study; no grade 4 events were observed. Dose reductions were required in 58% and 50% of patients, usually due to rash or arthralgia/arthritis. The investigators concluded: “A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy cell leukemia.” n

Disclosure: The study was funded by Associazione Italiana per la Ricerca sul Cancro and others. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Tiacci E, Park JH, De Carolis L, et al: Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med 373:1733-1747, 2015. See commentary on page 34.

clinical trial reporting of older patients with cancer. J Clin Oncol 30:893-894, 2012. 5. Kemeny MM, Peterson BL, Kornblith AB, et al: Barriers to clinical trial participation by older women with breast cancer. J Clin Oncol 21:2268-2275, 2003. 6. Hurria A, Levit LA, Dale W, et al: Improving the evidence base for treating older adults with cancer: American Society of Clinical Oncology Statement. J Clin Oncol 33:3826-3833, 2015.

DID YOU KNOW? FOR NEARLY 15 YEARS (1999-2014), NO FDAAPPROVED, SECOND-LINE REGIMEN EXTENDED OVERALL SURVIVAL VERSUS DOCETAXEL ACROSS A BROAD POPULATION OF PATIENTS WITH METASTATIC NSCLC1-4

NSCLC=non-small cell lung cancer.

Visit www.CYRAMZAHCP.com for more information CYRAMZA® (ramucirumab), in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

ADVANCING THE SECOND-LINE TREATMENT OF METASTATIC NSCLC5 CYRAMZA is the first antiangiogenic agent FDA approved in combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.5

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events (ATEs)

• Serious, sometimes fatal, ATEs including myocardial infarction, cardiac

arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

Hypertension

• An increased incidence of severe hypertension occurred in patients

receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). 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 (IRRs) • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, 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. In study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing

• Impaired wound healing can occur with antibodies inhibiting the VEGF

pathway. CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA, as an antiangiogenic therapy, has the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis

• Clinical deterioration, manifested by new onset or worsening

encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

• RPLS has been reported at a rate of <0.1% in clinical studies with

CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Proteinuria Including Nephrotic Syndrome

• Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio

for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are ≥2 g over 24 hours.

CYRAMZA plus docetaxel demonstrated a statistically significant improvement in overall survival vs docetaxel5 OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) CYRAMZA + docetaxel (n=628)

1.0

OS PROBABILITY

0.8

MAJOR OUTCOME MEASURE

10.5

15% INCREASE IN MEDIAN OS

MONTHS

(9.5, 11.2) Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

527

415

329

231

156

103

501

386

306

197

129

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively 5

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)5 • Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001) — The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively • ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)* CI=confidence interval; OS=overall survival; PFS=progression-free survival; ORR=objective response rate. *Intent-to-treat population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.6 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253) The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.5 Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to <2 g over 24 hours. Permanently discontinue CYRAMZA for urine protein levels >3 g over 24 hours or in the setting of nephrotic syndrome. Thyroid Dysfunction

• Monitor thyroid function during treatment with CYRAMZA.

Embryofetal Toxicity

• Based on its mechanism of action, CYRAMZA can cause fetal harm

when administered to pregnant women. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at least 3 months after the last dose of CYRAMZA.

Most Common Adverse Reactions

• The most commonly reported adverse reactions (all grades; grade 3/4)

occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/ mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%).

• The most common serious adverse events with CYRAMZA plus docetaxel

in study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

• In patients ≥65 years of age, there were 18 (8%) deaths on treatment

or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years of age, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel.

• Treatment discontinuation due to adverse reactions occurred more

frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

• For patients with nonsquamous histology, the overall incidence of

pulmonary hemorrhage was 7% and the incidence of grade ≥3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and

the incidence of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for grade ≥3 pulmonary hemorrhage for placebo plus docetaxel. • Clinically relevant adverse reactions reported in ≥1% and <5% of

CYRAMZA plus docetaxel-treated patients in study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions

• No pharmacokinetic interactions were observed between ramucirumab

and docetaxel.

Use in Specific Populations

• Pregnancy: Based on its mechanism of action, CYRAMZA can cause

fetal harm. Animal models link angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA use in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to newborn and infant development, and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA.

• Lactation: Because of the potential risk for serious adverse reactions in

nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA.

• Females of Reproductive Potential: Advise females of reproductive potential

that based on animal data CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warnings for hemorrhage, gastrointestinal perforation, and impaired wound healing, on next page. RB-L HCP ISI 24APR2015 References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/fda-docetaxel/print. Accessed August 26, 2014. 4. National Cancer Institute. Cancer drug information. FDA approval for ramucirumab. http://www.cancer.gov/ cancertopics/treatment/drugs/fda-ramucirumab#nsclc. Accessed May 4, 2015. 5. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2015. 6. 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. 2014;384(9944):665-673. RB96549 05/2015 PRINTED IN USA © Lilly USA, LLC 2015. All rights reserved. CYRAMZA is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information. WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications. INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown. In Study 4, the incidence of severe bleeding was 2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%), in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI (11%) as compared to placebo plus FOLFIRI (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA, as an antiangiogenic therapy, has 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. Proteinuria Including Nephrotic Syndrome In Study 4, severe proteinuria occurred more frequently in patients treated with CYRAMZA plus FOLFIRI compared to patients receiving placebo plus FOLFIRI. Severe proteinuria was reported in 3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases [0.6%] of nephrotic syndrome) compared to 0.2% of patients treated with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick and/or urinary protein creatinine ratio for the development of worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome. Thyroid Dysfunction Monitor thyroid function during treatment with CYRAMZA. In Study 4, the incidence of hypothyroidism reported as an adverse event was 2.6% in the CYRAMZA plus FOLFIRI treated patients and 0.9% in the placebo plus FOLFIRI treated patients. Embryofetal Toxicity Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to pregnant women. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for at 3 least months after the last dose of CYRAMZA. 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. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intratumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxeltreated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3. Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3 CYRAMZA plus docetaxel Placebo plus docetaxel (N=627) (N=618) Adverse Reactions (MedDRA) System Organ Class All Grades Grade 3-4 All Grades Grade 3-4 (Frequency %) (Frequency %) (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 10 10 Neutropenia 55 49 46 40 Thrombocytopenia 13 3 5 <1 Gastrointestinal Disorders Stomatitis/Mucosal inflammation 37 7 19 2 Eye Disorders Lacrimation increased 13 <1 5 0 General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 50 11 Peripheral edema 16 0 9 <1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 7 <1 Vascular Disorders Hypertension 11 6 5 2 Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel). Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 23 clinical trials, 86/2890 (3.0%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action, CYRAMZA can cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no available data on CYRAMZA in pregnant women to inform any drug-associated risks. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. The background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise pregnant women of the potential risk 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. Lactation Risk Summary There is no information on the presence of ramucirumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, advise women that breastfeeding is not recommended during treatment with CYRAMZA. CYRAMZA® (ramucirumab) injection RB-L HCP BS 04MAY2015

Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, CYRAMZA can cause fetal harm. Advise females of reproductive potential to use effective contraception while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Infertility Females Advise females of reproductive potential that based on animal data CYRAMZA may impair fertility. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population pharmacokinetic analysis. Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1.0-1.5 times ULN and any AST) or moderate (total bilirubin >1.5-3.0 times ULN and any AST) hepatic impairment based on population pharmacokinetic analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity. 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 8 mg/kg every 3 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 6 mg/kg every 3 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to docetaxel, refer to the current respective prescribing information. PATIENT COUNSELING INFORMATION • Hemorrhage: Advise patients that CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Arterial thromboembolic events: Advise patients of an increased risk of an arterial thromboembolic event. • Hypertension: Advise patients 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. • Gastrointestinal perforations: Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • Impaired wound healing: Advise patients 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. • Pregnancy and fetal harm: Advise females of reproductive potential of the potential risk for maintaining pregnancy, risk to the fetus, and risk to postnatal newborn and infant development and to use effective contraception during CYRAMZA therapy and for at least 3 months following the last dose of CYRAMZA. • Lactation: Advise patients not to breastfeed during CYRAMZA treatment. • Infertility: Advise females of reproductive potential regarding potential infertility effects of CYRAMZA. Additional information can be found at www.CYRAMZAhcp.com.

RB-L HCP BS 04MAY2015

ASCOPost.com | DECEMBER 10, 2015

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FDA Update

Nivolumab Receives Two FDA Approvals in November

ivolumab (Opdivo) is a monoclonal antibody that binds to the programmed cell death protein 1 (PD-1) receptor and blocks its interaction with its ligands PD-L1 and PD-L2, releasing PD-1 pathway–mediated inhibition of the immune response. Late last month, the U.S. Food and Drug Administration (FDA) approved nivolumab as a single agent for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma. This followed the approval a day earlier on November 24 of nivolumab to treat patients with metastatic renal cell carcinoma who have received a prior antiangiogenic therapy.

Melanoma Indication The approval of nivolumab for previously untreated BRAF wild-type advanced melanoma is based on data from the phase III CheckMate 066 trial. The trial included treatment-naive patients with unresectable or metastatic BRAF wild-type melanoma who were randomly assigned to receive nivolumab or dacarbazine. The primary endpoint of the trial was overall survival, and secondary endpoints were progression-free survival and objective response rate.

CheckMate 066 Nivolumab demonstrated superior overall survival vs chemotherapy in the first-line setting. Results were based on the analysis conducted on 47% of the total planned events for overall survival. The median overall survival was not reached for nivolumab and was 10.8 months (95% confidence interval [CI] = 9.3–12.1) in the dacarbazine arm (hazard ratio [HR] = 0.42, 95% CI = 0.30–0.60, P < .0001). Median progression-free survival more than doubled with nivolumab: 5.1 months vs 2.2 months for patients treated with dacarbazine (HR = 0.43, 95% CI = 0.34–0.56, P < .0001). Objective response rate with nivolumab was 34% compared to 9% with dacarbazine. At the time of analysis, 88% of nivolumabtreated patients had ongoing responses, which included 43 patients with ongoing responses of 6 months or longer. In the trial, serious adverse reactions occurred in 36% of patients receiving nivolumab. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving nivolumab, the most frequent being gamma-glutamyl transferase increase (3.9%) and diarrhea (3.4%). Adverse reactions led to permanent discontinua-

tion of nivolumab in 7% of patients and dose interruption in 26% of patients. The most common adverse reactions in CheckMate 066 (> 20%) reported with nivolumab vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%).

Advanced Kidney Cancer Indication The FDA also approved nivolumab to treat patients with metastatic renal cell carcinoma who have received a prior antiangiogenic therapy. “[Nivolumab] provides an important therapy option for patients with renal cell carcinoma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It is one of few therapies that have demonstrated the ability to extend patients’ survival in treating this disease.” Temsirolimus (Torisel), approved in 2007, is the only other FDAapproved therapy that has demonstrated overall survival in renal cell cancer.

Clinical Trial The safety and efficacy of nivolumab for this use were demonstrated in an open-label, randomized study of 821 patients with advanced renal cell carcinoma whose disease worsened during or after treatment with an antiangiogenic agent. Patients were treated with nivolumab or everolimus (Afinitor). Those treated with nivolumab lived an average of 25 months after starting treatment compared to 19.6 months in those treated with everolimus. This effect was observed regardless of the PD-L1 expression level of patients’ renal cell tumors. Additionally, 21.5% of those treated with nivolumab experienced a complete or partial shrinkage of their tumors, which lasted an average of 23 months, compared to 3.9% of those taking everolimus, lasting an average of 13.7 months.

Adverse Events The most common side effects of nivolumab for this use are conditions relating to abnormal weakness or lack of energy, cough, nausea, rash, difficulty breathing, diarrhea, constipation, decreased appetite, back pain, and joint pain. Nivolumab also has the potential to cause serious immune-mediated side effects involving the lungs, colon, liver, kidneys, hormone-producing glands, and brain. n

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Perspective Hematology Continued from page 28

Molecularly Targeted Therapy Brings New Hope to Patients With Relapsed/Refractory Hairy Cell Leukemia By Philip A. Thompson, MBBS (Hons), and Farhad Ravandi, MD

he treatment of hairy cell leukemia is one of the great success stories in hematologic malignancies, with patients now having a survival that is only slightly inferior to an age-matched normal population. Purine analogs, such as cladribine, are the mainstay of first-line therapy, with approximately 80% of patients achieving complete remission.1,2 Remissions are generally highly durable, with the majority of patients remaining progression-free 10 years after a single course of cladribine.3 Nonetheless, treatment is not curative, and eventually many patients will relapse and require retreatment. Most patients who relapse after initial treatment with cladribine will respond to retreatment with the same drug; however, invariably, subsequent responses are shorter in duration than the initial response. In addition, there are cumulative toxicities associated with the repeated use of purine analogs, including immunodeficiency and damage to bone marrow stem cells.4 For this reason, despite the generally favorable outcomes, novel treatment approaches are required both in first-line treatment and in relapsed or refractory disease.

lost; dose-dependent downstream MEK and ERK dephosphorylation was seen, indicating silencing of BRAF kinase activity; and there were dramatic changes in gene expression profiling, including downregulation of targets of BRAFMEK-ERK signaling and, interestingly, genes encoding diagnostic markers in hairy cell leukemia, such as CD25 (interleukin 2 receptor alpha) and tartrate-resistant acid phosphatase (TRAP).7 Cell death by apoptosis occurred. Notably, in

had high-risk disease, as indicated by purine analog-refractory disease or early relapse, or multiple relapses post purine analog therapy; all patients had cytopenias indicating the need for treatment. Unlike in melanoma, treatment in hairy cell leukemia was given briefly, for 12 to 24 weeks, rather than indefinitely until disease progression. The overall response rate was remarkable: 96% to 100% of patients responded, despite 41% to 54% having

The availability of a highly active oral therapy that has precisely targeted the key driver mutation responsible for hairy cell leukemia is a major breakthrough for patients with refractory disease. However, the challenge for researchers is now how best to apply this therapy. —Philip A. Thompson, MBBS (Hons), and Farhad Ravandi, MD

Key Driver Mutation An activating mutation in the BRAF gene (BRAF V600E) is a key driver mutation in classic hairy cell leukemia5,6 and the hallmark of the disease; it results in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway. Elegant work published previously by Dr. Tiacci’s group4 demonstrated the central biologic importance of activating BRAF mutations in classic hairy cell leukemia. Specifically, treatment of classic hairy cell leukemia cells (but not cells from similar diseases such as splenic marginal zone lymphoma with villous lymphocytes or hairy cell leukemia variant) either in vitro or in vivo with BRAF or MEK inhibitors resulted in dramatic morphologic and molecular changes: “Hairy” cytoskeletal projections were Dr. Thompson is Assistant Professor and Dr. Ravandi is Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

vitro, both MEK-ERK dephosphorylation and apoptosis could be partially rescued by stromal cell co-culture.

A Closer Look at Vemurafenib BRAF inhibitors achieve high response rates in malignant melanoma carrying the BRAF V600E mutation; hairy cell leukemia is considerably less genetically complex than malignant melanoma, and therefore targeting the mutant BRAF is attractive. As summarized in this issue of The ASCO Post, Tiacci and colleagues recently reported the results of two phase II studies of the BRAF inhibitor vemurafenib (Zelboraf) in classic hairy cell leukemia.4 A total of 54 patients with relapsed/refractory classic hairy cell leukemia and confirmed BRAF V600E mutation were enrolled in the two studies. Patients

disease refractory to the most recent prior therapy; 35% to 42% had a complete remission. Treatment was associated with rapid improvement in hematologic parameters. Median relapse-free survival was 9 months in the Italian study, and progression-free survival at 1 year was 73% in the U.S. trial. Achieving complete remission was associated with longer progression-free survival. Vemurafenib was associated with frequent toxicities but no grade 4 or 5 adverse events; dose reductions were required in over half the patients (most commonly by 25% to 720 mg twice daily) and were not associated with inferior progression-free survival. Frequent adverse events included rash, arthritis and arthralgia, pyrexia, and abnormal liver function tests. Two patients developed clinical pancreatitis. Five patients developed nonmelanoma skin cancers,

and one patient developed melanoma. The precise relationship of the cutaneous malignancies to vemurafenib could not be determined, since the majority of patients had a history of similar skin tumors. However, vemurafenib and the BRAF inhibitor dabrafenib (Tafinlar) have been associated with the development of squamous cell carcinomas of the skin in studies in malignant melanoma.8-10 In the Italian study, downregulation of CD25 and ultrastructural changes with loss of “hairy” cytoplasmic projections were seen, similar to previous observations11; the loss of CD25 expression is important, since it likely renders soluble CD25 a less reliable marker of residual disease during BRAF inhibitor therapy. Notably, in the Italian study, 13 of 26 patients had immunohistochemical analysis for phosphorylated ERK performed on bone marrow biopsies, the day after completion of therapy. Of these 13 patients, 6 had residual phosphorylated ERK–expressing hairy cell leukemia cells present; although numbers were small, those patients with residual phosphorylated ERK expression appeared to have inferior progression-free survival. A previously published case report demonstrated residual ERK phosphorylation in a patient treated with vemurafenib for hairy cell leukemia, despite an excellent response.12 Combined, these data suggest that there is an alternative mechanism of BRAF-MEKERK pathway activation, which may lead to treatment resistance; notably, during in vitro treatment with BRAF inhibitors, co-culture of classic hairy cell leukemia cells with bone marrow stroma appears to antagonize both apoptotic effects of treatment and dephosphorylation of MEK-ERK. Precise understanding of the mechanism of residual MEK-ERK activation during treatment with BRAF inhibitors is essential to allow the rational design of combination therapies, which may enhance activity and prevent resistance. One patient in the U.S. study, who was refractory to vemurafenib retreatment after relapse, was found to have two activating, subclonal KRAS mutations; this is a previously described mechanism of resistance to BRAF inhibitors

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Perspective

in melanoma13 and confers resistance through rephosphorylation of MEK and ERK.

Challenges for Researchers The availability of a highly active oral therapy that has precisely targeted the key driver mutation responsible for hairy cell leukemia is a major breakthrough for patients with refractory disease. However, the challenge for researchers is now how best to apply this therapy. There are many questions to be answered by subsequent, well-designed studies. First, the optimal dose and duration of therapy for relapsed/refractory patients are unclear from the existing data. Patients on these studies had durable remissions, even after cessation of treatment, suggesting that time-limited therapy may be possible, although it is unclear whether continued maintenance therapy (perhaps at a lower dose to limit adverse effects) could produce a prolonged remission duration; additionally, many patients required dose reduction due to toxicity, which did not appear to negatively impact progression-free survival; this finding may suggest that lower doses could have been used with similar efficacy and, potentially, reduced toxicity. The ability to deliver time-limited therapy (and/or lower doses) is of major importance, given both the side effects associated with the drug (particularly the concern regarding pancreatitis and malignant cutaneous tumors) and the very high cost of such novel therapies for both patients and society. The issue of cost will assume even more importance if the use of BRAF inhibitors is contemplated earlier in the disease course, when more patients will likely be treated for longer durations. Second, vemurafenib monotherapy may not achieve optimal MAPK pathway inhibition, as shown by the demonstration of residual phosphorylated ERK expression in residual hairy cell leukemia cells in the bone marrow in almost half the patients on the current study. This argues for the use of a more potent BRAF inhibitor, such as dabrafenib, or potentially dual BRAF/ MEK inhibition, which achieves superior progression-free survival compared with BRAF inhibition alone in

malignant melanoma.9,10 In vitro data in classic hairy cell leukemia certainly provide a solid rationale for the use of dabrafenib alone or in combination with MEK inhibitors: Dabrafenib is more capable of overcoming the protective effect of bone marrow stroma than is vemurafenib, and its ability to overcome this protective effect, to induce dephosphorylation of MEK and ERK and to induce apoptosis of classic hairy cell leukemia cells is further enhanced by its use in combination with the MEK inhibitor trametinib (Mekinist).11 Additionally, the combination of dabrafenib and trametinib significantly reduced the incidence of cutaneous squamous cell carcinomas during treatment of BRAFmutated malignant melanoma, which would be an added advantage of combination therapy.9,10 A phase II study of dabrafenib plus trametinib for patients with relapsed/refractory classic hairy cell leukemia is currently ongoing. Third, it is important to identify the mechanisms of rephosphorylation of MEK and ERK in the presence of bone marrow stromal cells. Identifying the specific activated pathways and/or the development of mutations involving other kinases such as KRAS is essential to plan subsequent therapies for patients developing BRAF inhibitor resistance and BRAF inhibitor–based combination strategies.

First-Line Setting In other indolent lymphoproliferative disorders, such as chronic lymphocytic leukemia, the development of highly effective targeted therapies for relapsed patients has been rapidly followed by studies of novel therapies in the first-line setting, in an effort to replace conventional therapy. However, given the generally very favorable outcomes of patients with purine analog-based therapy and the unique toxicity profile of BRAF inhibition (particularly the development of cutaneous squamous cell carcinomas), we would anticipate that its use in the earlier disease setting may initially be restricted to elderly patients or those who have comorbidities that may limit the tolerability of purine analog therapy. Perhaps a more important question is whether BRAF inhibitors can

be integrated with existing therapies in first-line therapy or at the time of first relapse to improve progressionfree survival. Detailed preclinical studies are required to understand how best to combine or sequence these treatments both to enhance efficacy and limit toxicity.

Minimal Residual Disease Interpretation of any future studies comparing novel treatments such as BRAF inhibitors or BRAF inhibitor– based combinations with existing purine analog-based treatments will be complicated, due to the very long progressionfree survival achieved with first-line purine analog therapy. As a result, surrogate primary endpoints for progression-free survival, most notably minimal residual disease, will be required. We and others have previously shown that minimal residual disease can be detected in most patients following cladribine therapy.14 Given the known association between the depth of remission and progression-free survival, we anticipate that achievement of minimal residual disease negativity through the use of consolidation treatment will translate into a progressionfree survival benefit, with fewer patients consequently requiring salvage therapy. However, long-term follow-up will be required to prove this theory. The availability of potent, molecularly targeted therapy in classic hairy cell leukemia represents a great advance for the few patients with disease refractory to purine analogs. We anticipate that integration of BRAF inhibitors with existing treatment in earlier stages of the disease and use of more potent BRAF inhibitors or combinations of BRAF and MEK inhibitors will further improve results in the future. Given the effectiveness of nucleoside analogs with or without monoclonal antibodies in the majority of patients, cost and convenience considerations are likely to play a major role in the adoption of these agents. n Disclosure: Drs. Thompson and Ravandi reported no potential conflicts of interest.

References 1. Grever MR: How I treat hairy cell leukemia. Blood 115:21-28, 2010. 2. Maevis V, Mey U, Schmidt-Wolf G,

et al: Hairy cell leukemia: Short review, today’s recommendations and outlook. Blood Cancer J 4:e184, 2014. 3. Chadha P, Rademaker AW, Mendiratta P, et al: Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA): Long-term follow-up of the Northwestern University experience. Blood 106:241-246, 2005. 4. Tiacci E, Park JH, De Carolis L, et al: Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia. N Engl J Med 373:1733-1747, 2015. 5. Tiacci E, Trifonov V, Schiavoni G, et al: BRAF mutations in hairy-cell leukemia. N Engl J Med 364:2305-2315, 2011. 6. Tiacci E, Schiavoni G, Forconi F, et al: Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood 119:192195, 2012. 7. Basso K, Liso A, Tiacci E, et al: Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors. J Exp Med 199:59-68, 2004. 8. Su F, Viros A, Milagre C, et al: RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366:207-215, 2012. 9. Flaherty KT, Infante JR, Daud A, et al: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694-1703, 2012. 10. Long GV, Stroyakovskiy D, Gogas H, et al: Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371:1877-1888, 2014. 11. Pettirossi V, Santi A, Imperi E, et al: BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity. Blood 125:1207-1216, 2015. 12. Samuel J, Macip S, Dyer MJ: Efficacy of vemurafenib in hairy-cell leukemia. N Engl J Med 370:286-288, 2014. 13. Nazarian R, Shi H, Wang Q, et al: Melanomas acquire resistance to BRAF(V600E) inhibition by RTK or NRAS upregulation. Nature 468:973-977, 2010. 14. Ravandi F, O’Brien S, Jorgensen J, et al: Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia. Blood 118:3818-3823, 2011.

Treating patients with polycythemia vera (PV)

When monitoring hematocrit (Hct), keeping levels below 45% made a difference in the rate of thrombotic complications > In a study published in The New England Journal of Medicine in 2013, 365 adult patients with PV were randomized into 2 groups1: More-intensive treatment, n = 182, target Hct <45% (low Hct)

Less-intensive treatment, n = 183, target Hct 45% to 50% (high Hct)

The rate of cardiovascular death and major thrombosis was ≈4-fold higher with Hct level of 45% to 50% compared with Hct level of <45% Rate of Cardiovascular Death and Major Thrombosis: Study Published in The New England Journal of Medicine, 2013 Probability of Remaining Event-free

Primary End Point: Death From Cardiovascular Causes or Thrombotic Events 1.0

Low Hct (<45%)

P = 0.004 by log-rank test

0.9

High Hct (45% to 50%)

0.8

Hazard ratio Low Hct High Hct

0.7 0.0

Number at risk Low Hct 182 (0) High Hct 183 (6)

5/182 (2.7%) 18/183 (9.8%) 12

1.00 3.91 (95% CI, 1.45%-10.53%) 24

95 (0) 92 (2)

62 (0) 54 (1)

18 (0) 12 (0)

0 1

Months 177 (1) 168 (0)

168 (2) 160 (3)

154 (1) 143 (4)

129 (1) 110 (2)

Adapted with permission from Massachusetts Medical Society.

> In this randomized clinical trial: • • • • • •

Baseline characteristics were balanced between both groups ≈50% had received an initial diagnosis of PV within 2 years before randomization 67.1% were at high risk because of advanced age or previous thrombosis Therapy options for maintaining Hct levels were phlebotomy, cytoreductive drugs, or both The composite primary end point was the time until death from cardiovascular causes or major thrombotic events Platelet levels did not differ in the 2 arms, whereas white blood cell counts persisted at significantly higher levels in the high-Hct group compared with the low-Hct group (P < 0.001)

Reference: 1. Marchioli R et al. N Engl J Med. 2013;368(1):22-33.

45%

more or less? Hct

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JCO Spotlight Sarcoma

Improved Progression-Free Survival With Trabectedin vs Dacarbazine After Chemotherapy Failure in Liposarcoma or Leiomyosarcoma By Matthew Stenger

n a phase III trial reported in the Journal of Clinical Oncology, George D. Demetri, MD, of Harvard Medical School and Dana-Farber Cancer Institute, Boston, and colleagues found that treatment with trabectedin (Yondelis) significantly improved progression-free survival vs dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior conventional chemotherapy.1 On the basis of this phase III trial, on October 23, 2015, the U.S. Food and Drug Administration approved trabectedin as a treatment option for patients with metastatic and/or unresectable leiomyosarcomas and liposarcomas. Interim analysis of overall survival, the primary endpoint of the trial, showed a nonsignificant improvement with trabectedin. Trabectedin is a marine-derived drug that causes both cell-cycle arrest and induction of p53-independent apoptosis and affects the tumor microenvironment via cytotoxicity against tumor-associated macrophages and tissue-resident histiocytes.

Study Details The open-label NCT01343277 trial enrolled patients aged ≥ 15 years with

least a combination of an anthracycline and ifosfamide or an anthracycline plus at least one additional cytotoxic chemotherapy regimen. The primary endpoint was overall survival. The published report presented the final analysis of progression-free survival, performed at the first interim analysis of overall survival. Enrollment in the trial was targeted at 570 patients. The trabectedin and dacarbazine groups were generally balanced for age, sex, body mass index, histology, Eastern Cooperative Oncology Group performance status, best response to last line of prior chemotherapy, prior surgery, prior radiotherapy, time from initial diagnosis, and time from last progression.

Improved Progression-Free Survival Median progression-free survival was 4.2 months in the trabectedin group vs 1.5 months in the dacarbazine group on investigator assessment (hazard ratio [HR] = 0.55, P < .001). Hazard ratios were 0.57 (95% confidence interval [CI] = 0.45–0.72) on investigator radiographic assessment, 0.55 (95% CI = 0.40–0.75) on independent review, and

Trabectedin in Sarcoma ■■ At interim analysis, trabectedin significantly improved progression-free survival. ■■ At interim analysis, trabectedin was associated with a nonsignificant reduction in the risk of death.

locally advanced or metastatic disease from 85 sites in four countries between May 2011 and September 2013 (cutoff for interim analysis of overall survival). A total of 518 patients were randomly assigned 2:1 to receive trabectedin (n = 345) at a starting dose of 1.5 mg/ m2 via 24-hour intravenous infusion or dacarbazine (n = 173) at a starting dose of 1 g/m2 via 20- to 120-minute intravenous infusion on day 1 of 21-day cycles. Trabectedin-treated patients received dexamethasone premedication. Patients were previously treated with at

0.54 (95% CI = 0.41–0.71) on radiographic independent review. On subgroup analysis, hazard ratios for progression-free survival favored trabectedin across all 19 preplanned subgroups examined; hazard ratios were 0.50 (95% CI = 0.42–0.73) among patients with leiomyosarcoma and 0.55 (95% CI = 0.34–0.87) among those with liposarcoma. Median time to progression was 4.2 vs 1.5 months (P < .001). Progressionfree survival rates were 56% vs 34% at 3 months and 37% vs 14% at 6 months. Objective response rates were 9.9%

Trabectedin demonstrates superior disease control vs conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. —George D. Demetri, MD

in the trabectedin group vs 6.6% in the dacarbazine group (P = .33), and median duration of response was 6.5 vs 4.2 months (P = .14). Furthermore, 51% vs 35% of patients had stable disease as best response, median duration of stable disease was 6.01 vs 4.17 months (P < .001), and clinical benefit rates were 34% vs 19% (P < .001).

Interim Analysis of Overall Survival The interim analysis of overall survival (64% censored) indicated a 13% reduction in risk of death in the trabectedin group vs the dacarbazine group (median = 12.4 vs 12.9 months, HR = 0.87, P = .37). Fewer trabectedintreated patients received subsequent anticancer therapy (47% vs 56%) and received such treatment later compared with dacarbazine patients (median time from randomization = 6.9 vs 3.7 months, HR = 0.47, P < .001). The most frequently used treatments were pazopanib (Votrient; 18% vs 28%), radiation (10% vs 15%), gemcitabine (9% vs 15%), and dacarbazine (17% vs 6%). At the time of analysis, 28% vs 15% of patients were still receiving study treatment.

Adverse Events The most common adverse events of any grade in the trabectedin group were nausea (73% vs 49%), fatigue (67% vs 51%), neutropenia (49% vs 29%), increased alanine transaminase (ALT; 45% vs 6%), and vomiting (44% vs 21%); the most common events in the dacarbazine group were fatigue and nausea. The most common grade 3 or 4

adverse events were neutropenia (37% vs 21%), increased ALT (26% vs 1%), thrombocytopenia (17% vs 18%), anemia (14% vs 12%), and increased aspartate transaminase (AST; 13% vs 0%). Discontinuation of treatment due to adverse events or death occurred in 12.6% vs 7.7% of patients (and due to withdrawal of consent in 3.2% vs 7.1%). Death within 60 days of the start of treatment occurred in 7.1% of the trabectidin vs 5.8% of the dacarbazine arm, with death considered treatment-related in 2.1% of the trabectedin group (sepsis/ septic shock in three patients, rhabdomyolysis/sepsis in one, renal failure in one, renal failure/cardiac arrest in one, and multiorgan failure in one). The investigators concluded: “Trabectedin demonstrates superior disease control vs conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies.” n

Disclosure: The study was supported by Janssen Pharmaceuticals and in part by Adelson Medical Research Foundation. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. Demetri GD, von Mehren M, Jones RL, et al: Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: Results of a phase III randomized multicenter clinical trial. J Clin Oncol. September 14, 2015 (early release online).

Visit The ASCO Post website at ASCOPost.com

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Perspective

Trabectedin in Liposarcoma/Leiomyosarcoma: The Drug Is Approved, Now the Real Drug Development Begins! By Laurence H. Baker, DO

ed by George Demetri, MD, of Dana-Farber Cancer Institute, Boston, expert medical oncology investigators from leading academic sarcoma centers and Janssen Pharmaceuticals employees performed a phase III trial in order to provide evidence for the U.S. Food and Drug Administration (FDA) approval of trabectedin (Yondelis).1,2 This approval was long overdue. The phase III study is summarized in this issue of The ASCO Post. In an editorial that accompanied the phase III trial publication,3 Gary Schwartz, MD, of Herbert Irving Comprehensive Cancer Center, New York, opined that the study confirmed “what our European colleagues claimed a decade ago.” In fact, at the 2009 ASCO Annual Meeting, the American community of sarcoma physicians was nearly unanimous that trabectedin was an active drug useful for prolonged periods of time for a minority of sarcoma patients. The challenge was to design a convincing strategy to demonstrate this.

ple with this question. This is perhaps in large part because there are so few drugs to treat metastatic sarcoma with unambiguous benefit (think imatinib).

Study Design Details The study demonstrated the superiority of trabectedin over dacarbazine using a 2:1 randomization design. Randomization gives credence to the comparison of progression-free survival. Too often, particularly in sarcoma trials, a statement is made about progression-free survival in a single-arm study and compared to the European Organisation for Treatment of Cancer (EORTC) idea4 that

quite small in dedifferentiated and pleomorphic liposarcoma subtypes. Median progression-free survival with dacarbazine was 1.9 and 1.4 months for dedifferentiated and pleomorphic subtypes, compared with 2.2 and 1.5 months with trabectedin. Thus, the effect on progression-free survival overall in liposarcoma was 1.5 months for dacarbazine and 3.0 months for trabectedin. This difference was largely driven by the effect in the myxoid/round cell variant. This study included an independent imaging audit in a subset of 60% of the total population. The limited audit confirmed the investigator interpretation of the clinical course of patients in the

Based in large part upon [the phase III trial of trabectedin], the FDA made the right decision to approve this drug. —Laurence H. Baker, DO

Noteworthy Benefit for Some Based in large part upon this trial, the FDA made the right decision to approve this drug. Trabectedin has modest activity against some soft-tissue sarcoma histotypes (myxoid round cell liposarcoma, leiomyosarcoma). For those patients who benefit, the beneficial period is noteworthy. The toxicity profile for both trabectedin and imidazole carboxamide (or dacarbazine) is comparable and usually easy to manage. What was unusual about the regulatory agency’s decision was that the study’s primary endpoint of overall survival was not met. Instead, the study showed an increase in the median progression-free survival of 4.2 months compared to 1.5 months in the control group treated with dacarbazine. Again, the trial raises the age-old question of how to define clinical benefit. Oncologists—sarcoma oncologists, in particular—continue to grapDr. Baker is Collegiate Professor for Cancer Developmental Therapeutics, Professor, Departments of Internal Medicine and Pharmacology, University of Michigan Medical School, Ann Arbor.

progression-free survival can be a principal endpoint in phase II trials. However, without demonstrating that the cancer was progressing immediately before receiving a new therapy, progression-free survival can be misestimated by a few weeks or months. Randomization alone gives protection against a false observation of a progression-free survival difference. Using a 2:1 schema led more patients to receive the “experimental drug” than the approved standard. In turn, this likely reduced the total number of patients required for statistical certainty of an observation. Compared to a 1:1 schema, Korn and Freidlin5 estimated that a 2:1 schema increases the total number of patients by 15% while maintaining the same power calculation. To some extent, however, the reduced number of patients receiving dacarbazine compromised the comparison of liposarcoma subtypes. There were 47 patients in the liposarcoma control arm, and only 3 patients were reported to have the pleomorphic liposarcoma subtype. The median reported difference in progression-free survival is

trial. Perhaps it is time to end the practice of an independent imaging review. This practice was put in place to address the potential bias of the radiologist interpreting the clinical scans. There was the potential for bias when the radiologist would review the patient’s chart to see which treatment had been received. It is an ongoing challenge to have the radiologist first review the clinical record. Instead, the funding should be used to support pathology review. In sarcoma, the incidence of histologic subtype error varies by as much as 25%.

Mechanism of Action Approximately 40% of all sarcomas have an associated chromosomal translocation and subsequent fusion gene that acts as a transcriptional regulator. This has been known and accepted for decades, yet no direct therapeutic intervention has been forthcoming despite knowing the molecular target. Is trabectedin the first drug to directly interfere with the fusion protein FUS-CHOP that results from t(12;16) (q13;p11), the balanced translocation pathognomonic of myxoid/round cell liposarcoma?

DiGiandomenico et al6 provided xenograft-derived data that suggest a selective mechanism of action of trabectedin in the myxoid/round cell variant, whereby it causes functional deactivation of the chimera and subsequent derepression of differentiation. If this is so, it raises some questions: Is there another mechanism to explain the occasional patient with another subtype of liposarcoma that benefits from trabectedin? Should other soft-tissue sarcomas, such as synovial sarcoma, have been included in this study rather than excluded? Should bone sarcomas such as Ewing sarcoma, which also has a pathogenomic fusion gene to target, have been included? Again, preliminary data from Grohar et al7 suggested this possibility. Hopefully, with additional laboratory and clinical studies, these and other questions can be addressed. Many have commented that the real drug development work does not begin until regulatory approval. n

Disclosure: Dr. Baker is a member of the data monitoring committee for Morphotek and is on the advisory committee for Teva.

References 1. FDA approves trabectedin for advanced liposarcoma and leiomyosarcoma. The ASCO Post, October 23, 2015. 2. Demetri GD, von Mehren M, Jones RL, et al: Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy. J Clin Oncol. September 14, 2015 (early release online). 3. Schwartz GK: Trabectedin and the Lsarcomas: A decade-long odyssey. J Clin Oncol. September 14, 2015 (early release online). 4. Van Glabbeke M, Verweij J, Judson I, et al: Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas. Eur J Cancer 38:543-549, 2002. 5. Korn EL, Freidlin B: Outcomeadaptive randomization: Is it useful? J Clin Oncol 29:771-776, 2011. 6. DiGiandomenico S, Frapolli R, Bello E, et al: Mode of action of trabectedin in myxoid liposarcomas. Oncogene 33:5201-5210, 2014. 7. Grohar PJ, Segars LE, Yeung C, et al: Dual targeting of EWS-FLI1 activity and the associated DNA damage response with trabectedin and SN38 synergistically inhibits Ewing sarcoma cell growth. Clin Cancer Res 20:1190-1203, 2014.

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In the Clinic Dermatologic Oncology

Cobimetinib in BRAF-Mutant Unresectable or Metastatic Melanoma in Combination With Vemurafenib 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 November 10, 2015, the U.S. Food and Drug Administration approved cobimetinib (Cotellic) for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib (Zelboraf).1,2 Cobimetinib is not indicated for treatment of patients with wild-type BRAF melanoma.

Supporting Efficacy Data Approval was based on demonstration of improved progression-free survival and overall survival with the addition of cobimetinib to vemurafenib in a phase III double-blind trial.2,3 In the trial, 495 patients with previously untreated unresectable or metastatic melanoma with BRAF mutation detected by the cobas® 4800 BRAF V600 mutation test were randomized to receive vemurafenib at 960 mg twice daily with either cobimetinib at 60 mg (n = 247)

OF NOTE Cobimetinib carries warnings/precautions for new primary malignancies, hemorrhage, cardiomyopathy, severe dermatologic reactions, serous retinopathy and retinal vein occlusion, hepatotoxicity, rhabdomyolysis, severe photosensitivity, and embryofetal toxicity.

of 0, 45% had an elevated serum lactate dehydrogenase level, 10% had received prior adjuvant therapy, and < 1% had previously treated brain metastases. Median progression-free survival was 12.3 months (95% confidence interval [CI] = 9.5–13.4 months) in the cobimetinib group vs 7.2 months (95% CI = 5.6–7.5 months) in the placebo group (hazard ratio [HR] = 0.56, P < .001). In interim analysis, median overall survival was not reached (95% CI = 20.7 months to not reached) vs 17 months (95% CI = 15.0 months to not reached; HR = 0.63, P = .0019). Confirmed objective response rate was 70% vs 50% (P < .001).

How It Works Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2, components of the BRAF pathway. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E and V600K mutations induce constitutive activation of the BRAF pathway. Cobimetinib inhibited tumor growth in xenografts expressing BRAF V600E. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/ MEK/ERK pathway. Compared with either drug alone, coadministration of cobimetinib and vemurafenib resulted in increased apoptosis in vitro and reduced tumor growth in xenografts with BRAF V600E mutation. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF xenograft.

How It Is Used or placebo (n = 248) once daily on days 1 to 21 in 28-day cycles until disease progression or unacceptable toxicity. Patients with abnormal liver function tests, a history of acute coronary syndrome within 6 months, evidence of class II or greater congestive heart failure, active central nervous system lesions, or evidence of retinal pathology were excluded from the trial. Patients had a median age of 55 years (range, 23–88 years), 58% were male, 93% were white, 60% had stage M1c disease, 72% had an Eastern Cooperative Oncology Group performance status

The recommended dose of cobimetinib is 60 mg once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Recommended dose reductions are to 40 mg and then 20 mg, with permanent discontinuation of treatment if 20 mg cannot be tolerated. Recommended dose modifications follow. For asymptomatic and symptomatic cardiomyopathy, treatment should be interrupted for 2 and 4 weeks, and measurement of left ventricular ejection fraction should be repeated. Treatment can be resumed at the next lower dose if left ventricular

OF NOTE Cobimetinib is a reversible inhibitor of MAPK/ MEK1 and MEK2, components of the BRAF pathway.

ejection fraction is ≥ the lower limit of normal, absolute decrease in left ventricular ejection fraction from baseline is ≤ 10%, and, for symptomatic patients, symptoms resolve. Treatment should be permanently discontinued if left ventricular ejection fraction is < lower limit of normal, absolute decrease from baseline in left ventricular ejection fraction is >10%, or, for symptomatic patients, symptoms persist. Treatment should be withheld for up to 4 weeks and resumed at a lower dose with improvement to grade 0 or 1 or improvement in signs/symptoms;

other intolerable grade 2 or any grade 3 adverse reactions, or first occurrence of any grade 4 adverse reaction (treatment may also be permanently discontinued for first occurrence). Treatment should be interrupted or reduced in dose for intolerable grade 2 or any grade 3 or 4 dermatologic reaction. Permanent discontinuation of treatment is recommended for grade 4 hemorrhage, retinal vein occlusion, recurrent grade 4 liver function abnormality, and recurrent grade 4 adverse reactions. No dose modification is required for new primary cutaneous or noncutaneous malignancies. Coadministration of cobimetinib with strong (eg, itraconazole) or moderate CYP3A inhibitors should be avoided. If concurrent short-term use (≤ 14 days) of a moderate inhibitor (eg, erythromycin, ciprofloxacin) is unavoidable in patients receiving cobi-

Cobimetinib for BRAF-Mutant Unresectable or Metastatic Melanoma ■■ Cobimetinib (Cotellic) was granted approval for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib. ■■ The recommended dose of cobimetinib is 60 mg once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.

treatment should be permanently discontinued for no improvement within 4 weeks at the lower dose for grade 3 hemorrhage, serous retinopathy, first occurrence of grade 4 liver function abnormality, grade 4 creatine phosphokinase elevation (treatment can be resumed at a lower dose with improvement to grade 3) or any creatine phosphokinase elevation and myalgia, intolerable grade 2 or any grade 3 or 4 photosensitivity,

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

metinib at 60 mg, the dose should be reduced to 20 mg; after discontinuation of the moderate CYP3A inhibitor, cobimetinib can be resumed at 60 mg. Concomitant use with strong or moderate CYP3A inducers (eg, carbamazepine, efavirenz, phenytoin, rifampin, and St. John’s wort) should be avoided.

Safety Profile In the phase III trial, the most common adverse events of any grade occurring more frequently in the combination group were diarrhea (60% vs 31%), photosensitivity reaction (46% vs 35%), nausea (41% vs 25%), pyrexia (28% vs 23%), and vomiting (24% vs 13%). Vascular disorders of any grade included hypertension in 15% vs 8% and hemorrhage in 13% vs 7%, and eye disorders of any grade included impaired vision in 15% vs 4%, chorioretinopathy in 13% vs < 1%, and retinal detachment in 12% vs < 1%. The most common grade 3 or 4 adverse events were diarrhea (6% vs 1%), photosensitivity reaction (4% vs continued on page 42

MANY PEOPLE DIAGNOSED WITH SQUAMOUS NSCLC:

STILL WAITING FOR NEW TREATMENT OPTIONS TO EVOLVE1

EVERY ADVANCE MATTERS In 2012, there were an estimated 450,000 cases of squamous NSCLC worldwide.*2,3 Unfortunately, despite decades of research, the median overall survival for squamous NSCLC remains at approximately 8 to 10 months.4,5 Lilly Oncology is committed to finding treatment advances for people living with lung cancer.

VISIT SQUAMOUSNSCLC.COM TO LEARN MORE.

* Worldwide prevalence of squamous NSCLC based on World Health Organization/GLOBOCAN estimates of worldwide lung cancer prevalence and distribution of histology as reported by the American Cancer Society.

References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed February 16, 2015. To view the most recent and complete version of the guidelines, go online to http://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. 2. From Ferlay J., Soerjomataram I, Ervik M., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 23/02/2015. 3. American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/ non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed February 16, 2015. 4. Hoang T, Dahlberg SE, Schiller JH, et al. Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594. Lung Cancer. 2013;81(1):47-52. 5. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):1277-1280.

MARCH 2015

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The ASCO Post | DECEMBER 10, 2015

PAGE 42

FDA Update Record Number of Approvals

Drugs in the Pipeline

continued from page 1

While the past 2 years have seen an unprecedented accelerated pace in the number of new oncology drugs enter-

(PD-L1) and ibrutinib (Imbruvica) in the treatment of Waldenström’s macroglobulinemia. Originally approved in 2014 for patients with metastatic melanoma, pembrolizumab is the first anti–PD-L1 therapy approved for both squamous and nonsquamous metastatic NSCLC. Ibrutinib, a kinase inhibitor, was originally approved in 2013 for the treatment of patients with mantle cell lymphoma, and last year it received an FDA Breakthrough Therapy designation in the treatment of relapsed/ refractory chronic lymphocytic leukemia (CLL), advancing clinical care for high-risk patients with CLL. Another milestone in new oncology treatments in 2015 is filgrastimsndz (Zarxio), the first FDA-approved biosimilar product in the United States. Filgrastim-sndz is biosimilar to filgrastim (Neupogen) and helps prevent infections in patients receiving chemotherapy.

Cobimetinib for Melanoma continued from page 40

0%), and hypertension (4% vs 2%). Cutaneous malignancies or premalignant conditions during treatment consisted of cutaneous squamous cell carcinoma or keratoacanthoma in 6% vs 20%, basal cell carcinoma in 4.5% vs 2.4%, and second primary melanoma in 0.8% vs 2.4%. Noncutaneous malignancies occurred in 0.8% vs 1.2%. The most common grade 3 or 4 laboratory abnormalities with cobimetinib were increased gamma-glutamyltransferase levels (21% vs 17%), increased creatine phosphokinase levels (14% vs 0.5%), hypophosphatemia (12% vs 6%), and increased alanine transaminase levels (11% vs 5%). Adverse events led to cobimetinib dose interruption or reduction in 55%

treatment of lung cancer, 87 for leukemia, 78 for lymphoma, and 73 for breast cancer, among others. The scientific advancements in on-

While the past 2 years have seen an unprecedented accelerated pace in the number of new oncology drugs entering the market, the years ahead look even more promising for new treatment options. ing the market, the years ahead look even more promising for new treatment options. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), there are 771 new cancer drugs and vaccines in development, 80% of which are potentially first in class, representing approaches to treating cancer that are different from any other marketed therapy.2 They include nearly 100 new drugs for the

cology drugs, along with technologic and oncology practice innovations, have resulted in marked improvements in cancer survival rates and 14.5 million Americans now living with a history of cancer.3 And despite the ongoing challenge of how to meet the increasing costs of cancer therapies, novel drug discoveries are likely to continue to fuel innovation in cancer care, improving outcomes for patients. n

of patients, with the most common reasons being rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase levels (5%), and to treatment discontinuation in 15%, with the most common reasons being liver laboratory abnormalities (8%) and retinal detachment (2%). Cobimetinib carries warnings/precautions for new primary malignancies (cutaneous and noncutaneous), hemorrhage (including major events), cardiomyopathy (risk increased with combination therapy vs vemurafenib alone), severe dermatologic reactions, serous retinopathy and retinal vein occlusion, hepatotoxicity, rhabdomyolysis, severe photosensitivity, and embryofetal toxicity. Patients should be monitored for new

malignancies prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose of c obimetinib. The safety of cobimetinib has not been established in patients with decreased left ventricular ejection fraction. Left ventricular ejection fraction should be assessed before treatment, after 1 month of treatment, and then every 3 months. Ophthalmologic evaluation should be performed at regular intervals and for any visual disturbances. Liver function tests should be performed during treatment and as clinically indicated. Creatine phosphokinase should be monitored periodically and as clinically indicated for signs and symptoms of rhabdomyolysis. Patients should be monitored for signs/ symptoms of bleeding and should be

Disclaimer: The number of new drug indications or formulations included in the FDA approvals update cited in reference 1 includes drugs approved by the Center for Drug Evaluation and Research and may not reflect the complete number of oncology drugs approved for 2015.

References 1. U. S. Food and Drug Administration: Hematology/oncology (cancer) approvals & safety notifications. Available at www.fda.gov/ drugs/informationondrugs/approveddrugs/ ucm279174.htm Accessed December 1, 2015. 2. Pharmaceutical Research and Manufacturers of America: Nearly 800 medicines and vaccines in clinical testing for cancer offer new hope to patients: 2014 Report. Available at phrma.org/sites/default/files/pdf/2014-cancer-report.pdf. Accessed December 1, 2015. 3. American Cancer Society: Cancer Treatment & Survivorship Facts & Figures: 20142015. Available at cancer.org/acs/groups/ content/@research/documents/document/ acspc-042801.pdf. Accessed December 1, 2015.

advised to avoid sun exposure. Women of reproductive potential should be advised of the potential risk to a fetus and to use effective contraception. n References 1. U.S. Food and Drug Administration: Approved drugs. Cobimetinib. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472193. htm. Accessed November 23, 2015. 2. Cotellic™ (cobimetinib) tablets prescribing information, Genentech, Inc, November 2015. Available at http://www. accessdata.fda.gov/drugsatfda_docs/ label/2015/206192s000lbl.pdf. Accessed November 23, 2015. 3. Larkin J, Ascierto PA, Dréno B, et al: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371:1867-1876, 2014.

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Change your perspective on POMALYST Multiple Myeloma AD whatâ&#x20AC;&#x2122;s possible for your patients To Come with multiple myeloma

153

High-dose dex

6 9 Months (ITT population)

Hazard ratio (2-sided 95% CI) 0.45 (0.35, 0.59) Log-rank P-value=<0.001 (2-sided) Data cutoff: September 7, 2012

POMALYST + low-dose dexamethasone (dex) High-dose dex

Progression-free survival

Kaplan-Meier median: POMALYST + low-dose dex=3.6 [3.0, 4.6] Kaplan-Meier median: high-dose dex=1.8 [1.6, 2.1] Events: POMALYST + low-dose dex=164/302; high-dose dex=103/153

See where survival may lead

Progression-free survival (PFS) based on the assessment by the Independent Review Adjudication Committee (IRAC) review at the final PFS analysis.

107

Number of patients at risk:

302

0.0

0.2

0.4

0.6

0.8

1.0

POMALYST + low-dose dex

Proportion of patients

POMALYST + low-dose dex is the only approved therapy that delivered a survival benefit in patients who failed lenalidomide and bortezomib

POMALYST is only available through a restricted distribution program, POMALYST REMS速.

POMALYST速 (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

POMALYST Multiple Myeloma AD To Come

Hazard ratio 0.45 (95% CI: 0.35, 0.59; P <0.001)

Patients >75 years of age started treatment with 20 mg dex using the same schedule.

Learn more about the survival beneﬁt of POMALYST at www.mmperspective.com

Study Design: Phase 3 multicenter, randomized, open-label study, where POMALYST + low-dose dex was compared with high-dose dex in patients with relapsed and refractory multiple myeloma, who had received at least 2 prior treatment regimens, including lenalidomide and bortezomib, and demonstrated disease progression on or within 60 days of the last therapy (N=455). Patients with creatinine clearance ≥45 mL/min qualified for the trial. Patients in the POMALYST + low-dose dex arm (n=302) were administered 4 mg POMALYST orally on Days 1-21 of each 28-day cycle. Low-dose dex (40 mga) was administered once per day on Days 1, 8, 15, and 22 of a 28-day cycle. For the high-dose dex arm (n=153), dex (40 mga) was administered once per day on Days 1-4, 9-12, and 17-20 of a 28-day cycle. Treatment continued until patients had disease progression.

VENOUS AND ARTERIAL THROMBOEMBOLISM • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Antithrombotic prophylaxis is recommended.

POMALYST is available only through a restricted program called POMALYST REMS®.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, and Important Safety Information on the following pages.

• POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST 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

CONTRAINDICATIONS: Pregnancy

• For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of 2 reliable methods of contraception.

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.

See full prescribing information for complete boxed warning

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM

Median OS for POMALYST + low-dose dex was 12.4 months (95% CI: 10.4, 15.3) vs 8.0 months (95% CI: 6.9, 9.0) for high-dose dex

Hazard ratio 0.70 (95% CI: 0.54, 0.92; P =0.009)

The difference in OS between the POMALYST + low-dose dex vs high-dose dex was statistically signiﬁcant, with a 30% reduced risk of death

POMALYST + low-dose dex signiﬁcantly prolonged overall survival (OS)

reduced risk of progression or death

55%

POMALYST + low-dose dex delivered signiﬁcantly longer progression-free survival vs high-dose dex

POMALYST Multiple Myeloma AD To Come

POMALYST® (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL 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 and Arterial Thromboembolism • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.

POMALYST Multiple Myeloma AD To Come

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST 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 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 and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboembolic events (ATE) (myocardial infarction and stroke) have been observed in patients treated with POMALYST. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with POMALYST and low-dose dexamethasone (Low-dose Dex) vs 3.3% treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with POMALYST and Low-dose Dex vs 1.3% treated with highdose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with POMALYST and Low-dose Dex vs 1.3% treated with high-dose dexamethasone. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Hematologic Toxicity: In Trials 1 and 2 in patients who received POMALYST + Low-dose Dex, neutropenia (46%) was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. 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. Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor

WARNINGS AND PRECAUTIONS (continued) liver function tests monthly. Stop POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. Hypersensitivity Reactions: Angioedema and severe dermatologic reactions have been reported. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reactions, and do not resume therapy. Dizziness and Confusional State: In Trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 14% experienced dizziness and 7% a confusional state; 1% of patients experienced Grade 3 or 4 dizziness and 3% experienced a Grade 3 or 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. Neuropathy: In Trials 1 and 2, patients who received POMALYST + Low-dose Dex experienced neuropathy (18%) and peripheral neuropathy (~12%). In Trial 2, 2% of patients experienced Grade 3 neuropathy. 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 POMALYST. Patients at risk are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

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 >65 years of age were more likely than patients ≤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.

POMALYST Multiple Myeloma AD To Come

ADVERSE REACTIONS Nearly all patients treated with POMALYST + Low-dose Dex experienced at least one adverse reaction (99%). In Trial 2, the most common adverse reactions included neutropenia (51.3%), fatigue and asthenia (46.7%), upper respiratory tract infection (31%), thrombocytopenia (29.7%), pyrexia (26.7%), dyspnea (25.3%), diarrhea (22%), constipation (21.7%), Please see brief summary of full Prescribing back pain (19.7%), cough (20%), pneumonia (19.3%), Information, including Boxed WARNINGS, edema peripheral (17.3%), peripheral neuropathy (17.3%), on following pages. bone pain (18%), nausea (15%), and muscle spasms (15.3%). Grade 3 or 4 adverse reactions included neutropenia (48.3%), thrombocytopenia (22%), and pneumonia (15.7%). DRUG INTERACTIONS Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). POMALYST is only available through a restricted distribution program, POMALYST REMS®.

The ASCO Post | DECEMBER 10, 2015

PAGE 48

Announcements

NCCN Names Robert C. Young, MD, Interim Vice President of Oncology Research Program

he National Comprehensive Cancer Network (NCCN) has appointed Robert C. Young, MD, as Interim Vice President of the NCCN Oncology Research Program.

Dr. Young brings to NCCN more than 45 years of oncology experience. He is President of RCY Medicine, a consulting service focused on cancer center productivity, health-care quality,

and health policy, and served as President and CEO of Fox Chase Cancer Center for 18 years, following which he served 2 years as Chancellor. Dr. Young T:7” is internationally known for his exper-

tise in the treatment of lymphoma and ovarian cancer. As Interim Vice President, Dr. Young will be responsible for developing and managing NCCN’s centralized, stan-

POMALYST® (pomalidomide) capsules, for oral use

2.2 Dose Adjustments for Toxicities

The following is a Brief Summary; refer to full Prescribing Information for complete product information.

Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities

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.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL 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 and Arterial Thromboembolism • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the 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 should be given in combination with dexamethasone. 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).

Dose Modification • Interrupt POMALYST treatment, follow CBC weekly • Resume POMALYST treatment at 3 mg daily

• For each subsequent • Interrupt POMALYST drop <500 per mcL treatment • Return to more than or • Resume POMALYST equal to 500 per mcL treatment at 1 mg less than the previous dose Thrombocytopenia • Platelets <25,000 per mcL • Platelets return to >50,000 per mcL

• Interrupt POMALYST treatment, follow CBC weekly • Resume POMALYST treatment at 3 mg daily

• For each subsequent • Interrupt POMALYST drop <25,000 per mcL treatment • Resume POMALYST • Return to more than or equal to 50,000 per treatment at 1 mg less than previous dose mcL ANC, absolute neutrophil count 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. Permanently discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reaction [see Warnings and Precautions (5.6)]. 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. 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))]. 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)].

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-Physician 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 at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436. 5.3 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke) have been observed in patients treated with POMALYST. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with POMALYST and low dose-dexamethasone (Low-dose Dex), and 3.3% of patients treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with POMALYST and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with POMALYST and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone.

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1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST, in combination with dexamethasone, is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

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

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Announcements

Robert C. Young, MD

Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors. 5.4 Hematologic Toxicity In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, neutropenia was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 51% of patients in both trials. The rate of Grade 3/4 neutropenia was 46%. The rate of febrile neutropenia was 8%. 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)]. 5.5 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly. Stop POMALYST upon elevation of liver enzymes and evaluate. After return to baseline values, treatment at a lower dose may be considered. 5.6 Hypersensitivity Reactions Angioedema and severe dermatologic reactions have been reported. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reactions, and do not resume therapy [see Dosage and Administration (2.2)].

5.8 Neuropathy In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 18% of patients experienced neuropathy, with approximately 12% of the patients experiencing peripheral neuropathy. Two percent of patients experienced Grade 3 neuropathy in trial 2. There were no cases of Grade 4 neuropathy adverse reactions reported in either trial. 5.9 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. 5.10 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 and Arterial Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hepatotoxicity [see Warnings and Precautions (5.5)] • Hypersensitivity Reactions [see Warnings and Precautions (5.6)] • Dizziness and Confusional State [see Warnings and Precautions (5.7)] • Neuropathy [see Warnings and Precautions (5.8)]

• Risk of Second Primary Malignancies [see Warnings and Precautions (5.9)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience 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 Trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low-dose Dex (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty-seven percent of patients in the study had a dose interruption of either drug due to adverse reactions. Forty-two percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to adverse reactions was 11%. In Trial 2, data were evaluated from 450 patients (safety population) who received treatment with POMALYST + Low-dose Dex (300 patients) or Highdose Dexamethasone (High-dose Dex) (150 patients). The median number of treatment cycles for the POMALYST + Low-dose Dex arm was 5. In the POMALYST + Low-dose Dex arm, 67% of patients had a dose interruption of POMALYST, the median time to the first dose interruption of POMALYST was 4.1 weeks. Twenty-seven percent of patients had a dose reduction of POMALYST, the median time to the first dose reduction of POMALYST was 4.5 weeks. Eight percent of patients discontinued POMALYST due to adverse reactions. Tables 2 and 3 summarize the adverse reactions reported in Trials 1 and 2, respectively. In Trial 1 of 219 patients who received POMALYST alonea (N=107) or POMALYST + Low-dose Dex (N=112), all patients had at least one adverse reaction.* Adverse reactions ≥10% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropeniab (53%, 49%), Anemiab (38%, 42%), Thrombocytopeniab (26%, 23%), Leukopenia (13%, 20%), Febrile neutropeniab (<10%, <10%), Lymphopenia (4%, 15%); General disorders and administration site conditions: Fatigue and astheniab (58%, 63%), Edema peripheral (25%, 17%), Pyrexiab (23%, 32%), Chills (10%, 13%); Gastrointestinal disorders: Nauseab (36%, 24%), Constipationb (36%, 37%), Diarrhea (35%, 36%), Vomitingb (14%, 14%); Musculoskeletal and connective tissue disorders: Back painb (35%, 32%), Musculoskeletal chest pain (23%, 20%), Muscle spasms (22%, 20%), Arthralgia (17%, 15%), Muscular weakness (14%, 13%), Bone pain (12%, 7%), Musculoskeletal pain (12%, 17%), Pain in extremity (8%, 14%); Infections and infestations: Upper respiratory tract infection (37%, 29%), Pneumoniab (28%, 34%), Urinary tract infectionb (10%, 17%), Sepsisb (<10%, <10%); Metabolism and nutrition disorders: Decreased appetite (23%, 19%), Hypercalcemiab (22%, 12%), Hypokalemia (12%, 12%), Hyperglycemia (11%, 15%), Hyponatremia (11%, 13%), Dehydrationb (<10%, <10%), Hypocalcemia (6%, 12%); Respiratory, thoracic and mediastinal disorders: Dyspneab (36%, 45%), Cough (17%, 22%), Epistaxis (17%, 11%), Productive cough (9%, 13%), Oropharyngeal pain (6%, 11%); Nervous system disorders: Dizziness (22%, 18%), Peripheral neuropathy (22%, 18%), Headache (15%, 13%), Tremor (10%, 13%); Skin and subcutaneous tissue disorders: Rash (21%, 16%), Pruritus (15%, 9%), Dry skin (9%, 11%), Hyperhidrosis (8%, 16%), Night sweats (5%, 13%); Investigations: Blood creatinine increasedb (19%, 10%), Weight decreased (15%, 9%), Weight increased (1%, 11%); Psychiatric disorders: Anxiety (13%, 7%), Confusional stateb (12%, 13%), Insomnia (7%, 16%); Renal and urinary disorders: Renal failureb (15%, 10%).

and publishes important resources for clinical investigators.

Past Accomplishments Dr. Young has served as President of ASCO, The American Cancer Society, and the International Gynecological Cancer Society, respectively, as well as Chairman of the NCCN Board of Directors and Chair In Trial 1, Grade 3/4 at least one adverse reaction reported in 92% of patients treated with POMALYSTa alone (N=107) and 91% with POMALYST + Low-dose Dex (N=112).* Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropeniab (48%, 41%), Anemiab (23%, 21%), Thrombocytopeniab (22%, 19%), Leukopenia (7%, 10%), Febrile neutropeniab (6%, 3%), Lymphopenia (2%, 7%); General disorders and administration site conditions: Fatigue and astheniab (12%, 17%), Edema peripheral (0%, 0%), Pyrexiab (<5%, <5%), Chills (0%, 0%); Gastrointestinal disorders: Nauseab (<5%, <5%), Constipationb (<5%, <5%), Diarrhea (<5%, <5%), Vomitingb (<5%, 0%); Musculoskeletal and connective tissue disorders: Back painb (14%, 10%), Musculoskeletal chest pain (<5%, 0%), Muscle spasms (<5%, <5%), Arthralgia (<5%, <5%), Muscular weakness (6%, 4%), Bone pain (<5%, <5%), Musculoskeletal pain (<5%, <5%), Pain in extremity (0%, <5%); Infections and infestations: Upper respiratory tract infection (<5%, <5%), Pneumoniab (20%, 29%), Urinary tract infectionb (2%, 9%), Sepsisb (6%, 5%); Metabolism and nutrition disorders: Decreased appetite (<5%, 0%), Hypercalcemiab (10%, 1%), Hypokalemia (<5%, <5%), Hyperglycemia (<5%, <5%), Hyponatremia (<5%, <5%) Dehydrationb (5%, 5%), Hypocalcemia (0%, <5%); Respiratory, thoracic and mediastinal disorders: Dyspneab (8%, 13%), Cough (0%, 0%), Epistaxis (<5%, 0%), Productive cough (0%, 0%), Oropharyngeal pain (0%, 0%); Nervous system disorders: Dizziness (<5%, <5%), Peripheral neuropathy (0%, 0%), Headache (0%, <5%), Tremor (0%, 0%); Skin and subcutaneous tissue disorders: Rash (0%, <5%), Pruritus (0%, 0%), Dry skin (0%, 0%), Hyperhidrosis (0%, 0%), Night sweats (0%, 0%); Investigations: Blood creatinine increasedb (6%, 3%), Weight decreased (0%, 0%), Weight increased (0%, 0%); Psychiatric disorders: Anxiety (0%, 0%), Confusional stateb (6%, 3%), Insomnia (0%, 0%); Renal and urinary disorders: Renal failureb (8%, 7%). * Regardless of attribution of relatedness to POMALYST. a POMALYST 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. b Serious adverse reactions were reported in at least 2 patients in any POMALYST treatment arm. Data cutoff: 01 March 2013 In Trial 2 of 450 patients who received POMALYST + Low-dose Dex (N=300) or High-dose-Dex (N=150), at least one adverse reaction was reported in 99% of patients. All Adverse Reactions ≥5% in POMALYST + Lowdose Dex arm, and at least 2% point higher than the High-dose-Dex arm included: Blood and lymphatic system disorders: Neutropeniab (51%, 21%), Thrombocytopenia (30%, 29%)a, Leukopenia (13%, 5%), Febrile neutropeniab (9%, 0%); General disorders and administration site conditions: Fatigue and asthenia (47%, 43%), Pyrexiab (27%, 23%), Edema peripheral (17%, 11%), Pain (4%, 2%)a; Infections and infestations: Upper respiratory tract infectionb (31%, 13%), Pneumoniab (19%, 13%), Neutropenic sepsisb (1%, 0%)a; Gastrointestinal disorders: Diarrhea (22%, 19%), Constipation (22%, 15%), Nausea (15%, 11%), Vomiting (8%, 4%); Musculoskeletal and connective tissue disorders: Back painb (20%, 16%), Bone Painb (18%, 14%), Muscle spasms (15%, 7%), Arthralgia (9%, 5%), Pain in extremity (7%, 6%)a; Respiratory, thoracic and mediastinal disorders: Dyspneab (25%, 17%), Cough (20%, 10%), Chronic obstructive pulmonary diseaseb (2%, 0%)a; Nervous system disorders: Peripheral neuropathy (17%, 12%), Dizziness (12%, 9%), Headache (8%, 5%), Tremor (6%, 1%), Depressed level of consciousness (2%, 0%)a; Metabolism and nutrition disorders: Decreased appetite (13%, 8%), Hypokalemia (9%, 8%)a, Hypocalcemia (4%, 6%)a;

of the National Cancer Institute (NCI) Board of Scientific Advisors. He also served as a member of the National Cancer Policy Board of the Institute of Medicine. Since 2010, Dr. Young has been a member of the NCCN Foundation Board of Directors, and he currently serves on the Board of Directors of AVEO Pharmaceuticals, Inc. n

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5.7 Dizziness and Confusional State In trials 1 and 2 in patients who received POMALYST + Low-dose Dex, 14% of patients experienced dizziness and 7% of patients experienced a confusional state; 1% of patients experienced Grade 3 or 4 dizziness, and 3% of patients experienced Grade 3 or 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.

dardized infrastructure for the conduct of clinical trials among its 26 NCCN member institutions and their community affiliates. The Oncology Research Program fosters collaboration among NCCN Member Institutions and pharmaceutical and biotechnology companies to bring promising and effective T:7” new treatments to patients with cancer

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FDA Update

FDA Approves Necitumumab Combination for Metastatic Squamous NSCLC

he FDA approved necitumumab (Portrazza) in combination with gemcitabine and cisplatin for first-line treatment of patients with metastatic squamous non–small cell lung cancer (NSCLC). Necitumumab is not indicated for treatment of nonsquamous NSCLC.

Necitumumab is a recombinant human IgG1 monoclonal antibody that

Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Cardiac disorders: Myocardial infarction, Atrial fibrillation, Angina pectoris, Cardiac failure congestive Ear and labyrinth disorders: Vertigo Gastrointestinal disorders: Abdominal pain General disorders and administration site conditions: General physical health deterioration, Non-cardiac chest pain, Multi-organ failure Hepatobiliary disorders: Hyperbilirubinemia Infections and infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis, Bacteremia, Pneumonia respiratory syncytial viral, Cellulitis, Urosepsis, Septic shock, Clostridium difficile colitis, Pneumonia streptococcal, Lobar pneumonia, Viral infection, Lung infection Investigations: Alanine aminotransferase increased, Hemoglobin decreased

citabine and cisplatin vs gemcitabine and cisplatin alone in patients with metastatic squamous NSCLC who had not received prior therapy for metastatic disease (n = 1,093). Patients received necitumumab at 800 mg by

Injury, poisoning and procedural complications: Fall, Compression fracture, Spinal compression fracture Metabolism and nutritional disorders: Hyperkalemia, Failure to thrive Nervous System disorders: Depressed level of consciousness, Syncope Psychiatric disorders: Mental status change Renal and urinary disorders: Urinary retention, Hyponatremia Reproductive system and breast disorders: Pelvic pain Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease, Pulmonary embolism, Respiratory failure, Bronchospasm Vascular disorders: Hypotension

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 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.

6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide postmarketing experience with POMALYST: Pancytopenia, tumor lysis syndrome, allergic reactions (e.g., angioedema, urticaria), elevated liver enzymes, hepatic failure (including fatal cases). 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 (e.g. ciprofloxacin and fluvoxamine) [see Dosage and Administration (2.3)]. 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. 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)] 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.

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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, 44% were aged older than 65 years, while 10% were aged older than 75 years. No overall differences in effectiveness were observed between these patients and younger patients. In these studies, patients older than 65 years were more likely than patients less than or equal to 65 years of age to experience pneumonia. 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.

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Skin and subcutaneous tissue disorders: Rash (8%, 1%), Pruritus (7%, 3%), Hyperhidrosis (5%, 1%); Investigations: Neutrophil count decreased (5%, 1%), Platelet count decreased (3%, 2%)a, White blood cell count decreased (3%, 1%)a, Alanine aminotransferase increased (2%, 1%)a, Aspartate aminotransferase increased (1%, 1%)a, Lymphocyte count decreased (1%, 1%)a; Renal and urinary disorders: Renal failure (10%, 12%)a; Injury, poisoning and procedural complications: Femur fractureb (2%, 1%)a; Reproductive system and breast disorders: Pelvic pain (2%, 2%)a. In Trial 2, Grade 3/4 at least one adverse reaction was reported in 86% of patients treated with POMALYST + Low-dose Dex (N=300) and 85% with High-dose Dex (N=150). Grade 3/4 Adverse Reactions ≥1% in POMALYST + Low-dose Dex arm, and at least 1% point higher than the High-dose-Dex arm, respectively, included: Blood and lymphatic system disorders: Neutropeniab (48%, 16%), Thrombocytopenia (22%, 26%)a, Leukopenia (9%, 3%), Febrile neutropeniab (9%, 0%); General disorders and administration site conditions: Fatigue and asthenia (9%, 12%)a, Pyrexiab (3%, 5%)a, Edema peripheral (1%, 2%)a, Pain (2%, 1%); Infections and infestations: Upper respiratory tract infectionb (3%, 1%), Pneumoniab (16%, 10%), Neutropenic sepsisb (1%, 0%); Gastrointestinal disorders: Diarrhea (1%, 1%)a, Constipation (2%, 0%), Nausea (1%, 1%)a, Vomiting (1%, 0%); Musculoskeletal and connective tissue disorders: Back painb (5%, 4%), Bone painb (7%, 5%), Muscle spasms (0%, 1%)a, Arthralgia (1%, 1%)a, Pain in extremity (2%, 0%); Respiratory, thoracic and mediastinal disorders: Dyspneab (6%, 5%), Cough (1%, 1%)a, Chronic obstructive pulmonary diseaseb (1%, 0%); Nervous system disorders: Peripheral neuropathy (2%, 1%)a, Dizziness (1%, 1%)a, Headache (0%, 0%)a, Tremor (1%, 0%)a, Depressed level of consciousness (1%, 0%); Metabolism and nutrition disorders: Decreased appetite (1%, 1%)a, Hypokalemia (4%, 3%), Hypocalcemia (2%, 1%); Skin and subcutaneous tissue disorders: Rash (1%, 0%), Pruritus (0%, 0%)a, Hyperhidrosis (0%, 0%)a; Investigations: Neutrophil count decreased (5%, 1%), Platelet count decreased (3%, 1%), White blood cell count decreased (3%, 0%), Alanine aminotransferase increased (2%, 0%), Aspartate aminotransferase increased (1%, 0%), Lymphocyte count decreased (1%, 0%); Renal and urinary disorders: Renal failure (6%, 5%); Injury, poisoning and procedural complications: Femur fractureb (2%, 1%); Reproductive system and breast disorders: Pelvic pain (1%, 0%). a Percentage did not meet the criteria to be considered as an adverse reaction for POMALYST for that category of event (i.e., all adverse events or Grade 3 or 4 adverse events). b Serious adverse reactions were reported in at least 3 patients in the POM + Low-dose Dex arm, AND at least 1% higher than the High-dose-Dex arm percentage. Data cutoff: 01 March 2013

binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands. Approval was based on the results of an open-label, multicenter, multinational, randomized trial of neciT:7” tumumab in combination with gem-

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Announcements

Amy K. Hara, MD, Named Chair of Diagnostic Radiology at Mayo–Arizona

my K. Hara, MD, has been named Chair of Diagnostic Radiology at Mayo Clinic’s Arizona campus. Dr. Hara, Professor of Radiology, joined Mayo Clinic in 2001. Her main research interests include computed tomography (CT) colonogra-

8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys. 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. 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.

viding mobile access of radiology images. Dr. Hara is a Past-Chair of the Education Exhibit Judging Committee of the Radiological Society of North America and a member of the Abdominal Imaging Committee of the American College of Radiology.

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.

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 and Arterial Thromboembolism Inform patients of the risk of developing DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Boxed Warnings and Warnings and Precautions (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 Warnings and Precautions (5.4)]. Hepatotoxicity Inform patients on the risks of developing hepatotoxicity, including hepatic failure and death, and to report signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.5)]. Hypersensitivity Inform patients of the risk for angioedema and severe skin reactions and to report any signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.6)]. 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 Warnings and Precautions (5.7)]. 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 Warnings and Precautions (5.8)]. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown [see Warnings and Precautions (5.9)]. 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 Warnings and Precautions (5.10)]. 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®, THALOMID®, and POMALYST REMS® are registered trademarks of Celgene Corporation. Pat. http://www.celgene.com/therapies © 2005-2015 Celgene Corporation All rights reserved. POM HCP Bsv.004 04/15

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)]. • 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)]. 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-Physician 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

After receiving her medical degree from the University of Missouri, she completed her diagnostic radiology residency at Mayo Clinic in Rochester,

Amy K. Hara, MD

Minnesota, and was part of the Clinical-Investigator Training Program. She completed a fellowship in abdominal imaging at Mallinckrodt Institute of Radiology at the Washington University School of Medicine in St. Louis. n

Necitumumab in NSCLC continued from page 50

intravenous infusion on days 1 and 8, gemcitabine at 1,250 mg /m2 on days 1 and 8 plus cisplatin at 75 mg/m2 on day 1 of each 3-week cycle (n = 545) or gemcitabine/cisplatin alone (n = 548).

Improved Survival Rates Necitumumab combined with gemcitabine/cisplatin demonstrated a statistically significant improvement in overall and progression-free survival vs gemcitabine/ cisplatin alone. Median overall survival was 11.5 months (95% confidence interval [CI] = 10.4–12.6) for patients assigned to necitumumab plus gemcitabine/cisplatin and 9.9 months (95% CI = 8.9–11.1) for those assigned to gemcitabine/cisplatin alone (hazard ratio [HR] = 0.84, 95% CI = 0.74–0.96, P = .01). Median progressionfree survival was 5.7 months for patients assigned to necitumumab plus gemcitabine/ cisplatin and 5.5 months for those assigned to gemcitabine/cisplatin alone (HR = 0.85, 95% CI = 0.74–0.98, P = .02). T:10”

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 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.

phy, also known as virtual colonoscopy; CT enterography; CT radiation dose; mobile imaging viewing; and dual-energy CT. Dr. Hara focuses on reducing CT radiation dose for abdominal CTs, abdominal dualenergy CT lesion characterization and asT:7”response, and prosessment of treatment

Side Effects The most common adverse reactions (all grades) observed in necitumumab-treated patients at a rate of at least 30% and at least 2% higher than the gemcitabine/cisplatin–alone arm were rash and hypomagnesemia. Serious and clinically significant adverse events included hypomagnesemia, venous and arterial thromboembolic events, dermatologic toxicities, infusion reactions, and increased toxicity and increased mortality in patients with nonsquamous NSCLC. n

The ASCO Post | DECEMBER 10, 2015

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Journal Spotlight Health-Care Disparities

Convergence of Breast Cancer Incidence but Continued Divergence of Mortality in Black Women and White Women By Matthew Stenger

n an article published in CA: A Cancer Journal for Clinicians, Carol E. DeSantis, MPH, and colleagues from the American Cancer Society reported that the incidence of breast cancer in black women has caught up to that in white women, whereas the risk of mortality continues to be higher in black women.1

Report Details Data on incidence trends, probabilities of developing cancer, and causespecific survival and mortality data were obtained from the Surveillance,

but did not change significantly in white, Hispanic, or American Indian/Alaska Native women. In 2012, rates in blacks and whites were virtually identical. During this period, incidence rates were significantly higher in black women vs white women in seven states (Alabama, Kentucky, Louisiana, Mississippi, Missouri, Oklahoma, and Tennessee), primarily located in the South. For the 5-year period, the incidence per 100,000 population was 128.1 in white women, 124.3 in black women, 91.9 in American Indian/Alaska Native women, 91.9 in Hispanic women, and 88.3

Widening racial disparities in breast cancer mortality are likely to continue, at least in the short term, in view of the increasing trends in breast cancer incidence rates in black women. —Carol E. DeSantis, MPH, and colleagues

Epidemiology, and End Results (SEER) program. Incidence rates by race/ethnicity, stage at diagnosis, and hormone receptor and HER2 status as well as incidence rates by state were obtained using data from the North American Association of Central Cancer Registries. Prevalence data on mammography by race/ethnicity and state were obtained from the 2012 Behavioral Risk Factor Surveillance System.

Incidence Approximately 231,840 new cases of invasive breast cancer and 40,290 breast cancer deaths are expected to occur among U.S. women in 2015, along with 60,290 new diagnoses of in situ breast cancer. From 2008 to 2012, breast cancer incidence rates increased by 0.4% per year in black women and by 1.5% per year in Asian/Pacific Islander women

in Asian/Pacific Islander women. The authors noted that the increase in incidence in black women has been driven by an increase in estrogen receptor–positive breast cancers and that this trend may reflect the increasing rate of obesity in black women—from 39% in 1999 through 2002 to 58% in 2009 through 2012. High recent body mass index has been associated with significantly increased risk of estrogen receptor–positive breast cancer in black women.

Stage at Diagnosis Stage distribution data for 2012 show that whites and Asians/Pacific Islanders had the highest proportions of localized breast cancers (64% and 63%, respectively) and the smallest proportions of regional (28% and 30%) and distant (5% and 5%) disease. Black women had the smallest proportion of

Racial Disparities in Breast Cancer ■■ Breast cancer incidence in black women converged with that in white women in 2012. ■■ Breast cancer mortality remains higher in black women.

localized breast cancers (53%) and the highest proportions of regional (35%) and distant (8%) disease. For localized, regional, and distant disease, respectively, proportions were 56%, 34%, and 6% among Hispanic women and 57%, 32%, and 6% among American Indians/Alaska Natives.

Receptor Status In 2012, black women had the highest proportion of triple-negative cases and the lowest proportion of hormone receptor–positive/HER2-negative cases. Proportions of cases that were hormone receptor–positive/HER2negative, hormone receptor–positive/ HER2-positive, triple-negative, and hormone receptor–negative/HER2positive were 76%, 10%, 11%, and 4% in white women, 62%, 11%, 22%, and 5% in black women, 71%, 12%, 12%, and 5% in Hispanic women, and 72%, 11%, 10%, and 7% in Asian/Pacific Islander women.

Mortality From 1989 to 2012, breast cancer death rates decreased by 36%, with this decrease being evident in all racial/ethnic groups except American Indians/ Alaska Natives. From 2003 through 2012, breast cancer mortality declined annually by 1.8% in whites, 1.5% in Hispanics, 1.4% in blacks, and 1.0% in Asians/Pacific Islanders but remained unchanged among American Indians/ Alaska Natives. A divergence in mortality between black and white women emerged in the early 1980s and has since continued to

widen, such that the mortality rate was 42% higher in black women in 2012. For 2008 to 2012, mortality per 100,000 was 21.9 in whites, 31.0 in blacks, 15.0 in American Indians/Alaska Natives, 14.5 in Hispanics, and 11.4 in Asians/ Pacific Islanders. The authors noted that the mortality difference between black women and white women likely reflects a combination of factors, including differences in incidence rates, stage at diagnosis, tumor characteristics, obesity, and comorbidities, as well as differences in access, adherence, and response to appropriate treatments, differences in quality of mammography screening, and delayed follow-up for abnormal mammography findings. In 2012, proportions of women aged ≥ 45 years with mammography within the past 2 years ranged by state from 66% to 86% among white women and from 68% to 89% among black women (in 34 states with sufficient sample sizes to permit estimates). The authors concluded: “Widening racial disparities in breast cancer mortality are likely to continue, at least in the short term, in view of the increasing trends in breast cancer incidence rates in black women.” n

Disclosure: The authors reported no potential conflicts of interest.

Reference 1. DeSantis CE, Fedewa SA, Goding Sauer A, et al: Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J Clin. October 29, 2015 (early release online).

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | DECEMBER 10, 2015

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Perspective

Reducing Racial Disparities in Breast Cancer Incidence and Mortality Trends to Improve Outcomes By Graham A. Colditz, MD, DrPH

recent report by DeSantis and colleagues from the American Cancer Society, summarized in this issue of The ASCO Post, presented breast cancer incidence and mortality data from an extensive analysis

at diagnosis, are the predominant mediators for the excess mortality among black women. The distribution of tumor characteristics in these national data further supports the fact that these features likely account for

Given the direct relation of obesity to poor survival after breast cancer diagnosis, a far greater focus on maintaining a healthy weight across all racial/ethnic groups is essential to further reduce disparities in incidence and also improve outcomes after diagnosis. —Graham A. Colditz, MD, DrPH

of the U.S. system of state-based tumor registries.1 The data showed that the incidence of breast cancer is increasing among non-Hispanic black women and has now approached and equaled that of white women. Historically, non-Hispanic black women had a lower incidence of breast cancer and higher mortality.

Impact of Tumor Characteristics With mammography more evenly used across race/ethnic groups, the incidence of breast cancer has converged. However, the excess proportion of triple-negative breast cancer in black women is quite remarkable. These tumors with limited effective treatment options accounted for 10% of breast cancers among non-Hispanic white women yet 22% among nonHispanic black women. Detailed analysis of data from the National Comprehensive Cancer Network system has previously shown that tumor characteristics such as triple-negative status, as well as stage Dr. Colditz is Associate Director, Prevention and Control, Siteman Cancer Center, Washington University School of Medicine and Barnes-Jewish Hospital, St Louis.

a substantial portion of the mortality excess. Among postmenopausal women, obesity is directly related to poorer outcomes, and the distribution of obesity in the U.S. population, with higher prevalence among nonHispanic black women, is an additional driver of the excess mortality.

Gap in Mortality From 1995 onward, the decline in mortality among non-Hispanic black women has paralleled the decline observed among white women when absolute age-adjusted mortality rates are plotted. That is to say, the reduction over almost 20 years is approximately 10 deaths/100,000 women/year in both groups of women. Progress is being made, but the gap in mortality has not been reduced in absolute terms— Non-Hispanic black women have approximately 8 excess breast cancer deaths/100,000 women compared with non-Hispanic white women.

Substantial Variation Among States The authors also summarized the evidence for mammography use as the likely equalizer to bring incidence rates together. Clearly, reproductive factors and obesity also contribute to

the incidence of breast cancer. There remains substantial variation among states in the proportion of women aged > 45 years who report having a mammogram in the previous 2 years. Within the states with data specific for African American women, there is also substantial variation, with differences of up to 20% between states (68% up to 89%). Access to health services and their use for detection, diagnosis, and subsequent treatment are not equitably distributed within the United States. Rectifying this unequal access must be among our highest priorities to reduce disparities in breast cancer mortality.

Weight Gain and Obesity The excess risk of triple-negative disease among non-Hispanic black women in these national data offers insight to one of the drivers for the excess mortality. Identifying more effective treatment strategies for these women remains a high priority. One might ask why there is an excess of estrogen receptor–negative or triplenegative disease. A recent prospective cohort data analysis addressing short-term weight change showed that in both premenopausal and postmenopausal women, substantial short-term weight gain is directly associated with estrogen receptor–negative breast cancer. For example, in the Nurses’ Health Study, weight gain over 4 years was more strongly related to premenopausal breast cancer incidence than to postmenopausal breast cancer incidence. Among premenopausal women, short-term weight gain was associated with an increased risk of estrogen receptor–negative disease.2 European prospective data confirmed the greater adverse effect of short-term weight gain among premenopausal women.3 National data show higher levels of obesity among non-Hispanic black women at each obesity class level than among non-Hispanic white women. For example, National Health and Nutrition Examination Survey data from

2007– 2012 showed that body mass index was 30– 34.9 kg/m2 in 26.03% of non-Hispanic black women, 35– 39.9 kg/m2 in 13.45%, and ≥ 40 kg/ m2 in 17.30%. In contrast, the corresponding figures for non-Hispanic white women were 17.58%, 9.37%, and 6.98%, respectively.4 Systematic review and meta-analysis of 82 studies revealed unequivocally that obesity at breast cancer diagnosis is significantly related to excess breast cancer mortality and total mortality.5 Greater weight gain during the premenopausal years in non-Hispanic black women resulted in the obesity prevalence numbers and drove the excess breast cancer risk. Given the direct relation of obesity to poor survival after breast cancer diagnosis, a far greater focus on maintaining a healthy weight across all racial/ethnic groups is essential to further reduce disparities in incidence and also improve outcomes after diagnosis. n Disclosure: Dr. Colditz reported no potential conflicts of interest.

References 1. DeSantis CE, Fedewa SA, Goding Sauer A, et al: Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J Clin. October 29, 2015 (early release online). 2. Rosner B, Eliassen AH, Toriola AT, et al: Short-term weight gain and breast cancer risk by hormone receptor classification among pre- and postmenopausal women. Breast Cancer Res Treat 150:643-653, 2015. 3. Emaus MJ, van Gils CH, Bakker MF, et al: Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study. Int J Cancer 135:2887-2899, 2014. 4. Yang L, Colditz GA: Prevalence of overweight and obesity in the United States, 2007-2012. JAMA Intern Med 175:1412-1413, 2015. 5. Chan DS, Vieira AR, Aune D, et al: Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 25:1901-1914, 2014.

The ASCO Post | DECEMBER 10, 2015

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Perspective

Closing the Racial Survival Disparity Gap in Breast Cancer: Models for Change From Chicago, New York, and Beyond By Bobby Daly, MD, MBA, and Olufunmilayo I. Olopade, MD, FACP, OON

t has long been said that white women of European ancestry are more likely to be diagnosed with breast cancer, but African American women are more likely to die of it. This statement has introduced multiple articles on the topic of the racial survival disparity in breast cancer, including our own recent analysis.1 However, this assertion no longer holds true. Recent work by DeSantis et al2 employing the Surveillance, Epidemiology, and End Results (SEER) program, summarized in this issue of The ASCO Post, has found that the 2012 incidence of breast cancer in white and African American women is now equivalent at 135 cases/100,000 women. The import of this convergence of incidence is its effect on breast cancer mortality and the racial survival chasm. The mortality disparity between African American and white women has continued to increase, with a death rate 42% higher in African American than white patients in 2012. In their analysis, DeSantis et al underscored positive trends and noted the remarkable strides in breast cancer screening and treatment, with a decrease in breast cancer mortality by 36% from 1989–2012—representing 249,000 breast cancer deaths averted in U.S. women. Examples of treatment breakthroughs include HER2-targeted therapies that benefit both white and African American women, who have a similar incidence of HER2positive tumors. However, although breast cancer death rates declined in both African American and white women, the long-term breast cancer mortality gap between these groups continues to widen.2

Survival and Research Differences When examined geographically, these survival differences are striking. Hunt et al3 looked at the racial disparity in breast cancer mortality for the 50 largest U.S. cities using rate ratios. (A rate ratio of 1.00 indicates no disparDr. Daly is a medical oncology fellow and Dr. Olopade is Director, Center for Clinical Cancer Genetics, University of Chicago Medical Center.

ity between black and white mortality rates, whereas a ratio greater than 1.00 indicates the black mortality rate is higher than the white mortality rate.) For example, in a stark contrast to New York, with a rate ratio of 1.19, Memphis had a rate ratio of 2.11. Of the 41 cities included in the analysis, 35 saw an increase in the black:white rate ratio between 1990–1994 and 2005–2009. Contributing to the survival disparity is a confluence of factors that has been discussed in the literature; but where is the medical establishment with regard to interventions to close this disparity gap? Lurie succinctly put it in the title of an editorial in The New England Journal of Medicine: “Health Dispari-

ducing disparities in their care rather than creating system interventions aimed at delivering more equitable care to patients. It has been argued that successful health disparities interventions are those that are multifaceted and address multiple stakeholders in the continuum of care. As Chin et al6 wrote, successful health disparities interventions are “culturally tailored to meet patients’ needs, employ multidisciplinary teams of care providers, and target multiple leverage points along a patient’s pathway of care.”

Making Strides in Chicago An illustrative case is that of patients with breast cancer in Chicago,

There is an opportunity to close the survival disparity gap by focusing on changes to the healthcare system—not to the individual patient—to improve the quality of care for minority populations. —Bobby Daly, MD, MBA, and Olufunmilayo I. Olopade, MD, FACP, OON

ties—Less Talk, More Action,” emphasizing that “those of us within the health care system need to test and implement effective strategies for the reduction of disparities.”4 Clarke et al5 attempted to answer this question in their article examining 30 years of disparities intervention research. The authors’ systematic scan of the disparities intervention literature found that interventions targeting providers (7%), the microsystem (immediate care team; 9%), organizations (3%), and policies (0.1%) were lacking, whereas the interventions employed most commonly targeted the patient (50%). Thus, most interventions charged patients with re-

where a system-wide intervention succeeded in making strides to close the breast cancer racial survival disparity. Hirschman et al7 examined the racial disparity in breast cancer mortality in Chicago in 2003 and found that African American women had a 68% higher breast cancer mortality rate than white women. The authors’ hypothesis was that the disparities in breast cancer mortality were due to “differential access to mammography, differential quality in mammography, and differential access to treatment for breast cancer.” The study sparked a conflagration of community effort in Chicago to address this disparity.8

A total of 102 individuals from 74 Chicago area organizations participated in the Metropolitan Chicago Breast Cancer Task Force. The Task Force found that “facilities that served predominantly minority women were less likely to be academic or private institutions (P < .03), less likely to have digital mammography (P < .003), and less likely to have breast imaging specialists reading films (P < .003).”8 In addition, African American women and their providers reported significant barriers to accessing quality care for breast cancer treatment. The objective of the Task Force was to improve the quality of care delivered to minority patients from screening to treatment through follow-up. These initiatives included a cohesive and comprehensive patient navigation project to improve access to quality cancer care; a Mammography Quality Initiative to improve the quality of mammography for women statewide; public policy work to advocate for the Illinois Breast and Cervical Cancer program, which provides screening and treatment for uninsured women; and community organizing to engage and build relationships with grassroots organizations and academic health-care institutions.9 To date, the Task Force has been successful in reversing the trend of growing disparity and decreasing the mortality gap to 40%, attributed to a pronounced reduction in mortality for African American women. Other system-wide interventions to reduce the racial survival disparity in cancer care have met with success in New York10 and Delaware.11

Improving Access to Endocrine Therapy As system-wide approaches are considered to address this survival disparity, health-care leaders must consider interventions that improve access to endocrine therapy. DeSantis et al noted that the increase in incidence in African American woman has been driven largely by an increase in estrogen receptor– positive breast cancers.2 Oral endocontinued on page 61

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Perspective

Bobby Daly, MD, MBA Olufunmilayo Olopade, MD

Changes to the Health-Care System

continued from page 54

As the example of Chicago demonstrates, there is an opportunity to close the survival disparity gap by focusing on changes to the healthcare system—not to the individual patient—to improve the quality of care for minority populations. With the noted decline in the rates of breast cancer mortality, DeSantis et al give us much reason to hope there will be continued innovation in breast cancer screening and treatment; as these improvements arrive, we must ensure there is equity of dissemination. The convergence of the incidence lines should serve as a further call for stakeholders across the continuum of breast cancer care to continue to support rigorous research to inform policy and improve on the models for system change demonstrated in Chicago, New York, and elsewhere. n

crine therapy has been demonstrated in clinical trials to be effective in preventing breast cancer recurrence and death in women with early-stage breast cancer.12 However, in a large study examining the days covered by filled prescriptions of tamoxifen in the first year of therapy for primary breast cancer patients, Partridge et al13 found that nonwhite patients had significantly lower adherence rates than white patients (odds ratio = 1.62, 95% confidence interval = 1.26–2.09). More research in this area will be needed to understand the barriers to endocrine therapy for African American patients, including financial toxicity assessments, to ensure they have access to these lifesaving treatments. In addition, the authors contended that the surge in estrogen receptor–positive breast cancer might reflect changes in lifestyle, including rising obesity and metabolic syndrome in U.S. women. This would be a modifiable risk factor, and health policy aimed at promoting exercise and nutrition could reverse this trend.

Disclosure: Dr. Daly serves on the Board of Directors for and received compensation from Quadrant Healthcare. Dr. Olopade has served on the Medical Advisory Board for CancerIQ.

References 1. Daly B, Olopade OI: A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in

breast cancer and proposed interventions for change. CA Cancer J Clin 65:221238, 2015. 2. DeSantis CE, Fedewa SA, Goding Sauer A, et al: Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J Clin. October 29, 2015 (early release online). 3. Hunt BR, Whitman S, Hurlbert MS: Increasing black:white disparities in breast cancer mortality in the 50 largest cities in the United States. Cancer Epidemiol 38:118-123, 2014. 4. Lurie N: Health disparities—Less talk, more action. N Engl J Med 353:727729, 2005. 5. Clarke AR, Goddu AP, Nocon RS, et al: Thirty years of disparities intervention research: What are we doing to close racial and ethnic gaps in health care? Med Care 51:1020-1026, 2013. 6. Chin MH, Clarke AR, Nocon RS, et al: A roadmap and best practices for organizations to reduce racial and ethnic disparities in health care. J Gen Intern Med 27:992-1000, 2012. 7. Hirschman J, Whitman S, Ansell D: The black:white disparity in breast cancer mortality: The example of Chicago. Cancer Causes Control 18:323-333, 2007. 8. Ansell D, Grabler P, Whitman S, et al: A community effort to reduce the black/white breast cancer mortality dis-

parity in Chicago. Cancer Causes Control 20:1681-1688, 2009. 9. Metropolitan Chicago Breast Cancer Task Force: Beyond October how far have we come? Breast cancer disparities: Improving access to and quality of breast health services in Chicago. October 2014. Available at http:// www.chicagobreastcancer.org/site/ files/904/93199/353837/718237/ State_of_Breast_Cancer_Disparties_ Report_Final_11.pdf. Accessed November 24, 2015. 10. Bickell NA, Shastri K, Fei K, et al: A tracking and feedback registry to reduce racial disparities in breast cancer care. J Natl Cancer Inst 100:1717-1723, 2008. 11. Grubbs SS, Polite BN, Carney J Jr, et al: Eliminating racial disparities in colorectal cancer in the real world: It took a village. J Clin Oncol 31:1928-1930, 2013. 12. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320:479-484, 1989. 13. Partridge AH, Wang PS, Winer EP, et al: Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 21:602-606, 2003.

Announcements

NIH Awards City of Hope $2.2 Million Grant for Investigation of Chronic Graft-vs-Host Disease

he National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) has awarded a $2.2 million grant to help City of Hope researchers explore the underlying mechanisms of graftvs-host disease, the leading cause of long-term sickness and death following transplantation of bone marrow cells from a donor. The grant, awarded to Defu Zeng, MD, Professor of Diabetes Immunology and Hematopoietic Cell Transplantation at the Beckman Research Institute of City of Hope, will be used by researchers to study the interactions of T cells and B cells during the development of graft-vs-host disease. “If successful, this research will provide new insights into the mechanisms

The proposed studies will provide new insights into how donor CD4positive T and B cells interact to induce and perpetuate chronic [graft-vshost disease], and will lead to the development of novel regimens for prevention and treatment of chronic [graft-vs-host disease]. —Defu Zeng, MD

of chronic [graft-vs-host disease] development and may identify targets to prevent autoimmunity,” Dr. Zeng said. Dr. Zeng is a leader in the field of treating autoimmune diseases

through the induction of mixed chimerism, in which donor cells are transplanted into a patient with mild conditioning, such that donor and patient immune cells and blood cells

coexist harmoniously without causing graft-vs-host disease. He is also an expert in designing mouse models of chronic graft-vs-host disease that reflect the development of the diseases in humans. Using these mice, Dr. Zeng and his team have shown that disruption of interactions between donor T and B cells can prevent chronic graftvs-host disease; the grant will allow them to expand on that work. “The proposed studies will provide new insights into how donor CD4-positive T and B cells interact to induce and perpetuate chronic [graftvs-host disease], and will lead to the development of novel regimens for prevention and treatment of chronic [graft-vs-host disease],” Dr. Zeng concluded. n

i am proof of extended survival in newly diagnosed GBM

Actor portrayal

Optuneâ&#x201E;˘ is intended as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM). Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery, and completion of radiation therapy together with concomitant standard of care chemotherapy. Optune was studied in the EF-14 trial, a prospective, international, multicenter, open-label, randomized, controlled, phase 3 trial in newly diagnosed GBM patients comparing Optune + TMZ with TMZ alone (N=700). The prespecified interim analysis occurred when the first 315 patients completed 18 months of follow-up. The primary endpoint was PFS (ITT); OS (per protocol) was a powered secondary endpoint; 1- and 2-year survival rates, PFS6, QoL, and radiological response rates, along with safety, were also secondary endpoints. The final analysis included all patients randomized to EF-14 who had CRF information available at the database cutoff of December 3, 2014. This included 695 of the 700 patients randomized at that time: 466 patients in the Optune + TMZ arm and 229 patients in the TMZ-alone arm.1,2

Please see the following Summary of Important Safety Information for Optune and visit www.Optune.com/IFU for Optune Instructions for Use for complete information regarding the deviceâ&#x20AC;&#x2122;s indication, contraindications, warnings and precautions. CI, confidence interval; CRF, case report form; GBM, glioblastoma; HR, hazard ratio; ITT, intent to treat; OS, overall survival; PFS, progression-free survival; PFS6, progression-free survival at 6 months; QoL, quality of life; TMZ, temozolomide. References: 1. Optune Instructions for Use. Novocure 2015. 2. Novocure Data on File. OPT-103.

Optune + TMZ significantly extended median overall survival by 4.9 months and median PFS by 3.2 months 1 20.5 months median OS with Optune + TMZ1

Fraction Survival

Overall Survival (interim analysis)1 1.0

Median OS from randomization (months)1

0.9

Log-rank P-value1

0.0042

HR (95% CI)1

0.666 (0.495-0.898)

0.8

Optune + TMZ

0.7

20.5 MONTHS

0.6 0.5

20.5

Median OS from diagnosis (months)2

Median OS

24.4

15.6

19.4

Per Protocol population

0.4

TMZ alone

Optune + TMZ (n=196)

0.3

15.6

TMZ alone (n=84)

MONTHS

0.2 0.1 + Censored

0.0 0

Overall Survival (months)

* In the final analysis (n=695), Optune + TMZ extended median OS by 4.4 months, and this was consistent with the interim analysis (n=315).1

Overall Survival (months)

Median PFS improved by >3 months with Optune + TMZ1

Fraction Survival

Progression-free Survival (interim analysis)1 1.0

Median PFS from randomization (months)1

7.2

0.9

Log-rank P-value1

0.0013

HR (95% CI)1

0.621 (0.468-0.823)

0.8

Optune + TMZ

0.7

7.2 MONTHS

0.6 0.5

Median PFS from diagnosis (months)2

Median PFS

0.4

TMZ alone

0.3

4.0

11.0

4.0

Median time from diagnosis to randomization was

7.8

3.8 months1

ITT population

Optune + TMZ (n=210) TMZ alone (n=105)

MONTHS

0.2 0.1

â&#x20AC;

+ Censored

0.0 0

Progression-free Survival (months)

In the final analysis (n=695), Optune + TMZ extended median PFS by 2.9 months, and this was consistent with the interim analysis (n=315).1

Progression-free Survival (months)

SELECTED SAFETY INFORMATION Do not use Optune in patients with an active implanted medical device, a skull defect (such as, missing bone with no replacement), or bullet fragments. Use of Optune together with implanted electronic devices has not been tested and may theoretically lead to malfunctioning of the implanted device. Use of Optune together with skull defects or bullet fragments has not been tested and may possibly lead to tissue damage or render Optune ineffective. Learn more at Optune.com ÂŠ2015 Novocure. All rights reserved. Optune and Novocure are trademarks of Novocure. OPT-117

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The ASCO Post | DECEMBER 10, 2015

Expert’s Corner INDICATIONS FOR USE Optune™ is intended as a treatment for adult patients (22 years of age or older) with histologicallyconfirmed glioblastoma multiforme (GBM). Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery, and completion of radiation therapy together with concomitant standard of care chemotherapy.

Health-Care Disparities

Understanding Health-Care Disparities Among Lesbian, Gay, Bisexual, and Transgender Patients to Ensure More Effective Cancer Care

A Conversation With Matthew B. Schabath, PhD By Jo Cavallo

SUMMARY OF IMPORTANT SAFETY INFORMATION Contraindications Do not use Optune in patients with an active implanted medical device, a skull defect (such as, missing bone with no replacement), or bullet fragments. Use of Optune together with implanted electronic devices has not been tested and may theoretically lead to malfunctioning of the implanted device. Use of Optune together with skull defects or bullet fragments has not been tested and may possibly lead to tissue damage or render Optune ineffective. Do not use Optune in patients that are known to be sensitive to conductive hydrogels. In this case, skin contact with the gel used with Optune may commonly cause increased redness and itching, and rarely may even lead to severe allergic reactions such as shock and respiratory failure. Warnings and Precautions Optune can only be prescribed by a healthcare provider that has completed the required certification training provided by Novocure (the device manufacturer). Do not prescribe Optune for patients that are pregnant, you think might be pregnant or are trying to get pregnant, as the safety and effectiveness of Optune in these populations have not been established. The most common (≥10%) adverse events involving Optune in combination with temozolomide were thrombocytopenia, nausea, constipation, vomiting, fatigue, medical device site reaction, headache, convulsions, and depression. Use of Optune in patients with an inactive implanted medical device in the brain has not been studied for safety and effectiveness, and use of Optune in these patients could lead to tissue damage or lower the chance of Optune being effective. If the patient has an underlying serious skin condition on the scalp, evaluate whether this may prevent or temporarily interfere with Optune treatment. Please see the Optune Instructions for Use (IFU) for complete information regarding the device’s indication, contraindications, warnings, and precautions at Optune.com/IFU.

Matthew B. Schabath, PhD

new study examining the healthcare needs of lesbian, gay, bisexual, and transgender/transsexual patients has found myriad disparities in access to cancer care.1 The researchers reviewed nearly 170 papers published over the past 15 years on the healthcare needs among this population. Although the majority of studies focused on family systems, human immunodeficiency virus/acquired immunodeficiency syndrome prevention and maintenance, and overall health, there have been limited efforts to systematically identify and address disparities in care across the cancer continuum, including prevention strategies, early detection, diagnosis, treatment, survivorship, and end-of-life care. To understand the impact of cancer on this medically underserved population, the researchers concentrated their efforts on seven cancer types that may disproportionately affect lesbian, gay, bisexual, and transgender/transsexual patients, including anal, breast, cervical, colorectal, endometrial, lung, and prostate cancers. Their findings showed significant disparities in both income and health-care equality and in medical outcomes compared with heterosexuals and are highlighted here: Lesbian, gay, bisexual, and transgender/transsexual individuals tend to have lower incomes, which impact their ability to access health insurance, and are less satisfied with their standard of living than heterosexuals. Health and utilization of health-care services among lesbian, gay, bisexual, and transgender/transsexual individu-

als are adversely affected by marginalization; and about 30% of lesbian, gay, bisexual, and transgender/transsexual adults do not seek health-care services or lack a regular health-care provider compared with 10% of heterosexual adults. Lesbian, gay, bisexual, and transgender/transsexual individuals experience significant barriers to accessing health care due to health insurance costs, fear of stigmatization, and a lack of trust in the physician-patient relationship—Patients fear they may receive substandard care or risk a breech in confidentiality if they disclose their sexual orientation or gender identity. Members of some lesbian, gay, bisexual, and transgender/transsexual subgroups have a higher incidence and mortality rates of certain cancers, including a higher incidence of anal cancer in men, lung cancer in both men and women, and breast and cervical cancers in lesbian and bisexual women. Implementing local, state, federal, and institutional policies that include lesbian, gay, bisexual, and transgender/transsexual populations; improving the mechanism for lesbian, gay, bisexual, and transgender/transsexual–related research, such as collecting and analyzing gender identity and sexual orientation data in cancer clinical trials; and including sexual orientation and gender identity questions on national population surveys and registries, such as the Surveillance, Epidemiology, and End Results (SEER) Program cancer registries, will help identify the demographics and disparities of this population and reveal gaps in cancer care, according to Matthew B. Schabath, PhD, senior author of the Cancer and Lesbian, Gay, Bisexual, Transgender/ Transsexual, and Queer/Questioning populations study. According to the latest estimates from the Centers for Disease Control and Prevention,2 3.4% of the population in the United States identifies as lesbian, gay, bisexual, and transgender/transsexual. Other studies put the

ASCOPost.com | DECEMBER 10, 2015

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Expert’s Corner

number between 3% and 12%.3 The ASCO Post talked with Dr. Schabath, Assistant Member of the Cancer Epidemiology Program at Moffitt Cancer Center in Tampa, Florida, about his research findings; why lesbian, gay, bisexual, and transgender/transsexual individuals may be at greater risk for certain cancers; and how to reduce health disparities and improve cancer care for this patient population.

Research Obstacles What were your biggest obstacles in researching the cancer health disparities in the lesbian, gay, bisexual, and transgender/transsexual population? In our study, we reference nearly 170 papers on the health of sexual minorities, but we reviewed close to 500 studies to get the 170 that we used. The most staggering problem we found is that the amount of research on sexual minorities is sparse, and the data in local or national databases are not well captured.

A Population at Risk Your study found higher incidences of certain cancer types, including anal, lung, breast, and cervical cancers, in the lesbian, gay, bisexual, and transgender/transsexual community. Do you know why these cancers are more prevalent in this population than in the heterosexual population? There are many contributing factors that add incremental levels of health risk to this population. We found that engaging in risky lifestyle behaviors, such as smoking, consuming excessive amounts of alcohol, having unprotected sex, and being overweight or obese, tends to happen more often in the lesbian, gay, bisexual, and transgender/transsexual population. Also, on average, this population tends to have lower incomes, and as a result many do not have health insurance and are unable to see a physician for regular checkups, mental health services, hormone therapy, or gender-affirmation surgery. Not be-

ing able to find a physician who is part of this community or who is knowledgeable about this population also discourages and delays care. Another risk factor is a lack of knowledge about cancer prevention screening strategies. For example, because a lesbian woman is not having sexual intercourse with a man, she might think she is not at risk for cervical cancer and so not have regular Pap tests. Or a gay man might not know he is at increased risk for anal warts, which increases his risk for anal cancer, and have unprotected sex.

believe all patients should be treated the same, regardless of their sexual status or gender identity, and we disagree because we do find differences in cancer risk and outcome in the lesbian, gay, bisexual, and transgender/transsexual population. Our study sheds light on the fact that this is a true health-disparities minority group, and oncologists need to be more aware of the uniqueness of this population. Sexual orientation and gender identity questions should be part of healthcare provider intakes, clinical trials, and academic research. As part of their

By identifying and addressing the health needs of lesbian, gay, bisexual, and transgender/transsexual patients, we can reduce health disparities and make a positive difference in their lives.” —Matthew B. Schabath, PhD

In addition, health-care providers may not realize the increased risk for anal cancer in gay men and administer secondary prevention methods such as an anal Pap test or a digital rectal exam to detect precancerous and cancerous lesions. Also, the human papillomavirus is transmitted through gay and lesbian and heterosexual sex, so these cases are examples where sexual minorities may be at greater risk for certain cancers. It is a combination of behavior, psychosocial status, and social economic status that contributes to higher risk and higher rates of cancer in this population. I also want to make clear that we are not saying that the elevated risk exists just in the seven cancers we mentioned in our study. These were the cancers that we could find enough data on to discuss with some certainty.

A Different Approach Needed What can the oncology community do to improve the care of lesbian, gay, bisexual, and transgender/transsexual patients? We have data that show oncologists

care, oncologists should ask patients about their preferences, concerns, and needs regarding treatment plans and end-of-life care and acknowledge the medical rights of not just the patients, but their partners and family members as well. This is an especially vulnerable population, and there needs to be greater awareness by the medical profession of the physical, emotional, and financial needs of the lesbian, gay, bisexual, and transgender/transsexual population.

Advocating for Change What institutional changes would you like to see made to improve the cancer care of lesbian, gay, bisexual, and transgender/ transsexual patients? We are advocating for several changes. To begin, it would be helpful for health insurers to incorporate a link on their provider directory to the Gay and Lesbian Medical Association’s database of physicians (glma. org), which would give patients an option to seek care from a lesbian, gay,

bisexual, and transgender/transsexual–friendly physician. Implementing local, state, federal, and institutional policies that reduce social disparities by being more sensitive to the needs and concerns of lesbian, gay, bisexual, and transgender/transsexual individuals would also help improve health outcomes. And including sexual orientation and gender identity information in electronic health records is essential to provide a foundation for understanding the status and needs of this population. Finally, in addition to including sexual orientation and gender identity questions on population surveys and cancer registries such as SEER and capturing the information in electronic health records, we also need to increase lesbian, gay, bisexual, and transgender/transsexual–related research to eliminate health-care disparities and design interventions for their specific issues. By identifying and addressing the health needs of lesbian, gay, bisexual, and transgender/transsexual patients, we can reduce health disparities and make a positive difference in their lives. n Disclosure: Dr. Schabath reported no potential conflicts of interest.

References 1. Quinn GP, Sanchez JA, Sutton SK, et al: Cancer and lesbian, gay, bisexual, transgender/transsexual, and queer/questioning (LGBTQ) populations. CA Cancer J Clin 65:384-400, 2015. 2. Ward BW, Dahlhamer JM, Galinsky AM, et al: Sexual orientation and health among U.S. adults: National health interview survey, 2013. Natl Health Stat Rep 77:1-10, 2014. 3. Gates GJ: How many people are lesbian, gay, bisexual and transgender? The Williams Institute, University of California, Los Angeles, School of Law; 2011. Available at http://williamsinstitute.law. ucla.edu/research/census-lgbt-demographics-studies/how-many-people-arelesbian-gay-bisexual-and-transgender/. Accessed November 24, 2015.

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The ASCO Post | DECEMBER 10, 2015

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Expert’s Corner Palliative Care

Evidence-Based Practice Needed in End-of-Life Care By Ronald Piana

Scott D. Halpern, MD, PhD

vidence-based oncology practice is a systematic approach to problem solving for cancer care providers, characterized by the use of the best evidence currently available for clinical decisionmaking. Over the past several decades, the oncology community, led by its major organizations such as ASCO and the National Comprehensive Cancer Network, has advanced the implementation of guidelines and other assessment tools to further integrate solid clinical evidence into daily practice, from diagnosis to treatment. However, the delivery of equitable, high-quality end-of-life care has suffered from a lack of study-based evidence. To shed light on this important issue, The ASCO Post recently spoke with Scott D. Halpern, MD, PhD, a nationally recognized expert in evidence-based endof-life care. He is Associate Professor of Medicine, Epidemiology, and Medical Ethics and Health Policy at the University of Pennsylvania, where he also is a practicing critical care physician. In addition, Dr. Halpern is the founding Director of the Fostering Improvement in End-of-Life Decision Science (FIELDS) program—the nation’s only research program devoted to applying principles of behavioral economics to improve treatment decisions made by seriously ill patients, their families, and clinicians.

Partners in Research Do you believe the private and public sectors can partner in a meaningful

way to improve end-of-life care? The incentives are unusually well aligned for partnerships between academic settings and large organizations such as health systems, insurers, or other risk-bearing entities. This is true because academics are interested in conducting research that will be highly impactful, which often requires large and generalizable samples of people to study. At the same time, public and private organizations that are responsible for health care for many Americans are interested in implementing programs that are most likely to result in the highest-possible value of the health care they support.

Advance Care Planning Please give an example(s) of initiatives or programs not backed by evidence that they improve patient outcomes. The most recent and important example is the Centers for Medicare & Medicaid Services (CMS) decision to reimburse physicians for documenting that they have spoken to patients about advance care planning. There is no high-quality evidence that advance care planning actually improves patient outcomes and no evidence at all that

Hopefully, the more general provisions for sustainable health insurance will facilitate and support a future health-care system that more actively seeks to develop, test, and implement evidence-based approaches to all kinds of care. —Scott D. Halpern, MD, PhD

modest payments to physicians will achieve these goals. However, the same dearth of evidence applies to virtually all proposed interventions, with the lone exception being outpatient palliative care consultation for patients with certain types of cancer—there is an increasingly robust evidence base that this truly benefits such patients. The CMS has recently announced plans to reimburse physicians for time spent engaged in advance planning discussions with their patients. Some say this is based more on economics than care. What’s your opinion? I disagree with the view that the recent CMS decision was motivated by the potential for cost savings. The current CMS leaders are incredibly committed to improving quality, first and foremost. I am highly skeptical that this

The IOM Report’s Challenges for Evidence-Based End-of-Life Care ■■ The increasing number of elderly Americans, including those with some combination of frailty, significant physical and cognitive disabilities, and multiple chronic illnesses ■■ The growing cultural diversity in the U.S. population, which makes it essential for clinicians to have the evidence needed to address a multicultural patient population ■■ Structural barriers in access to care that disadvantage certain population groups; ■■ Failure of the availability of palliative care services to keep pace with the growing demand ■■ Wasteful and costly systemic problems, including perverse incentives, a fragmented-care delivery system, and a lack of service coordination across programs ■■ The resulting unsustainable growth in costs of the current health-care delivery system over the past several decades

particular intervention will work, but it has little downside and stems from pristine motivations.

Evaluating the Quality of Evidence Have there been substantive studies done that have looked at and quantified what constitutes evidence-based end-of-life care? One can evaluate the quality of evidence for end-of-life interventions in the same ways as for any other interventions, using systematic reviews, “grade” assessments, and other metrics. However, few of them have been performed in the endof-life space. Of the ones that have, one showed there is as yet no evidence supporting physician orders for life-sustaining treatment documents, and another demonstrated there is reasonably highquality evidence supporting outpatient palliative care consultation for patients with certain cancers.

Moving Forward Has the Affordable Care Act (ACA) helped demonstrate the need for evidencebased end-of-life care? I am not aware of any provisions in the ACA that specifically call for evidence-based end-of-life care. However, there are many domains of medical care that are not specifically called out by the ACA. Hopefully, the more general provisions for sustainable health insurance will facilitate and support a future health-care system that more actively seeks to develop, test, and implement evidence-based approaches to all kinds of care. n Disclosure: Dr. Halpern reported no potential conflicts of interest.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | DECEMBER 10, 2015

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Journal Spotlight Thoracic Oncology

Nivolumab Improves Overall Survival vs Docetaxel in Advanced Previously Treated Squamous Cell NSCLC By Matthew Stenger

n a phase III trial reported in The New England Journal of Medicine, Julie Brahmer, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, and colleagues found that treatment with the programmed cell death protein 1 (PD-1) immune checkpoint inhibitor antibody nivolumab (Opdivo) improved overall and progression-free survival compared with docetaxel in patients with advanced previously treated squamous cell non– small cell lung cancer (NSCLC).

Study Details In this open-label international trial, 272 patients with stage IIIB or IV squamous cell NSCLC who had disease recurrence after one prior platinumcontaining regimen were randomly assigned between October 2012 and December 2013 to receive nivolumab at 3 mg/kg every 2 weeks (n = 135) or docetaxel at 75 mg/m2 every 3 weeks (n = 137) until disease progression or unacceptable toxicity. Randomization was stratified by prior use of paclitaxel and geographic region (United States or Canada vs Europe vs “rest of the world”—ie, Argentina, Australia, Chile, Mexico, and Peru). The nivolumab and docetaxel groups were generally balanced for all patient characteristics considered. The primary endpoint was overall survival.

Overall and Progression-Free Survival Minimum follow-up was approximately 11 months. Median overall survival was 9.2 months (95% confidence interval [CI] = 7.3–13.3 months) in the nivolumab group vs 6.0 months (95% CI = 5.1–7.3 months) in the docetaxel group (hazard ratio [HR] = 0.59, P < .001). At 1 year, overall survival was 42%

(95% CI = 34%–50%) vs 24% (95% CI = 17%–31%). Hazard ratios favored nivolumab across all prespecified subgroups, except for the “rest of the world” geographic subgroup and among the 29 patients aged ≥ 75 years. Median progression-free survival was 3.5 months (95% CI = 2.1–4.9 months) vs 2.8 months (95% CI = 2.1–3.5 months; HR = 0.62, P < .001). The rate of progression-free

disease progression, a nonconventional pattern of benefit was observed in 9, consisting of appearance of a new lesion followed by decrease from baseline ≥ 10% in the sum of target lesions, initial increase from nadir ≥ 20% in sum of target lesions followed by reduction from baseline ≥ 30%, or initial increase from nadir ≥ 20% in the sum of target lesions followed by at least two tumor assessments

Nivolumab is a PD-1 checkpoint inhibitor that showed a clinically meaningful survival benefit, with an improved safety profile, over that seen with the current standard of care in patients with advanced, previously treated squamous-cell NSCLC.… —Julie Brahmer, MD, and colleagues

survival at 1 year was 21% vs 6%. After discontinuation of treatment, systemic therapy was received by 36% of the nivolumab group (24% received docetaxel) and 30% of the docetaxel group. PD-1 ligand (PD-L1) expression levels were quantifiable in 83% of patients. PD-L1 expression across the prespecified levels of 1%, 5%, and 10% was not associated with overall or progression-free survival, with outcomes being consistently better with nivolumab and improvements with nivolumab being similar in magnitude to those in the overall population across all expression-level subgroups. Objective response was observed in 20% vs 9% of patients (P = .008). Similar rates of response were observed in nivolumab patients with PD-L1–negative and PD-L1–positive tumors. Among 28 nivolumab patients who continued to receive nivolumab after

showing no further progression (defined as 10% additional increase in the sum of target lesions and new lesions).

Adverse Events Treatment-related adverse events of any grade occurred in 58% of the nivolumab group vs 86% of the docetaxel group, including treatment-related grade 3 or 4 events in 7% vs 55%. The most common treatment-related adverse events of any grade in the nivolumab group were fatigue (16%), decreased appetite (11%), and asthenia (10%), and the most common in the docetaxel group were neutropenia (33%), fatigue (33%, grade 3 or 4 in 30%), alopecia (22%), and nausea (23%). Febrile neutropenia occurred in 10% of the docetaxel group. Among adverse events of special interest, one case each of grade 3 tubulointerstitial nephritis, colitis, and pneumonitis

were reported in nivolumab patients Treatment-related serious adverse events occurred in 7% vs 24% of patients, with the greater frequency in the docetaxel group reflecting primarily hematologic toxicity and infection. Treatment-related adverse events led to treatment discontinuation in 3% of the nivolumab group (pneumonitis in 2%) vs 10% of the docetaxel group (peripheral neuropathy in 3% and fatigue in 2%). Two additional patients in the nivolumab group discontinued treatment due to pneumonitis but were not included in the aforementioned rates (“one for whom the relationship was changed from not treatment-related to treatment-related after database lock, and one who discontinued treatment > 30 days after the most recent dose”). Treatment-related death occurred in no patients in the nivolumab group and in three patients in the docetaxel group. These deaths were attributed to interstitial lung disease, pulmonary hemorrhage, and sepsis. The investigators concluded: “Nivolumab is a PD-1 checkpoint inhibitor that showed a clinically meaningful survival benefit, with an improved safety profile, over that seen with the current standard of care in patients with advanced, previously treated squamouscell NSCLC. The benefit was observed regardless of prestudy PD-L1 expression level. Further research is needed to identify relevant biomarkers that have sufficient sensitivity and specificity to predict which patients are most likely to benefit.” n

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

Reference 1. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 373:123-135, 2015.

2015 San Antonio Breast Cancer Symposium Watch upcoming issues of The ASCO Post for reports from the San Antonio Breast Cancer Symposium, being held December 8–12, 2015.

OVERALL SURVIVAL AT 5 YEARS IN DLBCL IS

Could a better understanding of this disease be on the horizon?

60%

DLBCL is an aggressive disease2 Remarkably, more than half of patients are able to survive diffuse large B-cell lymphoma (DLBCL) for 5 years or longer.1,3

Although strides have been made in the science of DLBCL, we are determined to further our knowledge of this aggressive disease

To learn more, visit BCellResearch.com

References: 1. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2012. National Cancer Institute website. http://seer.cancer.gov/csr/1975_2012/results_single/sect_19_table.29_2pgs.pdf. Updated April 23, 2015. Accessed June 15, 2015. 2. Jaffe ES, Harris NL, Stein H, Campo E, Pileri SA, Swerdlow SH. Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008:158-166. 3. Larouche J-F, Berger F, Chassagne-ClĂŠment C, et al. Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. J Clin Oncol. 2010;28(12):2094-2100.

The ASCO Post | DECEMBER 10, 2015

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JCO Spotlight Guidelines

ASCO Clinical Practice Guideline: Use of Biomarkers to Guide Systemic Therapy for Women With Metastatic Breast Cancer By Matthew Stenger

s reported in the Journal of Clinical Oncology by Catherine Van Poznak, MD, and colleagues, ASCO has issued a clinical practice guideline on the use of biomarkers to guide decisions on systemic therapy in women with metastatic breast cancer.1 The statement is based on an ASCO expert panel review of systematic reviews, meta-analyses, randomized controlled trials, prospectiveretrospective studies, and prospective comparative observational studies reported between 2006 and September 2014. The panel was co-chaired by Lyndsay N. Harris, MD, of Seidman Cancer Center, Case Western Reserve University, Cleveland, and Dr. Van Poznak, of the University of Michigan Comprehensive Cancer Center, Ann Arbor.

Guideline Questions The expert panel sought to develop answers to the following questions: (1) Should metastases be biopsied or otherwise sampled to test for changes from the primary tumor with respect to estrogen receptor, progesterone receptor, or HER2 status? (2) For women with metastatic breast cancer and known estrogen receptor, progesterone receptor, and HER2 status, which additional tumor markers have demonstrated clinical utility to initiate systemic therapy or direct selection of a new systemic therapy regimen? (3) For women with metastatic breast cancer and known estrogen receptor, progesterone receptor, and HER2 status, which additional tumor markers have demonstrated clinical utility to guide decisions on switching to a different drug or regimen or discontinuing treatment? (4) For biomarkers shown to have clinical utility to guide decisions on sys-

temic therapy for metastatic disease in questions 2 and 3, what are the appropriate assays, timing, and frequency of measurement?

Key Points The key points of the guideline are reproduced below, with the type of recommendation, evidence quality, and strength of recommendation shown in parentheses. Patients with accessible, newly diagnosed metastases from primary breast cancer should be offered biopsy for confirmation of disease process and testing of estrogen receptor, progesterone receptor, and HER2 status. They should also be informed that if discordances are found, evidence is lacking to determine whether outcomes are better with treatment regimens based on receptor status in the metastases or the primary tumor. With discordance of results between primary and metastatic tissues, the panel consensus is to preferentially use the estrogen receptor, progesterone receptor, and HER2 status from the metastasis to direct therapy, if supported by the clinical scenario and the patient’s goals for care. (Type: evidence-based for biomarker change from primary to metastasis, but no evidence to address systemic therapy choices affecting health outcome when biomarker change occurs. Evidence quality: insufficient. Strength of recommendation: moderate.) Decisions on initiating systemic therapy for metastatic breast cancer should be based on clinical evaluation, judgment, and patient preferences. There is no evidence at this time that initiating therapy solely on the basis of biomarker results beyond those of estrogen receptor, progesterone receptor, and HER2 improves health outcomes. (Type: evidence-based. Evidence quality: low.

In patients already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on clinical evaluation, judgment of disease progression or response, and the patient’s goals for care. —Catherine Van Poznak, MD, and colleagues

Strength of recommendation: moderate.) Recommendations for tissue biomarkers: In patients already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on clinical evaluation, judgment of disease progression or response, and the patient’s goals for care. There is no evidence at this time that changing therapy based solely on biomarker results beyond estrogen receptor, progesterone receptor, and HER2 improves health outcomes, quality of life, or cost-effectiveness. (Type: evidence-based. Evidence quality: low. Strength of recommendation: moderate.) Recommendations for circulating tumor markers: In patients already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on clinical evaluation, judgment of disease progression or response, and the patient’s goals for care. There is no evidence at this time that changing therapy based solely on circulating biomarker results improves health outcomes, quality of life, or costeffectiveness. (Type: evidence-based. Evidence quality: intermediate. Strength of

recommendation: moderate.) Carcinoembryonic antigen (CEA), CA 15-3, and CA 27-29 may be used as adjunctive assessments to contribute to decisions regarding therapy for metastatic breast cancer. Data are insufficient to recommend use of CEA, CA 15-3, and CA 27-29 alone for monitoring response to treatment. The recommendation for use is based on clinical experience and panel informal consensus in the absence of studies designed to evaluate the clinical utility of the markers. As such, it is also reasonable for clinicians not to use these markers as adjunctive assessments. (Type: informal consensus. Evidence quality: insufficient. Strength of recommendation: moderate.) n

Disclosure: Dr. Van Poznak has received research funding from Amgen and Novartis (via her institution) and has reported patents, royalties, or other intellectual property associated with UpToDate. For full disclosures of the other authors, visit jco.ascopubs.org.

Reference 1. Van Poznak C, Somerfield MR, Bast RC, et al: Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 33:2695-2704, 2015.

ASCO Guideline on the Use of Biomarkers in Treatment Decisions in Metastatic Breast Cancer: Shedding Light on an Often Mysterious Art Beginning on page 1, Elizabeth Reed, MD, shares her perspective on the ASCO clinical practice guideline regarding the role of biomarkers in treating women with metastatic breast cancer.’

ASCOPost.com | DECEMBER 10, 2015

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Perspective Breast Cancer

Elizabeth Reed, MD continued from page 1

cancer antigen 27-29 (CA 27-29), and circulating tumor cells. The limited data from randomized, controlled studies almost certainly explain the high priority ASCO assigned to this project to aid in appropriate use of biomarker tests in this patient population. The guideline also re-emphasizes the importance of distinguishing the predictive vs prognostic value of clinical information.

Clinical Context and Biomarker Results The guideline recommends biopsy of a site of disease if accessible at the time of first relapse. This step serves to affirm the diagnosis conclusively and allows retesting of estrogen receptor, progesterone receptor, and HER2 status. Thus, treatment is for selected patients with metastatic disease on the basis of estrogen receptor, progesterone receptor, and HER2 testing of the active, and present tumor. When biomarkers of the metastatic disease differ from those of the primary tumor, it is unknown which tumor biomarker profile will best predict the most Dr. Reed is Professor, Internal Medicine, Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha.

ficacy of therapy. Again, the guideline allows that markers may be used with clinical information and patient preference to determine the need for change in treatment but expressly warn against changing therapy based on biomarkers alone. Some would argue that there is no role for circulating biomarkers in assessing treatment efficacy, but others use the biomarker trend to support clinical judgment in patients who have signs, symptoms, and tumor imaging that may be difficult to interpret, or when marker trends may decrease costly and uncomfortable imaging. The measurement of persistent circulating tumor cells after some therapy was acknowledged to be prognostic of poorer outcome when compared with patients in whom circulating tumor cells became undetectable; but persistent circulating tumor cells did not predict that a change in therapy improved outcome, and the use of circulating tumor cells was not recommended. The panel should be commended for gleaning the data from a limited number of trials and lending its great clinical experience to publish a guideline that enlightens the often mysterious art of managing metastatic breast cancer. n

effective approach to treatment. Retesting metastatic tumor is especially attractive when the primary tumor is negative for endocrine or HER2 biomarkers, and retesting checks the accuracy of the initial assays. However, in the situation in which tests of the metastatic site are negative for biomarkers and positive in the primary tumor, extra caution must be taken in assessing the results. For both situations, the guideline panel sagely advises that treatment decisions must be informed by the clinical context as well as biomarker results. For example, if an older woman with a history of estrogen receptor–positive breast cancer develops bone metastases 10 years after completing adjuvant endocrine therapy, and the bone biopsy demonstrates the tumor to be estrogen receptor–negative, then the clinical team must consider the results of the estrogen receptor assessment may have been influenced by current pathology practices. The clinical team must also assess the possibility that the tumor has changed expression of the estrogen receptor. The clinical team, together with the patient must use best clinical judgment to making a plan of care.

Assessing Treatment Efficacy The guideline also addresses the use of circulating biomarkers to gauge the ef-

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

References 1. Van Poznak C, Somerfield MR, Bast RC, et al: Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 33:2695-2704, 2015. 2. Harris L, Fritsche H, Mennel R, et al: American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25:5287-5312, 2007. 3. Wolff AC, Hammond ME, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118-145, 2007. 4. Wolff AC, Hammond ME, Hicks DG, et al: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997-4013, 2013. 5. Hammond ME, Hayes DF, Dowsett M, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:27842795, 2010.

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

Erin Cordeiro, MD, on Neoadjuvant Chemotherapy and Short-Term Outcomes in Breast Cancer Surgery see page 16

Bradley J. Monk, MD, FACS, FACOG, on Current Treatment and Patient Management in Ovarian Cancer see page 18

George D. Demetri, MD, on Trabectedin After Chemotherapy Failure in Liposarcoma or Leiomyosarcoma see page 38

Stuart M. Lichtman, MD, on Clinical Trial Design in Older Patients see page 27

Carol E. DeSantis, MPH, on Divergence of Breast Cancer Mortality in Black Women and White Women see page 52

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The ASCO Post | DECEMBER 10, 2015

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Journal Spotlight Breast Cancer

Regional Nodal Irradiation in Early Breast Cancer Yields Significant Disease-Free Survival Benefit in Two Trials By Matthew Stenger

wo phase III trials recently reported in The New England Journal of Medicine indicated that the addition of regional nodal irradiation was associated with no or marginal overall survival benefit but significantly improved disease-free survival in patients with early-stage breast cancer.1,2

NCIC MA.20 Trial In the National Cancer Institute of Canada (NCIC) Clinical Trials Group MA.20 trial,1 reported by Timothy J. Whelan, BM, BCh, of McMaster University and Juravinski Cancer Centre at Hamilton Health Sciences, Ontario, Canada, and colleagues, 1,832 women with node-positive or high-risk node-

Survival Median follow-up was 9.5 years. At the 10-year follow-up, rates of overall survival were 82.8% in the nodal-irradiation group vs 81.8% in the control group (hazard ratio [HR] = 0.91, P = .38). Ten-year rates were 82.0% vs 77.0% for disease-free survival (HR = 0.76, P = .01), 95.2% vs 92.2% for isolated locoregional disease–free survival (HR = 0.59, P = .009), and 86.3% vs 82.4% for distant disease–free survival (HR = 0.76, P = .03).

Toxicity Among acute adverse events, rates of grade ≥ 2 pneumonitis (1.2% vs 0.2%, P

Among women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence. —Timothy J. Whelan, BM, BCh, and colleagues

negative disease treated with breastconserving surgery and adjuvant systemic therapy were randomly assigned between March 2000 and February 2007 to undergo whole-breast irradiation with (n = 916) or without (n = 916) regional nodal irradiation, including internal mammary, supraclavicular, and axillary lymph nodes. The primary outcome was overall survival. The nodal-irradiation and control groups were generally balanced for age, initial sentinel node biopsy, axillary nodes removed, number of positive axillary nodes, tumor size , estrogen receptor status, progesterone receptor status, adjuvant chemotherapy, adjuvant endocrine therapy, and boost irradiation.

= .01) and radiation dermatitis (49% vs 40%, P < .001) were higher in the nodal-irradiation group. Among delayed events, rates of grade ≥ 2 lymphedema (8.4% vs 4.5%, P = .001), skin telangiectasia (6.9% vs 4.3%, P = .02), and subcutaneous fibrosis (4.1% vs 2.0%, P = .01) were higher in the nodal-irradiation group. There was no difference between groups in the rates of second cancers (11.0% vs 10.0%). The investigators concluded: Among women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence.

Regional Nodal Irradiation in Early Breast Cancer ■■ In the NCIC MA.20 trial, the addition of regional nodal irradiation did not significantly improve overall survival; improvements in disease-free, isolated locoregional disease–free, and distant disease–free survival were observed. ■■ In the EORTC trial, regional nodal irradiation was associated with a marginal effect on overall survival; significant improvements were observed in disease-free and distant disease-free survival and breast cancer mortality.

In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease–free survival were improved, and breast-cancer mortality was reduced. —Philip M. Poortmans, PhD

EORTC 22922-10925 Trial In a trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Radiation Oncology and Breast Cancer Groups,2 reported by Philip M. Poortmans, PhD, of Radboud university medical center, Nijmegen, Netherlands, and colleagues, 4,004 women with a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement were randomly assigned between 1996 and 2004 to undergo whole-breast or thoracic-wall irradiation with (n = 2,002) or without (n = 2,002) regional nodal irradiation (internal mammary and medial supraclavicular nodes) after surgery. The primary endpoint was overall survival. The nodal-irradiation and control groups were balanced for age (median, 54 years in both), surgery (mastectomy in 24% in both, breast-conserving in 76% in both), tumor size (≤ 2 cm in 60% in both), number of involved axillary nodes (0 in 44% in both, 1–3 in 43% in both), and adjuvant treatment (none in 16% and 15%, chemotherapy in 25% in both, hormonal therapy in 29% and 30%, both in 30% in both). Among patients undergoing mastectomy, 73% of the patients in both groups underwent chest-wall irradiation. Adjuvant systemic treatment was administered to 99% of patients with node-positive disease and 66% of patients with node-negative disease.

Survival Median follow-up was 10.9 years. Rates of overall survival at 10 years were 82.3% in the nodal-irradiation group vs 80.7% in the control group (hazard ratio [HR] = 0.87, P = .06).

Ten-year rates were 72.1% vs 69.1% for disease-free survival (HR = 0.89, P = .04), 78.0% vs 75.0% for distant disease–free survival (HR = 0.86, P = .02), and 12.5% vs 14.4% for breast cancer mortality (HR = 0.82, P = .02). A greater overall survival benefit appeared to be associated with nodal irradiation among patients who received both adjuvant chemotherapy and hormonal therapy (HR = 0.72, 95% confidence interval = 0.55–0.94).

Toxicity Acute side effects of regional nodal irradiation were reported to be modest. Among long-term effects, pulmonary fibrosis occurred in 4.4% of the nodal irradiation group vs 1.7% of the control group (P < .001), cardiac fibrosis occurred in 1.2% vs 0.6% (P = .06), and cardiac disease occurred in 6.5% vs 5.6% (P = .25). Second cancers were observed in 9.5% vs 11.1%. The investigators concluded: “In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease–free survival were improved, and breast-cancer mortality was reduced.” n

Disclosure: The NCIC MA.20 trial was funded by the Canadian Cancer Society Research Institute and others. The EORTC trial was funded by Fonds Cancer. For full disclosures of the study authors, visit www.nejm.org.

References 1. Whelan TJ, Olivotto IA, Parulekar WR, et al: Regional nodal irradiation in early-stage breast cancer. N Engl J Med 373:307-316, 2015. 2. Poortmans PM, Collette S, Kirkove C, et al: Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med 373:317-327, 2015.

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Perspective

Nodal Irradiation in Node-Positive Breast Cancer: It Is Not Time to Change Practice By Alice Chung, MD, and Armando E. Giuliano, MD

anagement of the regional nodes in breast cancer has evolved from the era of the extended radical mastectomy to exclusion of axillary dissection in appropriately selected patients. Throughout this evolution, studies of nodal irradiation have been shown to improve locoregional control, usually without a clear impact on overall survival. Concerns regarding toxicity and a possible lack of survival benefit resulted in the selective use of nodal irradiation only for the highest risk patients. With improvements in radiation techniques that minimize radiation exposure to vital structures and publication of studies and a meta-analysis suggesting a survival benefit from postmastectomy nodal irradiation,1 the potential utility of nodal irradiation in a more moderate-risk population has been proposed, even for women treated with breast-conserving therapy. As summarized in this issue of The ASCO Post, the National Cancer Institute of Canada Clinical Trials Group MA.20 clinical trial, reported by Whelan and colleagues, was a randomized study that evaluated irradiation of the ipsilateral internal mammary, supraclavicular, and axillary nodes in N1 or high-risk node-negative patients treated with breast-conserving surgery.2 The European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial, reported by Poortmans and colleagues, evaluated the role of internal mammary and medial supraclavicular nodal irradiation in women with centrally or medially located tumors regardless of nodal involvement and externally located tumors with nodal disease. Most patients had fewer than three involved nodes.3 Both trials had follow-up of approximately 10 years and demonstrated significant reductions in local and distant recurrences. Disease-free survival was reduced by nodal irradiation

Dr. Chung is Assistant Professor of Surgery, Division of Surgical Oncology, Cedars-Sinai Medical Center, Los Angeles, California, and Dr. Giuliano is Professor of Surgery, Executive Vice Chair, Surgery, Associate Director, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center.

from 82% to 77% in the MA.20 trial and from 72% to 69% in the EORTC trial. The isolated regional recurrence rate in the MA.20 study was reduced from 2.5% in the whole-breast irradiation arm to 0.5% in the nodalirradiation arm. The MA.20 trial did not show an improvement in overall survival with the addition of nodal

ported in the EORTC trial. One may argue that reduction in recurrence should eventually translate into reduction in mortality. The Early Breast Cancer Trialists’ Collaborative Group’s meta-analysis of radiotherapy after breast-conserving surgery showed that one breast cancer death in 15 years could be avoided for every

Radiation therapy clearly decreases local tumor recurrence, but its effect on overall survival and which patients may benefit remain unclear. Comprehensive nodal irradiation is not for all node-positive patients. —Alice Chung, MD, and Armando E. Giuliano, MD

irradiation, whereas the EORTC trial showed a minimal survival benefit (1.6%) from internal mammary/supraclavicular nodal irradiation. Toxicity in the MA.20 trial included higher rates of grade ≥ 2 acute pneumonitis and lymphedema in the nodal-irradiation group. In the EORTC trial, there was a 3% rate of pulmonary fibrosis and a 1% occurrence of cardiac fibrosis—only in patients treated with internal mammary/supraclavicular nodal irradiation.

Are Results Practice Changing? The results of these trials confirm that nodal irradiation in the moderate-risk population indeed reduces recurrence, but the very modest survival benefit demonstrated in the EORTC trial may not be enough to change clinical practice. The purpose of nodal irradiation is to reduce nodal recurrence. However, the difference in regional recurrence between the two arms in the MA.20 trial was only 2%, which is unlikely to lead to a significant improvement in survival. Regional recurrence rates were not re-

four recurrences that were avoided in 10 years.4 However, the reduction in breast cancer mortality observed in the meta-analysis was significant only when the absolute reduction in recurrence was greater than 10%.5 This recurrence rate is markedly greater than the recurrence reduction seen in the MA.20 or EORTC trial; therefore, the results of the meta-analysis may not be applicable to these trials. In addition, medical management of breast cancer has changed since the inception of these trials, and it is possible that the rates of recurrence with modern-day systemic therapy would be even lower than those reported in the trials.

Further Risk Stratification Needed Treatment recommendations in this group of patients remain a challenge, as there is a need for further risk stratification. Clearly, not all patients with one to three positive nodes or node-negative medial tumors will benefit from comprehensive nodal irradiation. The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial showed no survival advantage

with surgical treatment of the regional nodes in sentinel node–positive patients treated with breast-conserving surgery.6 This trial led to a marked reduction in the treatment of axillary nodes in low-risk node-positive patients. Although patients in the ACOSOG Z0011 trial had less nodal burden of disease than those in the MA.20 or EORTC trial, the ACOSOG Z0011 study clearly showed that some women with nodal metastases do not require nodal-specific therapy.

Certain Subgroups May Benefit The MA.20 and EORTC trials evaluated a higher-risk population and demonstrated a significant reduction in recurrences with comprehensive nodal radiation, but the survival benefit was marginal. However, within this population, there may be certain subgroups that benefit from nodal irradiation. Subgroup analyses in the MA.20 trial showed that the treatment effect of nodal irradiation was greater in patients with estrogen receptor–negative or progesterone receptor–negative tumors, but the subgroup analyses were not adequately powered. A series of retrospective studies have identified certain high-risk features among patients with T1-2,N1 tumors who have undergone mastectomy, including young age, tumor size > 2 cm, high grade, > 25% of excised nodes involved with metastases, medial tumor location, estrogen receptor–negative status, lymphovascular invasion, and no use of systemic therapy.7-11 In the future, we must rely on patient and tumor characteristics to identify which patients within this population may be both at increased risk for recurrence and may benefit from more-extensive nodal therapy. More radiation is not likely to improve survival in patients with subclinical metastases at the time of initial treatment. The trials by Whelan et al. and Poortmans et al. address important questions in a challenging and common clinical scenario. As the landscape of oncologic care continues to evolve, selection of patients and individualized treatment will continue to shift toward more of a basis in tumor biology and genomics, leading to encontinued on page 78

The ASCO Post | DECEMBER 10, 2015

PAGE 78

Announcements

NCCN Foundation Appoints Three New Representatives to Board of Directors

he National Comprehensive Cancer Network (NCCN) Foundation has appointed three new representatives to its Board of Directors: Heather Kopecky, PhD, MBA; Marc Samuels, JD, MPH; and Susan Stein, MPH. There are currently 15 members of the Board of Directors, responsible for the strategic direction for the NCCN Foundation, which obtains funding to publish the library of NCCN Guidelines for Patients and the NCCN Quick Guide Series, as well as research grants for young investigators at the NCCN member institutions.

Heather Kopecky, PhD, MBA Dr. Kopecky is a Senior Client Partner at Korn Ferry International, where she serves as an industry expert in executive search and coaching, as well as a consultant for prominent academic medical centers, multihospital nonprofit health systems, higher education, and professional health-care associations. Previously, Dr. Kopecky had appointments at Baylor College of Medicine, The University of Texas, and Texas Women’s University. Dr. Kopecky is currently a member of the American

represented the Texas Society of Clinical Oncology, as well as several oncology physician practices and NCCN member institutions in Texas and other states; he has cowritten many pieces of legislation related to compendia, oral parity, accelerated coverage of biologics, and the Houston Biotechnology Park. Heather Kopecky, PhD, MBA

College of Healthcare Executives, the Healthcare Financial Management Association, the American Organization of Nurse Executives, and the National Association of Corporate Directors. She also serves as a volunteer with the Red Cross Disaster Services Human Resources System.

Marc Samuels, JD, MPH Mr. Samuels is the Chief Executive Officer of ADVI, an advisory services firm to the life science and health-care services sectors with end-to-end strategic offerings and a focus on accelerating growth and increasing value. Previously, Mr. Samuels founded HillCo HEALTH and was a partner in HillCo Partners, which merged with Accelus Health Partners to form ADVI in 2013. He has

cations company focused on translating complex science into clear and concise scientific communication to educate health-care providers, support clinical decision-making, and improve patient outcomes. Connexion Healthcare serves the world’s leading biotech and pharmaceutical companies through its two Centers of Excellence: Oncology and Rare Disease. Ms. Stein began her career within the pharmaceutical industry, continuing to the agency side before founding Connexion Healthcare.

Marc Samuels, JD, MPH

Prior to his work at ADVI and HillCo, Mr. Samuels served both former President George H. W. Bush and thenTexas Governor George W. Bush on health-care issues in the White House Office of Policy Development and Texas Governor’s Office, respectively.

Susan Stein, MPH Ms. Stein is the Founder and CEO of Connexion Healthcare, a communi-

Susan Stein, MPH

She is a member of the Drexel School of Public Health Dean’s Advisory Council, Member of the Global Genes Board of Directors, and Co-Chair for the Alex’s Lemonade Stand Foundation Lemon Ball. n

Perspective Alice Chung, MD Armando E. Giuliano, MD continued from page 77

hancement in strategies for risk stratification. Radiation therapy clearly decreases local tumor recurrence, but its effect on overall survival and which patients may benefit remain unclear. Comprehensive nodal irradiation is not for all node-positive patients. n Disclosure: Drs. Chung and Giuliano reported no potential conflicts of interest.

References 1. McGale P, Taylor C, Correa C, et al: Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials.

Lancet 383:2127-2135, 2014. 2. Whelan TJ, Olivotto IA, Parulekar WR, et al: Regional nodal irradiation in early-stage breast cancer. N Engl J Med 373:307-316, 2015. 3. Poortmans PM, Collette S, Kirkove C, et al: Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med 373:317-327, 2015. 4. Darby S, McGale P, Correa C, et al: Effect of radiotherapy after breastconserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011. 5. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year

survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005. 6. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA 305:569-575, 2011. 7. Abi-Raad R, Boutrus R, Wang R, et al: Patterns and risk factors of locoregional recurrence in T1-T2 node negative breast cancer patients treated with mastectomy: Implications for postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys 81:e151-e157, 2011. 8. Macdonald SM, Abi-Raad RF, Alm El-Din MA, et al: Chest wall radiotherapy: Middle ground for treatment of patients with one to three positive lymph nodes after mastectomy. Int J Radiat On-

col Biol Phys 75:1297-1303, 2009. 9. Truong PT, Olivotto IA, Kader HA, et al: Selecting breast cancer patients with T1-T2 tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 61:1337-1347, 2005. 10. Truong PT, Lesperance M, Culhaci A, et al: Patient subsets with T1T2, node-negative breast cancer at high locoregional recurrence risk after mastectomy. Int J Radiat Oncol Biol Phys 62:175-182, 2005. 11. Sharma R, Bedrosian I, Lucci A, et al: Present-day locoregional control in patients with t1 or t2 breast cancer with 0 and 1 to 3 positive lymph nodes after mastectomy without radiotherapy. Ann Surg Oncol 17:2899-2908, 2010.

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YONDELIS速 (trabectedin) is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.

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YONDELIS速 is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin.

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YONDELIS® ( trabectedin) SIGNIFICANTLY IMPROVED PROGRESSION-FREE SURVIVAL (PFS) YONDELIS® resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine in a phase 3, open-label study • YONDELIS® improved median PFS* vs dacarbazine: 4.2 months with YONDELIS® vs 1.5 months for dacarbazine (hazard ratio [HR]†=0.55; 95% CI: 0.44, 0.70; P<0.001‡)

Kaplan-Meier Curve of PFS 100

Dacarbazine YONDELIS® Censored in dacarbazine Censored in YONDELIS®

90 80

Subjects, %

70 60 50 40 30 20 10 0 0

0 5

Progression-Free Survival, Months NUMBER OF SUBJECTS AT RISK: Dacarbazine YONDELIS®

173 345

35 133

10 71

2 29

1 10

*An exploratory analysis of independent radiology committee–determined PFS, in a subgroup consisting of approximately 60% of the total population, provided similar results to the investigator-determined PFS. †HR is estimated using Cox proportional hazards model with treatment group as the only covariate. ‡P value is based on unstratified log-rank test.

Study Design YONDELIS® was studied in a phase 3 randomized, open-label, active-controlled, multicenter trial of patients with unresectable, locally advanced or metastatic leiomyosarcomas (73%) or liposarcomas (27%).

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS

Neutropenic sepsis, including fatal cases, can occur. In Trial 1, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, was 43% (161/378). Median time to the first occurrence of Grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months). Median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18 patients (5%). Ten patients (2.6%) experienced neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4 patients (1.1%). Assess neutrophil count prior to administration of each dose of YONDELIS® and periodically throughout the treatment cycle. Withhold YONDELIS® for neutrophil counts of less than 1500 cells/microliter on the day of dosing. Permanently reduce the dose of YONDELIS® for life-threatening or prolonged, severe neutropenia in the preceding cycle. Rhabdomyolysis—YONDELIS® can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving YONDELIS®, including Grade 3 or 4 CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation. Among the 24 patients receiving YONDELIS® with Grade 3 or 4 CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in 4 of these 11 patients (1.1%). Median time to first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5 months). Please see the following pages for additional Important Safety Information and a Brief Summary of the full Prescribing Information.

YONDELIS®

13.7 months

The median overall survival was 13.7 months for patients treated with YONDELIS® vs 13.1 months for patients treated with dacarbazine in the pivotal trial (HR=0.93; 95% CI: 0.75, 1.15; P=0.49)

S:13 IN

T:14 IN

B:14.25 IN

2.7 months

Median duration of response was 2.7 months longer for YONDELIS® vs dacarbazine (6.9 months vs 4.2 months, respectively)

13 weeks

The median duration of treatment with YONDELIS® was 13 weeks (range, 1 to 127 weeks), with 30% of patients treated for more than 6 months and 7% for more than 1 year Liposarcoma and leiomyosarcoma are two of the most common subtypes of soft tissue sarcomas.1,2 References: 1. Blay J-Y, Sleijfer S, Schöffski P, et al. International expert opinion on patient-tailored management of soft tissue sarcomas. Eur J Cancer. 2014;50(4):679-689. 2. Ducimetière F, Lurkin A, Ranchère-Vince D, et al. Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One. 2011;6(8):e20294.

Median time to complete resolution was 14 days (range: 5 days to 1 month). Assess CPK levels prior to each administration of YONDELIS®. Withhold YONDELIS® for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue YONDELIS® for rhabdomyolysis. Hepatotoxicity, including hepatic failure, can occur. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels > 2.5 x ULN were not enrolled in Trial 1. In Trial 1, the incidence of Grade 3-4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378). Median time to development of Grade 3-4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3 to 4 elevations in LFTs, 114 (85%) experienced complete resolution with the median time to complete resolution of 13 days (range: 4 days to 4.4 months). In Trial 1, the incidence of drug-induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378). ALT or AST elevation greater than eight times the ULN occurred in 18% (67/378) of patients. Assess LFTs prior to each administration of YONDELIS®. Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation NOW APPROVED based on severity and duration of LFT abnormality.

IMPORTANT SAFETY INFORMATION Cardiomyopathy, including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur. In Trial 1, patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial 1, cardiomyopathy occurred in 23 patients (6%) receiving YONDELIS® and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS® and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving YONDELIS® and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving YONDELIS® was 5.3 months (range: 26 days to 15.3 months). Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before initiation of YONDELIS® and at 2- to 3-month intervals thereafter until YONDELIS® is discontinued. Withhold YONDELIS® for LVEF below lower limit of normal. Permanently discontinue YONDELIS® for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks. Extravasation Resulting in Tissue Necrosis—Extravasation of YONDELIS®, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of YONDELIS®. Administer YONDELIS® through a central venous line. Embryofetal Toxicity—Based on its mechanism of action, YONDELIS® can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of YONDELIS®. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of YONDELIS®. Adverse Reactions—The most common (≥20%) adverse reactions were nausea (75%), fatigue (69%), vomiting (46%), constipation (37%), decreased appetite (37%), diarrhea (35%), peripheral edema (28%), dyspnea (25%), and headache (25%). The most common (≥5%) grades 3-4 laboratory abnormalities are: neutropenia (43%), increased ALT (31%), thrombocytopenia (21%), anemia (19%), increased AST (17%), and increased creatine phosphokinase (6.4%). Effect of Cytochrome CYP3A Inhibitors—Avoid use of strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS®. Avoid taking grapefruit or grapefruit juice. If a strong CYP3A inhibitor for short-term use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the YONDELIS® infusion, and discontinue it the day prior to the next YONDELIS® infusion. Effect of Cytochrome CYP3A Inducers—Avoid administering strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) to patients who are taking YONDELIS®. Please see the following pages for Brief Summary of the full Prescribing Information.

NOW APPROVED

040598-150918

DRUG INTERACTIONS

YONDELIS (trabectedin) for injection, for intravenous use Brief Summary of Full Prescribing Information INDICATIONS AND USAGE YONDELIS® is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen [see Clinical Studies (14) in Full Prescribing Information]. CONTRAINDICATIONS YONDELIS is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin. WARNINGS AND PRECAUTIONS Neutropenic Sepsis: Neutropenic sepsis, including fatal cases, can occur with YONDELIS. In Trial 1, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, in patients receiving YONDELIS was 43% (161/378). The median time to the first occurrence of Grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months); the median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18 patients (5%) treated with YONDELIS. Ten patients (2.6%) experienced neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4 patients (1.1%). Assess neutrophil count prior to administration of each dose of YONDELIS and periodically throughout the treatment cycle. Withhold YONDELIS for neutrophil counts of less than 1500 cells/microliter on the day of dosing. Permanently reduce the dose of YONDELIS for life-threatening or prolonged, severe neutropenia in the preceding cycle [see Dosage and Administration (2.3) in Full Prescribing Information]. Rhabdomyolysis: YONDELIS can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients receiving YONDELIS. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving YONDELIS, including Grade 3 or 4 CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation. Among the 24 patients receiving YONDELIS with Grade 3 or 4 CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in 4 of these 11 patients (1.1%). The median time to first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5 months). The median time to complete resolution was 14 days (range: 5 days to 1 month). Assess CPK levels prior to each administration of YONDELIS. Withhold YONDELIS for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue YONDELIS for rhabdomyolysis [see Dosage and Administration (2.3) in Full Prescribing Information]. Hepatotoxicity: Hepatotoxicity, including hepatic failure, can occur with YONDELIS. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels >2.5 x ULN were not enrolled in Trial 1. In Trial 1, the incidence of Grade 3-4 elevated liver function tests (defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378) in patients receiving YONDELIS. The median time to development of Grade 3-4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3-4 elevations in LFTs, 114 (85%) experienced complete resolution with the median time to complete resolution of 13 days (range: 4 days to 4.4 months). In Trial 1, the incidence of drug-induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378) in patients receiving YONDELIS. ALT or AST elevation greater than eight times the ULN occurred in 18% (67/378) of patients receiving YONDELIS. Assess LFTs prior to each administration of YONDELIS. Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation based on severity and duration of LFT abnormality [see Dosage and Administration (2.3) in Full Prescribing Information]. Cardiomyopathy: Cardiomyopathy including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur with YONDELIS. In Trial 1, patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial 1, cardiomyopathy occurred in 23 patients (6%) receiving YONDELIS and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving YONDELIS and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving YONDELIS and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving YONDELIS was 5.3 months (range: 26 days to 15.3 months). Assess left ventricular ejection fraction (LVEF) by echocardiogram or multigated acquisition (MUGA) scan before initiation of YONDELIS and at 2- to 3-month intervals thereafter until YONDELIS is discontinued. Withhold YONDELIS for LVEF below lower limit of normal. Permanently discontinue YONDELIS for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks [see Dosage and Administration (2.3) in Full Prescribing Information]. Extravasation Resulting in Tissue Necrosis: Extravasation of YONDELIS, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of YONDELIS. Administer YONDELIS through a central venous line [see Dosage and Administration (2.5) in Full Prescribing Information]. Embryofetal Toxicity: Based on its mechanism of action, YONDELIS can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of YONDELIS. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of YONDELIS [see Use in Specific Populations].

YONDELIS® (trabectedin) for injection intravenous infusion over 20 to 120 minutes once every 3 weeks (n=172) [see Clinical Studies (14) in Full Prescribing Information]. All patients treated with YONDELIS were required to receive dexamethasone 20 mg intravenous injection 30 minutes prior to start of the YONDELIS infusion. In Trial 1, patients had been previously treated with an anthracycline- and ifosfamide-containing regimen or with an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen. The trial excluded patients with known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, such as cirrhosis or active hepatitis, and history of myocardial infarction within 6 months, history of New York Heart Association Class II to IV heart failure, or abnormal left ventricular ejection fraction at baseline. The median age of patients in Trial 1 was 57 years (range: 17 to 81 years), with 69% female, 77% White, 12% Black or African American, 4% Asian, and <1% American Indian or Alaska Native. The median duration of exposure to trabectedin was 13 weeks (range: 1 to 127 weeks) with 30% of patients exposed to YONDELIS for greater than 6 months and 7% of patients exposed to YONDELIS for greater than 1 year. In Trial 1, adverse reactions resulting in permanent discontinuation of YONDELIS occurred in 26% (98/378) of patients; the most common were increased liver tests (defined as ALT, AST, alkaline phosphatase, bilirubin) (5.6%), thrombocytopenia (3.4%), fatigue (1.6%), increased creatine phosphokinase (1.1%), and decreased ejection fraction (1.1%). Adverse reactions that led to dose reductions occurred in 42% (158/378) of patients treated with YONDELIS; the most common were increased liver tests (24%), neutropenia (including febrile neutropenia) (8%), thrombocytopenia (4.2%), fatigue (3.7%), increased creatine phosphokinase (2.4%), nausea (1.1%), and vomiting (1.1%). Adverse reactions led to dose interruptions in 52% (198/378) of patients treated with YONDELIS; the most common were neutropenia (31%), thrombocytopenia (15%), increased liver tests (6%), fatigue (2.9%), anemia (2.6%), increased creatinine (1.1%), and nausea (1.1%). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. The most common laboratory abnormalities (≥20%) were increases in AST or ALT, increased alkaline phosphatase, hypoalbuminemia, increased creatinine, increased creatine phosphokinase, anemia, neutropenia, and thrombocytopenia. Table 1: Selected Adverse Reactionsa occurring in ≥10% of Patients receiving YONDELIS and at a higher incidence than in the Control Arm - Trial 1 System Organ Class Adverse Reaction

Gastrointestinal disorders Nausea 75 Vomiting 46 Constipation 37 Diarrhea 35 General disorders and administration site conditions 69 Fatiguec Peripheral edema 28 Metabolism and nutrition disorders Decreased appetite 37 Respiratory, thoracic and mediastinal disorders Dyspnea 25 Nervous system disorders Headache 25 Musculoskeletal and connective tissue disorders Arthralgia 15 Myalgia 12 Psychiatric disorders Insomnia 15 a

b c

Dacarbazine (N=172) All Grades Grades 3-4 (%) (%)

7 6 0.8 1.6

50 22 31 23

1.7 1.2 0.6 0

8 0.8

52 13

1.7 0.6

1.9

0.6

4.2

1.2

0.3

0 0

8 6

1.2 0

0.3

Limited to adverse reactions at a rate of ≥10% in the trabectedin arm and at a rate higher in the trabectedin arm compared with dacarbazine arm by ≥5% in overall incidence or by ≥2% for Grade 3-4 adverse reactions. Toxicity grade is based on NCI common toxicity criteria, version 4.0. Fatigue is a composite of the following adverse event terms: fatigue, asthenia, and malaise.

Other clinically important adverse reactions observed in <10% of patients (N=755) with soft tissue sarcoma receiving YONDELIS were: Nervous system disorders: peripheral neuropathy, paresthesia, hypoesthesia. Respiratory, thoracic, and mediastinal disorders: pulmonary embolism. Table 2: Incidence of Selected Treatment-Emergent Laboratory Abnormalitiesa - Trial 1 Laboratory Abnormalities Chemistry Increased ALT Increased AST Increased alkaline phosphatase Hypoalbuminemia Increased creatinine Increased creatine phosphokinase Hyperbilirubinemia Hematology Anemia Neutropenia Thrombocytopenia

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Anaphylaxis [see Contraindications] • Neutropenic Sepsis [see Warnings and Precautions] • Rhabdomyolysis [see Warnings and Precautions] • Hepatotoxicity [see Warnings and Precautions] • Cardiomyopathy [see Warnings and Precautions] • Extravasation Resulting in Tissue Necrosis [see Warnings and Precautions] Adverse Reactions in Clinical Trials: 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 below reflect exposure to YONDELIS in 755 patients with soft tissue sarcoma including 197 (26%) patients exposed to YONDELIS for greater than or equal to 6 months and 57 (8%) patients exposed to YONDELIS for greater than or equal to 1 year. The safety of YONDELIS was evaluated in six open-label, single-arm trials, in which 377 patients received YONDELIS and one open-label, randomized, active-controlled clinical trial in which 378 patients received YONDELIS (Trial 1). All patients received YONDELIS at the recommended dosing regimen of 1.5 mg/m2 administered as an intravenous infusion over 24 hours once every 3 weeks (q3wk, 24-h). The median age was 54 years (range: 18 to 81 years), 63% were female, and all patients had metastatic soft tissue sarcoma. Tables 1 and 2 present selected adverse reactions and laboratory abnormalities, respectively, observed in Trial 1, an open-label, randomized (2:1), active-controlled trial in which 550 patients with previously treated leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) received YONDELIS 1.5 mg/m2 intravenous infusion over 24 hours once every 3 weeks (n=378) or dacarbazine 1000 mg/m2

YONDELIS (N=378) Grades 3-4 All Gradesb (%) (%)

YONDELIS All Grades Grades 3-4 (%) (%)

Dacarbazine All Grades Grades 3-4 (%) (%)

90 84 70 63 46 33 13

31 17 1.6 3.7 4.2 6.4 1.9

33 32 60 51 29 9 5

0.6 1.2 0.6 3.0 1.2 0.6 0.6

96 66 59

19 43 21

79 47 57

12 26 20

Treatment-emergent laboratory abnormalities including those higher in the trabectedin arm compared with the dacarbazine arm by ≥5% (all Grades) or by ≥2% (Grade 3-4). Incidence based on number of patients who had both baseline and at least one on-study laboratory measurement YONDELIS group (range: 373 to 377 patients) and dacarbazine group (range: 166 to 168 patients). a

DRUG INTERACTIONS Effect of Cytochrome CYP3A Inhibitors: Coadministration of YONDELIS with ketoconazole, a strong CYP3A inhibitor, increases systemic exposure of trabectedin by 66%. Avoid use of strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS. Avoid taking grapefruit or grapefruit juice during YONDELIS treatment. If a strong CYP3A

YONDELIS® (trabectedin) for injection inhibitor for short-term use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the YONDELIS infusion, and discontinue it the day prior to the next YONDELIS infusion [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Effect of Cytochrome CYP3A Inducers: Coadministration of YONDELIS with rifampin, a strong CYP3A inducer, decreased systemic exposure of trabectedin by 31%. Avoid administering strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John’s wort) to patients who are taking YONDELIS [see Clinical Pharmacology (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Risk Summary: Based on its mechanism of action, trabectedin can cause fetal harm when administered during pregnancy [see Clinical Pharmacology (12.1) in Full Prescribing Information]. There are no available data with the use of YONDELIS during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted with trabectedin; however, placental transfer of trabectedin was demonstrated in pregnant rats. Advise pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population are unknown; however, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Lactation: Risk Summary: There are no data on the presence of trabectedin in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions from YONDELIS in breastfed infants, advise a nursing woman to discontinue nursing during treatment with YONDELIS. Females and Males of Reproductive Potential: Contraception: Females: Advise female patients of reproductive potential to use effective contraception during and for 2 months after the last dose of YONDELIS [see Use in Specific Populations]. Males: YONDELIS may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for 5 months after the last dose of YONDELIS [see Nonclinical Toxicology (13.1) in Full Prescribing Information]. Infertility: YONDELIS may result in decreased fertility in males and females [see Nonclinical Toxicology (13.1) in Full Prescribing Information]. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Clinical studies of YONDELIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Hepatic Impairment: The pharmacokinetics of trabectedin has not been evaluated in patients with a total bilirubin greater than the upper limit of normal [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Renal Impairment: No dose adjustment is recommended in patients with mild [creatinine clearance (CLcr) 60-89 mL/min] or moderate (CLcr of 30-59 mL/min) renal impairment. The pharmacokinetics of trabectedin has not been evaluated in patients with severe renal impairment (CLcr <30 mL/min) or end stage renal disease [see Clinical Pharmacology (12.3) in Full Prescribing Information]. OVERDOSAGE There is no specific antidote for YONDELIS. Hemodialysis is not expected to enhance the elimination of YONDELIS because trabectedin is highly bound to plasma proteins (97%) and not significantly renally excreted. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myelosuppression: Inform patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider for fever or unusual bruising, bleeding, tiredness, or paleness. Rhabdomyolysis: Advise patients to contact their healthcare provider if they experience severe muscle pain or weakness. Hepatotoxicity: Advise patients to contact their healthcare provider immediately for yellowing of skin and eyes (jaundice), pain in the upper right quadrant, severe nausea or vomiting, difficulty in concentrating, disorientation, or confusion. Cardiomyopathy: Advise patients to contact their healthcare provider for new onset chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations. Hypersensitivity: Advise patients to seek immediate medical attention for symptoms of allergic reactions including difficulty breathing, chest tightness, wheezing, severe dizziness or lightheadedness, swelling of the lips or skin rash. Extravasation: Inform patients of the risks of extravasation and to notify their healthcare provider for redness, swelling, itchiness and discomfort or leakage at the injection site. Embryofetal toxicity: Advise pregnant women of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with YONDELIS [see Warnings and Precautions and Use in Specific Populations]. Females and males of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with YONDELIS and for at least 2 months after last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with YONDELIS and for at least 5 months after the last dose [see Warnings and Precautions and Use in Specific Populations]. Lactation: Advise females not to breastfeed during treatment with YONDELIS [see Use in Specific Populations].

Manufactured by: Baxter Oncology GmbH Halle/Westfalen Germany Manufactured for: Janssen Products, LP Horsham, PA © Janssen Products, LP. 2015 Under license from Pharma Mar, S.A. 042354-151026

PAGE 84

The ASCO Post | DECEMBER 10, 2015

Announcements

Cancer Researchers and Clinicians Elected as 2015 AAAS Fellows

he American Association for the Advancement of Science (AAAS) Council elected 347 fellows for 2015, in recognition of their contributions to innovation, education, and scientific leadership. The tradition of electing AAAS fellows began in 1874 to recognize members for their scientifically or socially distinguished efforts to advance science or its applications. The new fellows will be recognized in a Fellows Forum on February 13, 2016, at the 2016 AAAS Annual Meeting in Washington, D.C. This year saw a large election of cancer researchers and clinicians to fellow status. An abridged list of those elected is below. For a full listing of all 2015 AAAS elected fellows, please visit http://www.aaas.org/news/2015-aaasfellows-recognized-contributions-advancing-science.

Section on Biological Sciences Cheryl H. Arrowsmith, PhD, University of Toronto Michelle Barton, PhD, University of Texas MD Anderson Cancer Center Julie A. Brill, PhD, The Hospital for Sick Children Andrea Califano, PhD, Columbia University Nancy Cox, PhD, Vanderbilt University Gerald R. Crabtree, MD, Stanford University Frédéric J. de Sauvage, PhD, Genentech John DiGiovanni, PhD, University of Texas at Austin Beverly M. Emerson, PhD, Salk Institute for Biological Studies Gerald R. Fink, PhD, Whitehead Institute/Massachusetts Institute of Technology Maureen Anne Gannon, PhD, Vanderbilt University Leonard S. Jefferson, PhD, Pennsylvania State University Hannah L. Klein, PhD, New York University School of Medicine Alberto R. Kornblihtt, PhD, University of Buenos Aires/National Council of Research and Technology Damian J. Krysan, MD, PhD, University of Rochester Arthur Mallay Lesk, PhD, Pennsylvania State University Pierre P. Massion, MD, Vanderbilt University School of Medicine Michael J. Matunis, PhD, Johns Hopkins University Cynthia C. Morton, PhD, Brigham and Women’s Hospital Robert K. Moyzis, PhD, University

of California, Irvine Gerd P. Pfeifer, PhD, Van Andel Research Institute Joseph C. Reese, PhD, Pennsylvania State University David G. Schatz, PhD, Yale University Karlene Simprich, PhD, Stanford University Beth A. Sullivan, PhD, Duke University Medical Center LuZhe Sun, PhD, University of Texas Health Science Center at San Antonio Song Tan, PhD, Pennsylvania State University Kenneth W. Turteltaub, PhD, Lawrence Livermore National Laboratory Ratna K. Vadlamudi, PhD, University of Texas Health Science Center at San Antonio Wenyi Wei, PhD, Harvard Medical School Beverly Wendland, PhD, Johns Hopkins University Ning Zheng, PhD, University of Washington

Section on Medical Sciences Robert David Burk, MD, Albert Einstein College of Medicine John M. Carethers, MD, University of Michigan Health System Gen-Sheng Feng, PhD, University of California, San Diego Michael A. Frohman, MD, PhD, Stony Brook University Gabriel Hortobagyi, MD, FACP, University of Texas MD Anderson Cancer Center Robert E. Hurst, PhD, University of Oklahoma Health Sciences Center Christopher D. Kontos, MD, Duke University Medical Center Calvin J. Kuo, MD, PhD, Stanford University School of Medicine Robert J. Matusik, PhD, Vanderbilt University Medical Center Lopa Mishra, MD, University of Texas MD Anderson Cancer Center Beverly S. Mitchell, MD, Stanford University School of Medicine Mark R. Philips, MD, New York University School of Medicine Vito Quaranta, MD, Vanderbilt University School of Medicine Peter S. Rabinovitch, MD, PhD, University of Washington Jeffrey M. Rosen, PhD, Baylor College of Medicine Qing Yi, MD, PhD, Cleveland Clinic Nominations for the 2016 AAAS fellows cycle began on November 23, 2015. n

ASCOPost.com | DECEMBER 10, 2015

PAGE 85

Direct From ASCO

Making a Difference for Patients: An Interview With Dr. Daniel F. Hayes, 2015–2016 President-Elect

Daniel F. Hayes, MD, FASCO

aniel F. Hayes, MD, FASCO, began his term as ASCO PresidentElect this past June, and will serve as President in 2016–2017. A breast cancer specialist, he is Professor of Internal Medicine, the Stuart B. Padnos Professor in Breast Cancer, and the Clinical Director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center. ASCO Connection: How did you react when you learned that you had been selected as President-Elect? Dr. Hayes: I was thrilled and honored. I actually never thought I would want to [be President], until about 5 years ago, when Douglas Blayney, MD, FASCO, was President and asked me to be Scientific Program Committee Chair. That showed me all the work that ASCO does. I’d been a member for a long time but had never seen its inner workings. That experience stimulated me to run for the Board of Directors, and I was fortunate to be elected. That was a great experience, and that’s when I realized what an honor it would be to represent this organization as President. When I got the news that I had been elected, I was elated. AC: What unique perspective and experience do you bring to the ASCO leadership? DH: For the past 30 years, I’ve been

a clinician taking care of patients, I’ve been involved in clinical research, and I’ve run a laboratory conducting translational research. In that respect, I represent clinicians and researchers on both sides of the bench. As nearly everyone has, I’ve had experiences with cancer in my own family. I’ve seen how devastating it can be. I’ve also seen what really terrific caregivers can do for patients and their families. I’ve been extraordinarily fortunate to have trained with some of the founders of oncology—the people who made the field what it is. They’ve given me perspective about giving back to people who have cancer and always working to better help our patients. AC: You’ve served on a number of ASCO committees since you joined in 1986. What experiences have been the highlights of your volunteer service? DH: The thing I’m most proud of is my experience on the Tumor Marker Guidelines Panel over the past 20 years. I was one of the charter members. The panel has established specific guidelines for breast and colon cancers on using particular markers, and it has led to a number of policy statements on how tumor markers should be studied and taken into the clinic. It’s been great to see those papers have an influence internationally. The panel’s work led to collaboration between ASCO and the College of American Pathologists (CAP)—I would talk to pathologists and they would talk to me, but ASCO and CAP didn’t have a formal relationship at the time. In 2007, given the remarkable results of trastuzumab, ASCO and CAP agreed to jointly convene a committee to review HER2 testing, jointly chaired by Antonio Wolff, MD, FACP, FASCO, and myself (ASCO), and Elizabeth Hammond, MD, and Jared Schwartz,

Save the Date

MD, PhD (CAP). This was so successful that another joint committee reviewed hormone receptors in breast cancer. Those two collaborations have led to some very productive initiatives, one of which involves helping low-income countries that would like to improve their training in pathology. It’s been a great experience to work with terrific colleagues in both organizations to take these ideas and make them work. I really enjoyed my time on the Breast Cancer Track of the Scientific Program Committee. I’ve been a member of the committee three times, Track Leader once, and chaired the whole committee once. It was a lot of work, and a lot of fun, and there was a great process in place that allowed track leaders and committee members to do their work and do it well. AC: What are some issues on which you hope to have an impact during your term? DH: Part of the job is just to keep the ship sailing in the right direction, and ASCO is absolutely moving in the right direction. It’s had great leadership over the years, and frankly, it’s pretty humbling to look backward and think about the shoes into which I’m stepping! I’m excited about ASCO’s work in regard to value. We’ve been worried about the cost of drugs for quite some time, but it’s about more than just cost. It’s about whether the therapies and the diagnostics we’re recommending really have value in terms of better care for our patients. ASCO’s Value Framework is going to be a really important roadmap. We need to continue to address issues in the oncology workforce, not just for physicians, but also for nurse practitioners and physician assistants. We also need to reach out to medical

students and doctors in training and get them excited about becoming oncologists. They don’t get much experience with oncology until their clinical years, and by that time many of them are interested in other fields. We need to show them what we do and why we do it. There are a lot of issues faced by clinicians in practice, and I’m excited to work with Stephen Grubbs, MD, in his new role as Director of ASCO’s Clinical Affairs Department. And of course, I’m very excited about CancerLinQ and all of its many possibilities. ASCO believes this will be a game changer for understanding more about care of patients with cancer, and we’ve just begun to scratch the surface of what it will provide. Finally, I will be faced with the challenge of welcoming a new CEO at the same time I receive the gavel, as Allen Lichter, MD, FASCO, steps down after a decade of incredible growth and success under his leadership. Of course, I’m excited about this opportunity and have enormous faith that the selection committee will have a terrific slate of enormously qualified and experienced candidates from which to choose. I am confident that ASCO will continue to fulfill its mission as the place for patients and their caregivers to go for help and guidance. Fundamentally, what I want to do is make a difference for all of our constituencies, but ultimately, for our patients. When I was on the ASCO Board of Directors, every decision that we made was based on whether it was best for patients. That’s what I hope to maintain. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Making a Difference for Patients: An Interview with Dr. Daniel F. Hayes, 2015– 2016 President-Elect” connection.asco.org 26 August 2015. All rights reserved.

Genitourinary Cancers Symposium

Cancer Survivorship Symposium

January 7–9, 2016

January 15–16, 2016

Moscone West Building

San Francisco Marriott Marquis

San Francisco, California

The ASCO Post | DECEMBER 10, 2015

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Direct From ASCO

Now Available: Holiday Cards From the Conquer Cancer Foundation

he holiday season has officially begun, but there is still plenty of time to share in the spirit of giving on behalf of someone special. When you donate to the Conquer Cancer Foundation through cards.conquercancerfoundation.org, the Foundation will mail greeting cards or email eCertificates in appreciation of your gift. These holiday cards can be sent in honor or in memory of a loved one and feature artwork

created by people affected by cancer. Your gift this month is especially meaningful; all donations will be tripled thanks to a matching gift grant. Sending a holiday tribute card this season is one of the many ways to help us create a world free from the fear of cancer. Please join us in spreading the word—and the holiday spirit! n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | DECEMBER 10, 2015

PAGE 87

Direct From ASCO

This December: Triple Your Impact

Gifts to the Conquer Cancer Foundation will be matched 2-to-1 by Raj Mantena, RPh

arlier this year, Conquer Cancer Foundation (CCF) Board Member Raj Mantena, RPh, announced his intention to match individual donations to CCF dollar-for-dollar, up to $1 million, throughout the month of September. His generous support of The Campaign

Raj Mantena, RPh

to Conquer Cancer—a comprehensive, $150 million fundraising campaign to take down cancer by supporting breakthrough research and sharing vital

knowledge with physicians, patients, and families—was instrumental in helping CCF work toward meeting its goal of raising $50,000 by September 30. Throughout the month of December, Mr. Mantena is yet again matching all donations to the Conquer Cancer Foundation 2-to-1, tripling the impact of gifts made between December 1 and 31. As with regular gifts, matching gift funds will support the Foundation mission area each donor selects. Options include the CCF Grants and Awards Program, Cancer.Net and ASCO’s patient information program, CancerLinQ (ASCO’s rapid learning system), and more. If a donor does not have a particular mission area in mind, he or she can always give to CCF’s “Area of Greatest Need,” supplying triple the support where it is needed most. No matter which mission area a do-

nor selects, all gifts count toward The Campaign to Conquer Cancer’s $150 million goal. While Mr. Mantena’s challenge means each donation goes three times as far, it also means that each gift brings the Foundation three times closer to realizing its vision: a world free from the fear of cancer. History has shown we can—and have—made progress: The cancer death rate has dropped 20% in the past 20 years thanks, in part, to the hard work of dedicated oncology professionals. But it is critical we continue this momentum, which cannot be maintained without the support of generous donors. Donors can participate in this matching gift challenge at conquercan-

cerfoundation.org/match or by mailing a check to the Conquer Cancer Foundation at P.O. Box 896076, Charlotte, NC 28289-6076. Mail donations must be postmarked by December 31, 2015, to qualify for the 2-to-1 match. Will you step up to the challenge? n © 2015. American Society of Clinical Oncology. All rights reserved.

Earn MOC Points With ASCO Barriers to Oncology Careers Focused on Cancer Prevention Could Be Addressed Through Education, Research Opportunities, Advocacy

new study in the Journal of Clinical Oncology (JCO) on the barriers facing oncology professionals to a career focus in cancer prevention found that a lack of mentors and exposure during training, unclear career path, and uncertainty regarding reimbursement caused reluctance to incorporate prevention into a career in cancer care. The study, “Barriers to a Career Focus in Cancer Prevention: A Report and Initial Recommendations From the American Society of Clinical Oncology Cancer Prevention Workforce Pipeline Work Group,” surveyed oncology fellows and their training program directors to determine how each group views careers in cancer prevention and to identify obstacles in the way of such careers. While 88% of the oncology fellows thought cancer prevention was important relative to treatment, only 15% indicated they would likely be interested in cancer prevention as a career focus. Training directors estimated that 10% of fellows starting an academic career or entering private practice would have

a career focus in cancer prevention. Top fellow-listed barriers to an academic career focused on cancer prevention were difficulty in obtaining funding and lower compensation. Additional barriers to an academic career with a prevention focus included unclear career model, lack of clinical mentors, lack of clinical training opportunities, and concerns about reimbursement. The authors of the study call for more educational resources for fellows, training directors, and practicing oncologists, an increase in funded training and clinical research opportunities, more content on prevention in accrediting examinations for clinical oncologists, and advocacy focused on broadening the scope and depth of reimbursement for prevention counseling and intervention services in order to address these barriers. To read the full JCO article, go to: http://jco.ascopubs.org/content/early/2015/10/26/JCO.2015.63.5979.full. n © 2015. American Society of Clinical Oncology. All rights reserved.

he American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) program promotes lifelong learning and the enhancement of the clinical judgment and skills essential for high-quality patient care. ASCO supports these principles by providing a variety of opportunities for oncology professionals to efficiently and easily earn MOC points.

ASCO MOC App The ASCO MOC app’s General Oncology course is a 30-question self-assessment designed for mobile devices. The app notifies participants every other day that new questions are available for completion. This “pulsed-education” technique assists with knowledge retention and easily fits into an oncologist’s busy schedule. Each multiple-choice question includes patient case information, educational links, and answer rationales. After successfully completing the activity, ABIM diplomates are eligible to claim 10 MOC points in SelfAssessment of Medical Knowledge directly through the app.

ASCO University MOC Courses ASCO University MOC Courses build oncology medical knowledge on a variety of topics to fulfill requirements. Each course comprises 30 case-

based, multiple-choice questions with detailed answer rationales and links to suggested readings. Participants can earn MOC points in Self-Assessment of Medical Knowledge and CME credits through these courses. Course topics include: • Breast Cancer • Comprehensive Oncology • Educational meeting reviews, including Palliative Care in Oncology Symposium, Breast Cancer Symposium, ASCO Annual Meeting, and Genitourinary Cancers Symposium • Gastrointestinal Cancers • Genitourinary Cancers • Leukemia/Lymphoma • Lung Cancer • Palliative Care • Prevention/Screening • Tobacco Cessation • Tumor Genomics continued on page 88

The ASCO Post | DECEMBER 10, 2015

PAGE 88

Direct From ASCO Earn MOC Points continued from page 87

MOC Self-Assessment Activities MOC Self-Assessment Activities are designed for educational meeting attendees who want to refresh their knowledge, update their skills, or prepare for their Board Certification or MOC examination. These activities can be added during the registration process for meetings where they are being offered. Previously, these activities have been offered at the ASCO Annual

Resource to Help Patients Manage Cancer Costs

elp your patients manage the financial impact of a cancer diagnosis with Cancer.Net’s Managing the Cost of Cancer Care booklet. This booklet provides information on the main financial categories for cancer care; an easy-to-understand explanation of health insurance benefits; information about the Affordable Care Act and cancer; tips for organizing financial information; a list of financial resources; and a cost and insurance dictionary. Download a free printable PDF at www.cancer.net or visit the ASCO University Bookstore at cancer.net/estore to order copies of this booklet for your office. ASCO members receive a 20% discount. n

Meeting and at cosponsored symposia, such as the Genitourinary Cancers Symposium, Palliative Care in Oncology Symposium, and Breast Cancer Symposium. Participants complete three steps in this activity: • Take an Online Pre-Test: This 30-question self-assessment is de-

signed to identify knowledge gaps. • Attend Sessions: To help fill knowledge gaps, test questions are reviewed and discussed by faculty throughout the Symposium. • Take an Online Post-Test: Once the 30-question post-test is successfully completed, participants are eligible to claim 10 MOC points in

Self-Assessment of Medical Knowledge. Data and scores can be sent directly to ABIM. To learn more about opportunities to earn MOC points through ASCO, visit university.asco.org/MOC. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | DECEMBER 10, 2015

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Announcements

MD Anderson Receives $22.2 Million in CPRIT Research Funding

he University of Texas MD Anderson Cancer Center was awarded more than $22 million in research grants from the Cancer Prevention and Research Institute of Texas (CPRIT). Thirty-six percent of funds awarded for Individual In-

vestigator Awards went to MD Anderson faculty, as well as nearly 40% of funds awarded for recruitment. Across Texas institutions, CPRIT awarded a total of $112 million in 73 new grants. The MD Anderson CPRIT awards included $14.8 mil-

lion for research, $6 million in recruitment funding, and $1.4 million for evidence-based cancer prevention services. These CPRIT awards will fund investigations in cancers of the liver, skin, pancreas, and ovary, as well

as lymphoma, leukemia, and other c ancers. “We are extremely grateful to the citizens of Texas for supporting truly important and life-saving cancer research,” said MD Anderson President Ronald DePinho, MD. n

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PAGE 91

Journal Spotlight Immunotherapy

Gut Bacteria May Facilitate Efficacy of Anti–PD-L1 Agents By Caroline Helwick

ould the manipulation of bacteria in the gut pack the same punch in melanoma as antibodies targeting the programmed cell death protein and its ligand (PD-1/PD-L1)? It’s possible, at least in mice, according to research from the University of Chicago, recently published in Science.1 The researchers reported that oral administration of Bifidobacterium alone improved tumor control to the same degree as anti–PD-L1 therapy and that the combination treatment nearly abolished tumor growth.

to the presence of melanoma. Tumors grew slowly in the Jackson Laboratory mice, whereas they grew aggressively in mice from Taconic Biosciences. This difference appeared to be immune-mediated, since tumor-specific T-cell responses and intratumoral CD8-positive T-cell accumulation were significantly higher in the Jackson vs Taconic mice, the researchers reported. However, when the mice were mixed and housed together, these differences in tumor growth were abolished. The

Our results clearly demonstrate a significant, although unexpected, role for specific gut bacteria in enhancing the immune system’s response to melanoma and possibly many other tumor types. —Thomas Gajewski, MD, PhD

“Our data suggest that manipulating the microbiota may modulate cancer immunotherapy,” wrote Ayelet Sivan, MD, and colleagues. Senior author Thomas Gajewski, MD, PhD, a melanoma expert who is Professor of Medicine and Pathology at the University of Chicago, added: “Our results clearly demonstrate a significant, although unexpected, role for specific gut bacteria in enhancing the immune system’s response to melanoma and possibly many other tumor types.”

Co-Housing and Shared Bacteria The checkpoint inhibitors ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda) have produced robust responses in advanced melanoma—although not in the majority of patients. The reasons for this lack of response remain unclear. Dr. Gajewski and his group found a similar pattern in mice implanted with melanoma tumors. From two different facilities, they obtained mice that were genetically similar but different in terms of their commensal gut microbes. It turned out the two groups also differed in their immune response

researchers hypothesized that by sharing exposure to various types of bacteria, the Taconic mice acquired microbes from the Jackson mice, which somehow enhanced their immunity to the tumors. Their hypothesis was validated when they transferred fecal matter from the Jackson mice to their weaker Taconic peers; thereafter, these mice were able to mount a strong immune response against the tumors. The transfer was sufficient to delay tumor growth and enhance induction and infiltration of tumor-specific CD8-positive T cells, supporting a microbe-derived effect, they wrote. Reciprocal transfer of fecal matter of Taconic mice into Jackson mice recipients had little effect on tumor growth and antitumor T-cell response.

Comparing Bacteria With Anti–PD-L1 Agent The researchers then compared the immune response after bacterial transfer of Jackson mice fecal matter with the effect of anti–PD-L1 antibodies (they used a mouse compound that is similar to the available agents for humans). Transfer alone resulted in significantly slower tumor growth, accompanied by

Gut Bacteria and Antitumor Immunity ■■ Oral administration of Bifidobacterium alone improved tumor control to the same degree as anti–PD-L1 therapy and the combination treatment nearly abolished tumor growth, according to a preclinical study. ■■ Mice that received this bacterium had robust induction of tumor-specific T cells in the periphery of the tumor and increased accumulation of antigenspecific CD8-positive T cells within the tumor—effects that were durable for several weeks. ■■ The next step in this research is to sequence the microbiota of patients with melanoma, correlating it with anti–PD-1/PD-L1 efficacy.

increased tumor-specific T-cell responses and infiltration of antigen-specific T cells into the tumor to the same degree as seen with anti–PD-L1 agents, they reported. When the two approaches were combined, the researchers observed enhanced tumor control and circulating tumor antigen–specific T-cell responses. The group then performed largescale sequencing of microbes in the digestive tract, to determine the type of bacteria responsible for the immune response. Although they found significant differences in 254 taxonomic families of bacteria between the two mouse populations, Bifidobacterium stood out as the most abundant in the Jackson cohort. To further test the power of Bifidobacterium, they administered this strain to the Taconic mice alone and in combination with anti–PD-L1 agents. Mice that received this bacterium displayed significantly improved tumor control vs their counterparts who did not; they had robust induction of tumor-specific T cells in the periphery of the tumor and increased accumulation of antigenspecific CD8-positive T cells within the tumor—effects that were durable for several weeks. Oral administration of Lactobacillus murinus, on the other hand, had no effect on tumor growth or T cell response, suggesting that modulation of antitumor immunity depends on the specific bacterium administered. “Collectively, these data point to Bifidobacterium as a positive regulator of antitumor immunity in vivo,” they concluded. Additional tests showed that the bacteria probably triggered the immune response by interacting with roaming dendritic cells. This augmented den-

dritic cell function led to enhanced CD8-positive T-cell priming and accumulation in the tumor microenvironment. Further investigations revealed evidence of enriched pathways for genes shown to be critical for antitumor responses.

Applicable to Humans? With animal experiments, the pivotal question is always whether the findings will be applicable to humans someday. To this question, Dr. Gajewski answered, “Yes. We are excited about the possibility that similar associations between specific gut bacteria and clinical outcomes with checkpoint blockade therapy might be found in humans. If so, then it should be possible to develop a probiotic to improve the efficacy of cancer immunotherapies.” The group’s next step is to sequence the microbiota of patients with melanoma, correlating it with anti–PD-1/ PD-L1 efficacy. “We think examining the clinical relevance of this effect should receive high priority,” Dr. Gajewski told The ASCO Post. “In addition, we are extending our laboratory work to gain a deeper understanding of the mechanisms involved and also to investigate whether additional types of bacteria beyond Bifidobacterium impact antitumor immunity—either positively or negatively.” n Disclosure: For full disclosures of the study authors, visit www.sciencemag.org.

Reference 1. Sivan A, Corrales L, Hubert N, et al: Commensal Bifidobacterium promotes antitumor immunity and facilitates antiPD-L1 efficacy. Science. November 5, 2015 (early release online).

PAGE 92

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; DECEMBER 10, 2015

Global Cancer Burden World Health Organization Region: The Americas Country: Argentina

Cancer on the Global Stage: Incidence and Cancer-Related Mortality in Argentina By Eduardo L. Cazap, MD, PhD, FASCO The ASCO Post is pleased to continue this special feature on the worldwide cancer burden. In this issue, we feature a close look at the cancer incidence and mortality rates in Argentina. The aim of this special feature is to highlight the global cancer burden for various countries of the world. For the convenience of the reader, each installment will focus on one country from one of the six regions of the world, as defined by the World Health Organization (ie, Africa, the Americas, South-West Asia, Europe, Eastern Mediterranean, and Western Pacific). Each section will focus on the general aspects of the country followed by the current and predicted rates of incidence and cancer-related mortality. It is hoped that through these issues, we can increase awareness and shift public policy and funds toward proactively addressing this lethal disease on the global stage.

rgentina, with its population of nearly 44 million, is the 33rd most populous country in the world and the third most populous in South America after Brazil and Colombia. With a median age Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

of 31.4 years, the average life expectancy at birth is 77.69 years. Argentina spends nearly 8.5% of its gross domestic product on health care, which is less than that of the United States but comparable to some of the European countries. Breast, colorectal, lung, and prostate cancers are the most frequently diagnosed cancers in Argentina, whereas lung, colorectal, breast, and prostate cancers account for the most cases of cancer-related mortality. Argentina currently ranks 49th in cancer frequency in the world, with an age-standardized rate of 216.7 cases/100,000 population. Similar to the rest of the world, Argentina will also witness an alarming rise in cancer burden over the next two decades. It is predicted that the incidence of new cancer cases will increase by nearly 43% (from 120,936 to 173,018), with a corresponding increase in cancer-related mortality by 48% (from 69,960 to 103,463). Several causes are presumed to be contributing to this increasing cancer burden and include rising tobacco use, infections leading to cancer, changing lifestyle, and an aging population. The tobacco usage rate stands at 22.7%, and the current human papillomavirus prevalence rate is 20.1% in women with normal cytology.

ASCOPost.com | DECEMBER 10, 2015

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Focus: Argentina Several efforts are underway in Argentina to address the cancer burden. They include the implementation of an integrated national strategy for treating noncommunicable diseases (2009). There are also multiple national and subnational cancer registries, which are predominantly population-based, and a Regional Network Hub from the International Agency for Research on Cancer (IARC) for Latin America is coordinated by the National Cancer Institute of Argentina (http://gicr.iarc.fr/en/Solution). Eduardo L. Cazap, MD, Numerous other national policies to curb smoking, tackle PhD, FASCO obesity (2012), alcohol prevention and control (2011), improve immunization rates for human papillomavirus (2011) and hepatitis B virus (1997) are also underway. Similarly, cancer screening for some of the common cancers (cervical, breast, and colorectal) are generally available in both the public and private sectors. This multitude of current efforts with additional future strategies should contribute significantly to addressing the rising cancer burden in Argentina. n

Table 1: General Facts

Dr. Cazap is President of the Latin-American & Caribbean Society of Medical Oncology and a member of the Executive Committee of the National Cancer Institute, Ministry of Health, Buenos Aires, Argentina.

Mobile telephones

66.4 million (2014)

Land lines

9.4 million (2014)

Population

43.5 million (2015)

Median age

31.4 years

Population growth rate

0.93% (2015)

Birth rate per 1,000 population

16.64 (2015)

Death rate per 1,000 population

7.33 (2015)

Life expectancy at birth

77.69 years

Health expenditure as % of GDP

8.5% (2015)

Physicians per 1,000 population

3.86 (2013)

Hospital bed density per 1,000 population

4.7 beds (2012)

Obesity prevalence rate

25,000

12,000

2,0000

10,000

26.5% (2014)

8,000

15,000

6,000 10,000

4,000

5,000

2,000

0 Breast

Colorectum

Lung

Prostate

Cervix Uteri

Kidney

Pancreas

Stomach

Bladder

NonHodgkin Lymphoma

Fig. 1: Top 10 Cancers by Incidence—Current Rates in Argentina.

Lung

Colorectum

Breast

Prostate

Pancreas

Stomach

Cervix Uteri

Liver

Kidney

Esophagus

Fig. 2: Top 10 Cancers by Mortality—Current Rates in Argentina.

120,000

200,000 180,000 160,000 140,000 120,000 100,000 80,000 60,000 40,000 20,000 0

100,000 80,000 60,000 40,000 20,000 0 2015

2020

2025

2030

2035

Fig. 3: Trends in the Incidence of New Cancer Cases in Argentina: 2015–2035.

GUEST EDITOR

Chandrakanth Are, MBBS, MBA, FRCS, FACS

r. Are is Jerald L & Carolynn J. Varner Professor of Surgical Oncology & Global Health, Vice Chair of Education, Program Director, General Surgery Residency, University of Nebraska Medical Center, Omaha.

2015

2020

2025

2030

2035

Fig. 4: Trends in Cancer-Related Mortality in the Argentina: 2015–2035.

Additional Readings 1. https://www.cia.gov/library/publications/the-world-factbook/rankorder/ 2119rank.html 2. http://www.who.int/cancer/country-profiles/en/ 3. http://www.hpvcentre.net/ 4. http://www.iccp-portal.org/cancer-plans 5. http://www.iccp-portal.org/sites/default/files/plans/Argentina 6. http://wcrf.org/int/cancer-facts-figures/data-cancer-frequency-country 7. http://www.msal.gob.ar/inc/ 8. http://gicr.iarc.fr/en/Solution

Note to Readers: If you are interested in participating in this continuing series on the global cancer burden and have an interesting perspective to share about a particular region of the world, contact Dr. Are at care@unmc.edu.

The ASCO Post | DECEMBER 10, 2015

PAGE 94

National Cancer Policy Forum Health-Care Disparities

Cancer Care in Low-Resource Areas: Some Improvements Over the Years, but Serious Problems Remain By Margot J. Fromer

“L

ow- and middle-income countries bear a larger share of the global cancer burden than does the developed world,” said Greta Massetti, PhD, Associate Director for Science, Centers for Disease Control and Prevention (CDC) Division of Cancer Prevention and Control and Co-Chair of the National Cancer Policy Forum workshop “Cancer Care in Low-Resource Areas,” held recently in Washington, DC. The same applies to poor areas in developed countries, which also suffer a disproportionate burden of cancer risk, incidence, and mortality. Cultural and socioeconomic factors exacerbate the problem and contribute to disparities. “Cancer mortality can be reduced, but outcomes vary significantly because control infrastructure is highly variable among and within countries,” she said. Cancer control comprises prevention, detection, and diagnosis coupled with informed decision-making, treatment, outcomes research, and survivorship. These factors are affected by what Dr. Massetti called crosscutting issues: communications, surveillance, social determinants of health disparities, genetic testing, decision-making, dissemination of evidence-based interventions, quality of care, epidemiology, and measurement, all of which tend to be in shorter supply and of poorer quality in low- and middle-income countries. In fact, despite the larger death toll from cancer, a large portion of healthrelated funding from private organizations and from U.S. and European governments to low- and middle-income countries is invested in treatment and prevention of infectious diseases like HIV/AIDS, tuberculosis, and malaria. For example, according to Dr. Massetti: • HIV/AIDS care receives $6.2 billion, with 2.1 million deaths. • Tuberculosis care receives $903 million, with 1.1 million deaths. • Malaria care receives $1.3 billion, with 711,000 deaths. • Cancer care receives $168 million, with 4.8 million deaths. Prevention is even more critical. “Thirty percent of all cancer deaths are preventable,” said Dr. Massetti. “This is especially true with regard to tobacco use, which causes 22% of all cancer

deaths and 71% of lung cancer deaths worldwide. Viral infections such as hepatitis B and C and human papillomavirus (HPV) are responsible for almost 20% of cancer deaths in low- and middle-income countries. Moreover, 80% of cancers in these countries present at a stage when cure is impossible and palliation is the only treatment.”

Cancer mortality can be reduced, but outcomes vary significantly because control infrastructure is highly variable among and within countries. — Greta Massetti, PhD

Challenges in Prevention, Control, and Early Detection Thomas J. Bollyky, Senior Fellow for Global Health, Economics, and Development, Council on Foreign Relations, raised three critical questions: (1) Are cancers and other noncommunicable diseases a crisis in low- and middle-income countries? (2) What is the U.S. interest in addressing that crisis? (3) What is a practical, cost-effective role for collective action?

Thomas J. Bollyky

The answer to the first question is a resounding yes. There has been a steep rise in cancer since 1990, from 18% of all deaths worldwide to almost 28% in 2012, and most of that increase has occurred in Africa and Asia. Noncommunicable disease–related deaths are rising faster than the population is increasing, and noncommunicable diseases are appearing in younger people with worse outcomes and increasing mortality. Moreover, the rise of noncommunicable diseases exceeds the decline of infectious diseases. The United States should have an interest in the worldwide cancer crisis, but that interest is not reflected in U.S. aid programs—at least not yet, said Mr. Bollyky. “We have no dedicated programs or national budget, although there are small-scale, ad hoc efforts to integrate objectives into U.S. global health programs. However, only $10.8 million was spent this way in 2013.” Investments to address noncommunicable diseases would support eco-

nomic development and trade because low- and middle-income countries represent about half of global growth since the 2008 financial crisis. The 2011 World Economic Forum estimated that noncommunicable diseases will represent $21.3 trillion in losses in developing countries in the next 2 decades. Therefore, helping these countries address their health crises can build fruitful partnerships with allies and prevent economic disaster. For the third question—how to help—Mr. Bollyky suggested: ■■ Increase U.S. investments in the areas where effective interventions already exist and where an existing U.S. aid infrastructure can be leveraged to improve access in low- and middle-income countries, such as international tobacco, HPV vaccination and screening, and hepatitis B immunization ■■ Increase U.S. investments in the diseases where effective interventions exist but require adaptation for wider use in low-infrastructure and resource settings in developing countries, such as for breast and stomach cancers, leukemia, and children’s cancers ■■ Greater U.S. cooperation with developing countries and the private sector on improving populationbased prevention of modifiable behavioral risks and developing lower cost chronic care strategies Kathleen M. Schmeler, MD, Associate Professor, Department of Gynecologic Oncology, MD Anderson Cancer Center, used cervical cancer as an example. In the United States, there are 12,900 new cases of cervical cancer each year, with 4,100 deaths. It is the 14th most frequent cancer among women. In low- and middle-income countries, it is one of the leading causes of cancer death, especially in Mexico,

South America, and sub-Saharan Africa. Each year, 400,000 women die of the disease globally. Cervical cancer rates are also high in underserved areas of the United States, such as the TexasMexico border where cervical cancer rates are 31% higher than in nonborder counties. About 1.3 million people live in four counties in Texas on the Mexican border; 90% of these people are Hispanic, 40% of whom live in poverty. Less than 5% of eligible women receive cervical cancer screening, and loop electrosurgical excision procedure services are available only 1 day a month. The rate of cervical cancer is 31% higher than the national average. While these are dismal statistics, Dr. Schmeler also painted a more positive picture regarding the availability of HPV vaccine in the United States. It is recommended for all girls and boys 11 and 12 years of age and requires three doses over 6 months. Despite the fact that the vaccine must be given prior to the onset of sexual activity, it has been 93% to 98% effective in preventing cervical dysplasia/cancer and is very safe.

Kathleen M. Schmeler, MD

The downside is that there are no school-based HPV vaccination programs; it must be done privately. Thus, only 40% of girls complete the vaccination series, as do 21.6% of boys. In Australia, Canada, and the United Kingdom, the rate is more than 70%, continued on page 97

Potential Impact of Biosimilars in the United States Biologics accounted for eight out of the ten highestexpenditure drugs in Medicare Part B spending in the United States with some treatments costing $100,000 or more per year.1,2 The cost of biologics is outpacing overall pharmaceutical spending growth.3 The advent of biosimilars is expected to help contain the cost of biologics, stimulate competition, improve patient access and encourage innovation.

EASING THE ECONOMIC STRAIN Biologics have been groundbreaking in the treatment of many diseases, including cancer, multiple sclerosis, autoimmune diseases and chronic kidney disease; however, relative to the number of patients treated, biologics comprise a disproportionate amount of healthcare resources and continue to outpace overall pharmaceutical spending growth.3 In the United States in 2013, the total spent on medicine was reported to be $329 billion, of which $92 billion, or 28%, was spent on biologics.4 Biological Spending as a Percentage of Total Spending on Medicine (2013)4

This class of drugs has undoubtedly improved patient outcomes, but their excessive costs have also placed limitations on the ability of some patients to access them. In a survey of 450 hematologists and oncologists, less than 40% considered a biologic easy to access from a cost perspective.7 Conversely, it has been predicted that biosimilars will lead to a $44 billion reduction in US spending on biologic drugs for the years 2014 to 2024, or about 4% of total biologic spending, ranging from $13 billion to $66 billion.8 In total, the use of biosimilars may save the US healthcare system $250 billion by 2024, a calculation based on the assumption that 11 of the most likely biosimilar candidates would enter the US market by that time (based on conservative estimates of utilization, cost and consumer inďŹ&#x201A;ation).9 Global Biologics Sales, 2002-20173

$169 billion

$46

billion 2007

2012

2017 (projected)

Biologics: $92 billion

Biologics continue to outpace overall spending growth and are expected to represent 19% to 20% of global market value by 2017.3

Total: $329 billion

US BIOSIMILARS OVER THE NEXT 5 YEARS

Almost 1 in every 3 drugs in development today in the United States is a biologic, and estimates indicate a 20% increase in the growth of the biologics market every year.5 As more approvals are granted, these costs can be expected to continue to increase. A growing pipeline, approval for more indications and more common conditions, along with increased utilization, are likely factors that are responsible for this growth. By 2025, experts predict that 71% of new drug approvals may consist of biologics.6

When biologic products were first developed in the 1980s, they were considered to be so specialized that generic versions seemed highly unlikely. Recently, however, the first biosimilar was approved in the United States, opening the door to less expensive alternatives to a class of drugs that has been complex and revolutionary, but very costly.10 By the year 2020, it is likely that the United States will be the cornerstone of the global biosimilars market, which may be as large as $25 billion.11 Predicted US Biosimilars Market Size (% of biologics market)11

$11-$25

Projected US New Drug Approvals: % Biologics6

2015

billion

$106

2002

28%

$221

billion

>50%

Upper Bound Base Case Lower Bound

$25 bil (10 %) $20 bil (8 %)

$11 bil (4 %)

2025

>70%

$1.9-$2.6 billion 2015

$2.6 bil $1.9 bil 2020

Driving US growth will be many biologic patents that have either expired or are due to expire in the near future, prompting competition from manufacturers to develop biosimilars for therapeutic and supportive care products.12

GLOBAL PERSPECTIVES FROM AN EVOLVING LANDSCAPE • “Pharmerging” markets: “Pharmerging” markets have been defined by IMS as a group of 21 countries (outside the United States) with emerging markets, based on macroeconomic metrics and pharmaceutical market forecasts.13 Biosimilar growth will be dependent on these geographic areas in terms of manufacturing and market size11 • Europe: To maximize growth prospects, major European markets that have been late adopters to the uptake of biosimilars (e.g., Spain and Italy), will need to follow in the path of countries such as Germany, which currently holds a 34% share in the European biosimilars market11 • Technology: Technological hurdles—such as patented delivery systems—may present a challenge for biosimilar manufacturers if they cannot be overcome expeditiously and thus prevent manufacturers from tapping into all therapeutic areas where biologic patents have expired11 • Volume effect: The potential exists for a significant volume effect of biologics consumption, as has been seen with granulocyte-colony stimulating factor (G-CSF) products in the United Kingdom and Sweden. In this case, physicians in the UK moved G-CSF back to first-line therapy to prevent hospital readmissions due to infections in cancer patients once cost-reductions from biosimilars were realized. Similar effects were seen in Sweden. If this occurs, market growth for biosimilars could be driven further upward11

BIOSIMILARS MAY IMPROVE PATIENT ACCESS The first major benefit of biosimilars is broadening the availability of effective biologics to previously underserved patient populations. Reductions in cost can ease the limitations that some patients face in accessing these needed therapies.14

BIOSIMILARS MAY HELP CONTAIN THE INCREASING COST OF BIOLOGICS The second major benefit is cost reduction. • Although biosimilars require the investment of substantial time and expense to develop, they ultimately provide cost savings compared with reference biological products15 • Economic impact studies project that biosimilars could save the United States $250 billion between 2014 and 20248

BIOSIMILARS MEAN GREATER COMPETITION AND MORE INNOVATION • Competition may enable biologic manufacturers to take advantage of the latest technologies and leverage what has been learned from the reference biologic to provide additional biosimilar products that can lead to cost savings16 • Biosimilars may provide originator companies an added incentive to invest in the development of innovative new biologics17

The Benefits of Biosimilars Cost savings

Greater patient access

Greater competition

More innovation

• Competitive landscape: Finally, the IMS Global forecast assumes that major markets will drive positive financial returns and biosimilar growth, which would consequently allow for competition, barring financial hurdles and poor uptake in major markets that produce only a limited number of competitors11 References: 1. US Government Accountability Office (GAO). Medicare information on highest-expenditure Part B drugs. GAO highlights of testimony before the Subcommittee on Health, Committee on Energy and Commerce, House of Representatives. 2013. 2. Engelberg AB, Kesselheim AS, Avorn J. Balancing innovation, access, and profits—market exclusivity for biologics. N Engl J Med. 2009;361(20):1917-1919. 3. IMS Institute for Healthcare Informatics. The global use of medicines: Outlook through 2017. Parsippany, NJ: IMS Institute for Healthcare Informatics; November 2013. 4. IMS Institute for Healthcare Informatics. Medicine use and shifting costs of healthcare: A review of the use of medicines in the United States in 2013. April 2014. 5. Simoens S. Biosimilar medicines and cost-effectiveness. Clinicoecon Outcomes Res. 2011;3:29-36. 6. Erickson BE. Untangling biosimilars. Chem Eng News. 2010;88(48):25-27. 7. Baer WH II, Maini A, Jacobs I. Barriers to the access and use of rituximab in patients with non-Hodgkin’s lymphoma and chronic lymphocytic lukemia: A physician survey. Pharmaceuticals (Basel). 2014;7:530-544. 8. Mulcahy AW, Predmore Z, Mattke S. The cost savings potential of biosimilar drugs in the United States. Perspective. Rand Corporation [website]. 2014. Available at http://www.rand.org/content/dam/rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf. Accessed April 28, 2015. 9. Miller S. The $250 billion potential of biosimilars. April 23, 2013. Express Scripts [website]. Available at http://lab.express-scripts.com/insights/ industry-updates/the-$250-billion-potential-of-biosimilars. Accessed May 19, 2015. 10. U.S. Food and Drug Administration (FDA). FDA approves first biosimilar product Zarxio [press release]. March 6, 2015. FDA [website]. Available at http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm436648.htm. Accessed April 29, 2015. 11. IMS Health. Shaping the biosimilars opportunity: A global perspective on the evolving biosimilars landscape. December 2011. 12. Camacho LH, Frost CP, Abella E, et al. Biosimilars 101: Considerations for U.S. oncologists in clinical practice. Cancer Med. 2014;3(4):889-899. 13. IMS Health. Pharmerging markets: Picking a pathway to success. June 2013. 14. Rak Tkaczuk KH, Jacobs IA. Biosimilars in oncology: From development to clinical practice. Semin Oncol. 2014;41(2)(suppl 3):S3-S12. 15. Federal Trade Commission Report. Emerging health care issues: Follow-on biologic drug competition. Washington, DC: Federal Trade Commission; June 2009. 16. Buffery D. Competition from biosimilars an incentive for innovation. Am Health Drug Benefits. 2010;3(1):27-28. 17. Biologics Price Competition and Innovation Act. 2009.

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045

P15-0727-5-Aug., 15.

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National Cancer Policy Forum Low-Resource Areas continued from page 94

likely due to school-based vaccination programs. Cervical cancer screening systems in the United States require a significant infrastructure including a pathologist for diagnosis, which is a critical problem in much of Africa. Per pathologist, there are 15,108 people in the United Kingdom and 19,232 people in the United

public-private partnerships, including the U.S. government via the President’s Emergency Plan for AIDS Relief ($3 million); the World Bank for HPV vaccination ($385,000); ASCO for improved histology testing; American Society for Colposcopy and Cervical Pathology for training; Becton, Dickinson and Company for donation of 100,000 autodestruct syringes; Merck and Company for donation of 7,800

Cancer prevention has a long time lag prior to its benefit, and many cultures are fatalistic and not future oriented. Moreover, the high cost of treatment leads to inequitable access. — Vivien D. Tsu, PhD, MPH

States. Contrast that with 200,000 to 500,000 people per pathologist in South Africa and Botswana, 5 million in Niger and the Congo—and none in Somalia and Chad. One way to partially counteract this dearth is developing new technology such as high-resolution microendoscopy, an optical imaging system developed by Rebecca RichardsKortum, PhD, at Rice University that allows for point-of-care diagnosis of precancerous lesions. It can be performed by nonphysician health workers and can be combined with a loop electrosurgical excision procedure or cryotherapy for a single-visit treatment approach.

Improvements Not Easy but Possible In Botswana, HPV had become an increasing problem, said Doyin Oluwole, MD, MRCP, FRCP, FWACP, CEO, Global Health Innovations and Action Foundation. “Overworked health staff were focused on childhood immunization and said that HPV vaccination could not begin until 2017. Moreover, there was neither a national injection safety policy nor use of autodisabled syringes. Management of stock was inadequate, and it was difficult to purchase HPV vaccine at a price below what was offered by manufacturers.”  Nevertheless, there were opportunities to decrease the incidence of HPV infection. The Ministry of Health provided leadership in advocacy and oversight and government allocated resources for training and purchase of vaccine. A national cervical cancer control program was supported through

doses of HPV quadrivalent vaccine (Gardasil) in 2013 and 44,000 in 2014; and the Bill & Melinda Gates Foundation/CDC Foundation for analysis of cervical cancer data systems. Results were tangible and sustainable: Botswana developed a national policy on cervical cancer control. The government now fully owns and leads the HPV vaccination program, and the cervical cancer control program is embedded in the national budget. Evaluation of the current plan (2012–2016) will use findings to plan for the next 5 years—with National Cancer Institute support. Dr. Schmeler also described the Extension for Community Healthcare Outcomes (ECHO) program established in 2003 by Sanjeev Arora, MD, FACP, FACG, of the University of New Mexico, Albuquerque, and Ernest Hawk, MD, MPH, of The University of Texas MD Anderson Cancer Center, Houston, in response to a hepatitis C crisis in New Mexico. The mission of Project ECHO is to expand care in rural and underserved areas through telementoring. The problem was twofold: Rural providers did not know how to treat hepatitis C virus, and their patients were unable to travel to university specialists. So the project identified primary care providers from 16 rural clinics and 5 prisons in New Mexico and began a telementoring program. The program consists of a weekly teleconference, where providers from community clinics present cases and feedback is given by university specialists, including hands-on training. Project ECHO compared 407 patients with hepatitis C virus treated at a university

hospital to 21 rural clinics and prisons. There was no difference in cure rates between the two groups and no difference in serious adverse events. Project ECHO has been so successful that it has been expanded to Uruguay, Colombia, Mexico, El Salvador, Guatemala, Peru, and Brazil—and in Africa to Zambia and Mozambique.

Sociocultural Considerations Vivien D. Tsu, PhD, MPH, Associate Director of Reproductive Health at PATH and Affiliate Professor of Epidemiology at the University of Washington, Seattle, said that culture is a matter of beliefs, customs, practices, and behaviors shared by a group, whereas the social realm includes education, income, occupation, ethnicity, race, religion, political affiliation, and geography. All of these factors can be determinants of illness and health in various ways and on various levels, and all influence health interventions. Good outcomes are most likely achieved when interventions take sociocultural factors into consideration. “We strive to make all health care effective, efficient, acceptable, and available equitably, but for cancer prevention and control, social and cultural factors make this particularly challenging,” said Dr. Tsu. She said there is a strong stigma attached to cancer because of its lethality, lack of understanding of the disease process, and fear of contagion. “Cancer prevention has a long time lag prior to its benefit, and many cultures are fatalistic and not future oriented. Moreover, the high cost of treatment leads to inequitable access.” Specifically, breast and cervical cancer deaths have outstripped maternal mortality and continue to rise, and in many areas of the world, there are escalating differences between rich and poor. There are, however, opportunities for prevention and control—for breast cancer, through early detection, and for cervical cancer, through HPV vaccination, screening, and treatment for precancer. Factors related to sexuality play a critical role in the development of these cancers and can affect a woman’s willingness to seek treatment for breast or genital symptoms, and many women fear that they will be blamed for their disease. They also fear loss of sexual function, fertility, and their breast(s). Some women may even be too modest to be examined in the first place. Electra D. Paskett, PhD, Marion N. Rowley Professor of Cancer Research and Director, Division of Cancer Pre-

vention and Control, The Ohio State University, Columbus, found similar problems in southeastern Ohio. The region, she said, is considered part of Appalachia, where only 24% of women aged 50 to 74 received a mammogram in the past year. The abnormal Pap test rate for the United States is 3% to 4%; in Gallia County, Ohio, an Appalachian county, it is 18% to 22%, and only about 60% followed recommendations for follow-up care. Barriers to the test, as well as other types of health care, include lack of insurance, poor health literacy, travel and financial concerns, and the need to interrupt the traditional function of women—to be home all the time. As a result, breast cancer is more likely to be diagnosed at a later stage in this area, compared to rates in urban women. One solution to the problem is the use of a multifaceted program such as the Forsyth County Cancer Screening Project, which increased breast and cervical cancer screening among poor and minority women. It was funded in 1992 to work in low-income communities in two cities in North Carolina. “Our goal was to take health-care messages to the people and listen to their concerns. We used lay health advisors, church groups, one-on-one meetings, anything we thought would get the message out,” said Dr. Paskett.

Electra D. Paskett, PhD

It worked. The rate of mammography increased by 18% and of Pap testing by 21%. More recently, patient navigators, lay-persons who are trained to assess and resolve individual barriers to return for follow-up care following an abnormal screening test coached patients about what test results meant, accompanied them to a hospital or clinic, made phone calls to schedule follow-up appointments and arrange transportation, and taught them how to be their own navigators. “Cost is still a barrier that affects asking for help, but a navigator can sometimes find ways around that problem too,” said Dr. Paskett.

Tobacco Control “Tobacco is the leading cause of cancer, and lung cancer is the leading cause continued on page 98

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National Cancer Policy Forum Low-Resource Areas continued from page 97

of all cancer deaths,” said Michael P. Eriksen, ScD, MSc, Dean of the School of Public Health, Georgia State University, Atlanta. It’s not just smoking; smokeless tobacco has become a global

Michael P. Eriksen, ScD, MSc

problem, used in at least 70 countries by more than 300 million people. Southeast Asia has the worst problem—89% of the world’s users live there and have the highest attributable disease burden. In India, smokeless tobacco use exceeds cigarette smoking. Smoking prevalence varies widely around the world, said Stella A. Bialous, RN, DrPH, Associate Professor in Residence, Social and Behavioral Sciences, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco. Globally, it dropped slightly between

2007 and 2013, and men smoke about five times as much as women. In highincome countries, the disparity between men and women is less than 50%, but in low- and middle-income countries, the differences are staggering: Men smoke eight to nine times more than women. As smoking prevalence decreases in the United States and Europe, the tobacco industry is aggressively seeking new consumers in low- and middle-income countries—and finding them. “Tobacco sales are increasing, and the industry may seem monolithic and indestructible, but it is not,” Dr. Bialous said. To counteract the effort, the World Health Organization (WHO) led the development of the WHO Convention on Tobacco Control in February 2005 as a response to the global tobacco epidemic. In addition to decreasing the number of smokers, this United Nations public health treaty encouraged governments to thwart tobacco industry efforts and believes there is a fundamental and irreconcilable conflict between the industry’s interests and public health policy interests. It encouraged everyone dealing with the tobacco industry to operate in an open and above-board manner, and because the tobacco industry’s products are lethal, the treaty emphasizes that these com-

Cessation [of tobacco use] is the best policy on an individual level. It is evidence-based, it saves lives, it is costeffective, and lung cancer patients who quit survive longer.” —Stella A. Bialous, RN, DrPH

panies should not be granted financial or other incentives to establish or run their businesses. Of the 193 countries in the world, 180 are belong to the Convention as of October 2015. The United States is not one of them. The WHO Framework Convention on Tobacco Control measures assist countries in reducing the demand for tobacco by monitoring use and prevention policies; protecting people from tobacco smoke; helping cessation; warning about the dangers of tobacco, enforcing bans on advertising, promotion, and sponsorship; and raising taxes on tobacco. But regardless of how many treaties are signed, unless people quit smoking, tobacco deaths will continue to rise dramatically, to about 520 million (this [the number of deaths] is cumulative in 100 years and not per year

or decade) by 2050. Even if the proportion of young adults who begin to smoke is halved by 2020, 500 million of them will still die by 2050. If adult consumption is halved by 2020, 340 million will still die. Despite these gloomy predictions, “Cessation is a pivotal policy on an individual level,” said Dr. Bialous. “It is evidence-based, it saves lives, it is cost-effective, and lung cancer patients who quit survive longer.” The tobacco industry must be continually monitored and measures developed to counter its influence, she added. Health professionals, especially in oncology, must actively encourage patients to stop smoking. n

Disclosure: Drs. Massetti, Bollyky, Schmeler, Tsu, Paskett, and Eriksen reported no potential conflicts of interest. Dr. Bialous has received funding from Bristol-Myers Squibb Foundation and Pfizer IGLC.

Announcements

UC San Diego Robotic Surgeon Christopher J. Kane, MD, Named Joseph D. Schmidt, MD, Presidential Chair in Urology

hristopher J. Kane, MD, a specialist in prostate cancer and an expert in robotic and other minimally invasive procedures for urologic surgery at the University of California, San Diego (UCSD), has been appointed the inaugural holder of the Joseph D. Schmidt, MD, Presidential Chair in Urology in the School of Medicine.

The Joseph D. Schmidt, MD, Presidential Chair in Urology was established through charitable donations and matched through the University of California’s Presidential Match for Endowed Chairs. The endowed chair will provide a dedicated source of funds to support the chair holder’s urologic research, teaching, and service activities at UCSD Health.

Joseph D. Schmidt, MD, Presidential Chair in Urology

An Accomplished Urologist

The $3.3 million endowed faculty chair was created in honor of Joseph D. Schmidt, MD, Professor Emeritus, who served UCSD from 1976 through his recent retirement in August 2015. Dr. Schmidt is revered for his excellent patient care and for training 60 urology residents in his time at UCSD. He served as Chief of the Division of Urology at UCSD for 30 years.

Professor of Surgery at UCSD School of Medicine and Chair of the Department of Urology at UCSD Health, Dr. Kane is internationally recognized for his patient care and research in prostate cancer, renal cell carcinoma, and minimally invasive surgical treatment of urologic diseases and disorders. Dr. Kane serves on the editorial boards of several major urology jour-

nals, as well as the National Comprehensive Cancer Network (NCCN) Prostate Cancer Management Guidelines Committee. He also co-chairs the National Cancer Institute’s Renal Cell Carcinoma Advisory Task Force. Dr. Kane performs more than 200 robotic cancer surgeries each year, and is highly experienced in nerve-sparing robotic prostatectomies, robotic radical cystectomy for bladder cancer, and robotic partial nephrectomy for kidney cancer. “The funding from the Joseph D. Schmidt, MD, Presidential Chair in Urology allows me to dedicate more time to the urologic cancers research program,” Dr. Kane said. “It also allows me to fund initiatives, like our comprehensive urologic oncology database, that are a research resource for the entire division.”

Christopher J. Kane, MD

Dr. Kane received his medical degree from Uniformed Services University of the Health Sciences. He completed his residency at the Naval Medical Center in Oakland, California. Prior to joining USD Health, Dr. Kane held leadership positions at UC San Francisco and the Naval Medical Center San Diego. A retired Navy Captain and a decorated veteran of Desert Storm, he is Board certified in urology. n

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Expert’s Corner Cost of Care

The Complex Interactions of Treatment Costs, Clinical Outcomes, and Patient Expectations A Conversation With Barry R. Meisenberg, MD By Ronald Piana operational duties that a medical director of a cancer center is charged with. I’m also the Chair for Quality Improvement and Healthcare Systems Research at Anne Arundel Medical Center.

Two Financial Issues

Barry R. Meisenberg, MD

clinical dilemma that is receiving a great deal of attention in the oncology community is the undue financial burden some patients face during their treatment and into survivorship. While much emphasis is put on methods to reduce and help patients navigate the complex payment system, little is known about patient attitudes toward cost considerations influencing treatment decisions.

What was the goal of your recent study? To begin, like many in the oncology community, we’re concerned about the financial burden on our patients. To that end, we were thrilled when in 2013 the term “financial toxicity” was first described because it crystalized what the issues were. In that term lies the concept that some of the financial toxicity might be ameliorable. In our study, we first sought to determine how prevalent financial stress was among our cancer patients, and then we wanted to know what our patients wanted to do about it. There hasn’t been much research looking at these two issues in combination. As early as 2009, ASCO came up with a guideline recommending

that physicians discuss cancer costs with patients. Many surveys indicate that patients want to be told about the costs of their cancer care early in the treatment cycle.

Patient Attitudes

Underlying Thought Process

What do your data tell us about patient reactions to these conversations? Some data suggest that patients welcome a cost conversations with their oncologists but don’t insist on it. However, our study data indicated that patients did not want to have discussions about costs—either to society or themselves—because that might influence treatment decisions. We conducted the survey in the summer of 2014. It was a convenience survey—a nonprobability sampling technique whereby the researcher solicits opinions from “convenient” subjects—and we recognize that this model has limitations, but it is similar

Did you come to any conclusions about why patients are strongly set against factoring costs into their treatments? Although these data need to be verified, the findings indicate that patients are not cost-sensitive, even when it comes to their own out-of-pocket costs. The clinical importance is that in any discussion about costs we have with our patients, we need to know where their attitudes come from. The study gave some direction in that regard. We speculated that there might be a bias toward new and more expensive therapies, equating novelty and higher costs with better results. This finding is similar to the way consumers concep-

—Barry R. Meisenberg, MD

Current Role Please describe your current work as Medical Director of the Geaton and JoAnn DeCesaris Cancer Institute. I’m a hematology-oncology clinician and outcomes researcher. Thirty percent of my time is spent seeing patients. I do program building for patients with cancer here at the Cancer Center, and I handle the typical administrative and Adapted from Meisenberg BR.2

Impact on Treatment Decisions How did patients in your study feel about tailoring treatment decisions to prevent undue financial stress? Our patients strongly disagreed with the idea of altering treatments according to costs—either society’s or their own out-of-pocket. That finding is similar to other studies, such as one by A ndrea J. Bullock, MD, and colleagues in 2012.1 So our finding wasn’t new. When we narrowed the question down to whether their personal finances should be factored into the treatment decision-making, once again, they strongly disagreed with that notion. Then we asked the study group: If you were to see that the treatment options were similar in efficacy, would you then want your therapy to be based on cost. A slightly larger minority of patients said yes, but the plurality still said no.

Even high-income families can have significant treatment-related financial stress. Some of these reactions might stem from generalized fear, but cost burden is not relegated to low-income patients.

To bring clarity to this important issue, The ASCO Post spoke with Barry R. Meisenberg, MD, Medical Director of the Geaton and JoAnn DeCesaris Cancer Institute at the Anne Arundel Medical Center, a Johns Hopkins Clinical Research Network–affiliated regional health system headquartered in Annapolis, Maryland. Dr. Meisenberg recently conducted a study on this question.

to other studies in this area of inquiry. We used an instrument called a Personal Financial Wellness Scale, which is an eight-item validated scale that assesses participants’ perceptions about their personal financial situation. As it turned out, we had an entirely insured patient population, but they still had high levels of financial concerns and burdens. Interestingly, this finding didn’t necessarily correlate with income level. Even high-income families can have significant treatmentrelated financial stress. Some of these reactions might stem from generalized fear, but cost burden is not relegated to low-income patients.

Uncertainties About Patient Insights Into Costs of Cancer Care ■■ Do patients a priori regard lessexpensive therapies as inferior? ■■ Are patients’ decisions about cancer care sensitive to costs— either society’s costs or their own? ■■ Will the phenomenon of anticipated regret (thinking now about how they might feel in the future if a less costly alternative does not deliver the cure they are hoping for) cause patients to demand treatment regardless of costs? ■■ In what way, and at what time, will patients benefit most from cost-of-care discussions? ■■ What presentation of data is most helpful in understanding these issues? ■■ Do the answers to these questions vary by age, gender, nation, and culture?

tualize higher prices with better-quality products. There’s also a phenomenon called anticipated regret (see sidebar),2 which proposes that when facing a decision, individuals may prepare for the possibility of feeling regret after the uncertainty is resolved and, thus, incorporate in their choice a desire to eliminate or reduce this possibility. Also—and this is important for our professional society—advertising by drug companies and cancer centers creates the illusion that there are miracles waiting. This, in turn, creates a medical consumer trend of wanting a specific treatment or drug no matter what it costs. To that end, at our institution we are very careful in our marketing techniques, and we are equally cautious about how we talk about advances in treatment.

End-of-Life Care Discussions Do you feel that the recent decision by the Centers for Medicare & Medicaid Services (CMS) to reimburse physicians for discussions about end-of-life care fits into continued on page 100

The ASCO Post | DECEMBER 10, 2015

PAGE 100

Announcements

Dario Marchetti, PhD, Named Director of the Center for Biomarkers

ario Marchetti, PhD, recently joined Houston Methodist Hospital as the new Director of the Center for Biomarkers. Over the past 7 years, Dr. Marchetti’s laboratory at Baylor College of Medicine has made key discoveries in the biology and clinical use of circulating tumor cells. Dr. Marchetti’s team also has identified biomarkers that could one day

lead to a circulating tumor cell biomarker test that may guide the treatment of brain metastases in patients with breast cancer. Circulating tumor cells are proving to be viable diagnostic tools for noninvasive, real-time assessment of

molecular profiles during the course of cancer progression, Dr. Marchetti said. However, he pointed out that current technologies prevent researchers from identifying the majority of the circulating tumor cells from breast cancer patients that metasta-

size to the brain. Most cancer deaths are due to metastasis, and brain metastases are increasing in frequency with poor survival rates. Dr. Marchetti and his team are working to develop a biomarker program with Houston Methodist faculty

Barry R. Meisenberg, MD continued from page 99

the general theme of trying to avoid financial toxicity? The issue of cancer patients requesting expensive, aggressive end-oflife care even though it doesn’t offer cure and often doesn’t enhance quality of life, is much more complicated than a CMS reimbursement policy. I agree with those who don’t think lack of reimbursement to be a barrier to the important and difficult discussions with advanced cancer patients.3 It is a professional responsibillity. Personally, I think the reimbursement issue is a distraction from the larger issues. The ASCO value framework may facilitate those discussions. There was a terrific paper on a CanCORS study led by the late Jane Weeks, MD, MSc, looking at 1,193 patients, which found that 69% of patients with lung cancer and 81% of those with colorectal cancer did not report understanding that chemotherapy was not at all likely to cure their cancer.4 These data from our study and others looking at this issue behoove the oncology community to develop and test better tools to explain the complex interactions of cost and clinically meaningful outcomes. n Disclosure: Dr. Meisenberg reported no potential conflicts of interest.

References 1. Bullock AJ, Hofstatter EW, Yushak ML, et al: Understanding patients’ attitudes toward communication about the cost of cancer care. J Oncol Pract 8(4):e50-e58, 2012. 2. Meisenberg BR: The financial burden of cancer patients: Time to stop averting our eyes. Support Care Cancer 23:12011203, 2015. 3. Halpern SD: Toward evidence-based end-of-life care. N Engl J Med 373:20012003, 2015. 4. Weeks JC, Catalano PJ, Cronin A, et al: Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med 367:1616-1625, 2012.

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Announcements

Dario Marchetti, PhD

across numerous disciplines, but they will primarily focus on brain metastasis. Dr. Marchetti’s main priorities are to better understand why cancer recurs and how to decipher the molecular heterogeneity of circulating tumor cell subsets shed from tumors responsible for metastases. Dr. Marchetti received his doc-

torate in molecular biology from the University of Pavia, Italy. He serves on the editorial boards of numerous journals; is a grant reviewer for national and international funding agencies (including the National Institutes of Health and the Department of Defense); and is a consultant for several biotechnology companies. n

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Announcements

Montefiore and Einstein Receive $3.9 Million NCI Calabresi Grant

ontefiore Einstein Center for Cancer Care (MECCC) and the Albert Einstein Cancer Center (AECC) announced receipt of a $3.93 million grant from the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), for the prestigious Paul

Calabresi Career Development Award for Clinical Oncology. This competitive NIH institutional research career development grant provides MECCC and AECC an average of $786,000 annually over 5 years, the largest amount given to any participating institution in the country.

The Calabresi Grant This award is an innovative resource for clinicians and scientists to build invaluable skills geared toward true bench-to-bedside cancer therapeutic research. This is accomplished through a coordinated program of mentoring

from senior AECC faculty, an established innovative series of formal courses provided by the Block Institute for Clinical and Translational Research at Einstein and Montefiore, and research projects with an interdisciplinary collaborative design. n

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Announcements

Philip W. Kantoff, MD, Named Chairman of the Department of Medicine at Memorial Sloan Kettering Cancer Center

hilip W. Kantoff, MD, has been named the new Chairman of the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSK). An accomplished leader,

physician, researcher, and mentor, Dr. Kantoff served the Dana-Farber Cancer Institute and Harvard Medical School (HMS) since 1987 in a variety of capacities.

In his new role, Dr. Kantoff will continue to see patients in addition to heading a program of laboratorybased research. MSK’s experts in medical oncology and nearly all in-

ternal medicine subspecialties will report to Dr. Kantoff.

Previous Appointments Dr. Kantoff was previously Director of the Lank Center for Genitourinary Oncology, Chief of the Division of Solid Tumor Oncology, Vice Chair of the Department of Medical Oncology, and Chair of the Executive Committee on Clinical Research at Dana-Farber, as well as Professor of Medicine at

Philip W. Kantoff, MD

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HMS. He was the Jerome and Nancy Kohlberg Endowed Chair at HMS, Leader of the Dana-Farber/Harvard Cancer Center Prostate Cancer Program, and Director of its Prostate Cancer Specialized Program of Research Excellence (SPORE). In his role as Director of the Lank Center, Dr. Kantoff oversaw robust programs of clinical care and research as well as laboratory research. His laboratory focused on the genetics and genetic epidemiology of prostate cancer, mechanisms of resistance to therapies, and the role of noncoding RNAs in prostate cancer, as well as the discovery of biomarkers that may be useful prognostic tools and/ or therapeutic targets. He served as a clinical researcher and principal investigator in significant trials devoted to the development of new therapeutic targets for men with advanced prostate cancer. As Professor of Medicine at HMS since 2004, Dr. Kantoff ’s comprehensive research program focused on the molecular basis of genitourinary cancers and improved treatment for patients with prostate, kidney, bladder, and testicular cancers. Dr. Kantoff currently serves as the Chairman of the Global Treatment Science Network of the Prostate Cancer Foundation. He is a member of numerous professional societies and editorial boards and is board certified in internal medicine and medical oncology. n

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Palliative Care in Oncology End-of-Life Care

Practicing the Humanistic and Holistic Approach to End-of-Life Care A Conversation With B.J. Miller, MD By Jo Cavallo

n 1990, when Bruce (B.J.) Miller, MD, was an undergraduate at Princeton University, the practice of medicine was far from his mind. Then a student in Chinese and Asian studies and later an art history major, Dr. Miller would come to pursue a career specializing in palliative medicine after an accident during his sophomore year at Princeton resulted in the loss of his legs below the knee and his left forearm. That experience, said Dr. Miller, allows him to bring a unique perspective to his work. “I went into medicine not out of some great love for medical science,” said Dr. Miller. “I was looking to gain a tool bag to be of service to patients and one where my experiences as a

skills necessary to effectively address the needs of the dying.

Core Activities Please describe the work you do at Zen Hospice Project. The core of what we do is in direct care for patients at the end of their lives. The six-bedroom residential care facility we call the Guest House is a comfortable, beautiful place, which is intentional because we feel very strongly that the aesthetic world and the environment in which we live and function impacts how we feel. It is common for people to walk through the door and say it feels like coming home or “I’m glad this isn’t a hospital.”

While some of what it takes to be an effective provider is in delivering what we know to be a really good system of physical care, the additional value we bring to that system is found in elements steeped in the existential, spiritual, and relational components of care. —Bruce (B.J.) Miller, MD

patient and my growth and aspirations as a person and a human being in this world were relevant to the job. The fact that the world needs more palliative care docs was also appealing to me.” Today, Dr. Miller is Executive Director of Zen Hospice Project, a San Francisco–based nonprofit residential care facility that brings together the spiritual and humanitarian approaches to end-of-life care, and Assistant Clinical Professor of Medicine and Attending Physician at the Symptom Management Service of the University of California, San Francisco (UCSF) Helen Diller Comprehensive Cancer Center. He was recognized for his work in hospice and palliative medicine with the 2014 American Academy of Hospice and Palliative Medicine Project on Death in America Palliative Medicine Community Leadership Award. The ASCO Post talked with Dr. Miller about his work in palliative and end-of-life medicine and the

We are also increasingly involved in providing training and support for health-care workers. For almost 30 years we have trained volunteers who work at our Guest House and at Laguna Honda Hospital, San Francisco’s safety net long-term-care facility. Now, we train health-care professionals, including home health aides, as well. And 3 years ago, we developed and continue to host Integrative Approaches for End-of-Life Care, an interprofessional course at UCSF. Because we strongly believe in the importance of engaging the community in the work we are doing and since so many people have a hard time with the subject of mortality and do not understand what palliative care is, we hold public events to introduce these concepts to the very community we are trying to serve. For example, we invite community members into the Guest House to experience the environment, and we host Death Cafes so people can discuss death in a safe and social atmo-

sphere, which helps break down the fear many people have of death and dying. Over the years, various healthcare professionals have asked us how to start a similar Zen Hospice program in their residential facility or how to start a palliative care program in a hospital setting, so we just started hanging out our shingle as a consulting group to help health-care systems, payers, and individuals develop programs of their own. We recognize that this field needs to develop on multiple planes, and we are trying to do our part.

Essential Skills What skills are necessary to be an effective provider in end-of-life care and help patients with cancer die comfortably and with dignity? Palliative care and contemplative care are our disciplines. While some of what it takes to be an effective provider is in delivering what we know to be a really good system of physical care, the additional value we bring to that system is found in elements steeped in the existential, spiritual, and relational components of care. The standards of training in the field of palliative medicine include disciplines in the physical, emotional, and spiritual realms, but when it comes to existential suffering and trying to find meaning in life and reconcile difficult relationships and come to terms with the fact that we die, the field still has much to learn. At Zen Hospice, we flesh out those other spheres. How we do that is through the training we provide to staff and volunteers about how to mindfully care for the dying, which focuses on the fundamentals of hospice and palliative care within a broader context of contemplation and awareness and is inherently humanistic or spiritual in practice, and we have found the result to be profound. We are asked all the time if people have to be Buddhist to work here or to be a patient here, and the answer is absolutely not. The training we provide is informed by Buddhist principles, but we are a secular organization by license and in every other way. The guiding principles we adhere to cultivate a sense of being

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.

in the here and now, unburdened by future concerns that may or may not happen, and everyone can relate to that discipline.

Helping Patients Find Fulfillment Do the humanistic and holistic approaches that you bring to end-of-life care allow patients to live more fully until death occurs? Yes, because with good palliative care and symptom management, we can usually clear away so many of the distracting forces, such as unabated nausea or pain, preventing a peaceful death. Palliative care is pretty good in those areas. What it is not so good at is helping patients find fulfillment in the time they have left, and that is a big part of how we see our work functioning best. Once we get our patients’ physical symptoms under control, the relational work begins. It may be in helping patients review their life and construct their personal legacy or in reconciling relationships that have gone awry, and that is where the works starts to feel creative. After the mindfulness part of our work, we see what we do as a creative pursuit. If how we live and die is an experience, then we can help create meaningful experiences for our patients as part of their environment of care—for example, tending to patients’ senses to help them stay connected to the pres-

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Palliative Care in Oncology ent moment of life by cooking them a wonderful meal, holding their hand, and talking or singing to them. These are the things that immediately reward us for being alive.

Patient Concerns What are your patients’ greatest concerns: fear of dying? leaving loved ones? leaving life unfinished? My sense is that they mirror the fears about death and dying in the general population. In a 2012 survey by the California HealthCare Foundation on the attitudes of California citizens on death and dying, among their biggest concerns was being a burden on their loved ones.1 As a provider of residential hospice and palliative care, we assume many of the caregiver roles often supplied by family and friends, so they are free to go back to their role of just being family and friends with the patient and not taking on the extra responsibility of caregivers. The two other main patient concerns, according to the survey, were fear of being in pain, which hospice and palliative medicine are very good at controlling, and being at peace spiritually, which we are very well suited to help patients achieve given our Buddhist roots.

Cancer Centers and Hospitals How would you assess the way palliative care is practiced in cancer centers, and what can they do to improve care for their terminally ill and dying patients? Cancer centers and hospitals have different financial pressures, different regulatory burdens, and different staff-

ing requirements than we do, but for the dying patient, the experience is the same regardless of where the person is getting care. A simple answer about how to improve care in cancer centers and hospitals would be to develop a palliative care program and support it well. Beyond that, there are nuances in the field that need to be developed, including the existential and spiritual pieces I talked about earlier. Those elements are playing out within the patient no matter what the setting, so they need the attention of all these disciplines. It may be that cancer centers need to add chaplains, members of a peer support group, or patient navigators to their multidisciplinary medical teams, or they may need to train hospital volunteers to provide patients with basic human accompaniment in their final days. In my position at the UCSF Helen Diller Comprehensive Cancer Center, I find that I spend a lot of my time apologizing to patients for a medical system that is not prepared to provide the humanistic and holistic care they need and for oncologists who are not trained in palliative medicine or who do not have the time to spend with dying patients. A concern I hear a lot from patients is that they feel abandoned by their oncologist once they are no longer receiving active treatment for their cancer. I know that oncologists are under a lot of pressure and have limited time to spend with each patient, and it is impossible to expect them to do everything, so the prob-

lem is complicated. But if cancer centers could address patients’ concerns about their feelings of abandonment, maybe through the development of a volunteer program that is well staffed and trained to cultivate awareness and sensitivity to what patients may be experiencing, it would go a long way to easing their fears. It might be as simple as having a volunteer sit quietly by the patient’s bedside. Just the presence of another human being in the room can be comforting. The last suggestion I would add is to make the cancer center seem less like a factory and fearful place and more like a comfortable, safe environment. This can be done in several ways—for example, by installing more windows and allowing more natural and nonfluorescent light into hospital rooms and by

tending to patients’ senses with more flavorful foods and aromatic smells. These are remedial changes. However, I would really love to see building designers and architects take on the challenge of pivoting hospitals to a more patient-centric environment. I wonder why no great architect has taken up that challenge—yet! n

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

Reference 1. Lake Research Partners and the Coalition for Compassionate Care of California: Final Chapter: Californians’ Attitudes and Experiences With Death and Dying. California HealthCare Foundation, February 2012. Available at chcf.org/publications/2012/02/final-chapter-death-dying. Accessed November 19, 2015.

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Integrative Oncology

The ASCO Post | DECEMBER 10, 2015

Foot Care in Oncology: The Cancer Patient From Ankle to Toe By Mischa P. M. Nagel, David J. Kopsky, MD, Fiona Damstra, MD, Mario E. Lacouture, MD, and Barrie Cassileth, MS, PhD

here is as yet no clinical or research focus on foot complications that result from cancer therapies. Foot conditions, however, are common and have a considerable negative impact on patients’ ambulation, quality of life, and consistent dosing of antineoplastic agents.1-4 There are currently no guidelines in the United States for screening or care of cancer treatment–related foot events. This is in contrast with foot care protocols for patients with diabetes and arthritis, where podiatric care is a critical component of disease control. Systematic and evidence-based foot care in oncology commands attention, given the wide range of agents resulting in adverse events that affect the feet. Moreover, complications may develop at a faster pace in cancer patients in the setting of immunosuppression and comorbidities. Given the serious impact and potential development of complications, patients and health-care providers must be informed as to how to prevent and address these untoward events. The oncology team and caregivers need oncologyspecific guidelines. “Dermatologic toxicities are diverse and can have an enormous impact on the cutaneous health of patients, overall costs of treatment, health-care–related quality of life, and consistent anticancer therapy.”5 Some of the most common complications resulting from cancer treatments include: • Chemotherapy-induced peripheral neuropathy • Hand-foot syndrome (resulting from cytotoxic agents) • Hand-foot skin reaction (resulting from targeted therapies) • Paronychia and onycholysis • Edema, lymphedema • Skin and soft-tissue infections These events may impede a patient’s ability to use footwear, bear weight, ambulate, or perform activities of daily living.2 Mr. Nagel is Director, Supplement BV/Medical Foot, Van Dooren Advice, Amsterdam. Dr. Kopsky is Director of Clinical Operations at the Institute for Neuropathic Pain, Amsterdam. Dr. Damstra is is a rehabilitation physician at the Jan van Breemen Institute, Amsterdam. Dr. Lacouture is Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan Kettering Cancer Center, New York. Dr. Cassileth is Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.

Awareness of Foot Complications Preventive evaluation and management strategies, such as those performed during de rigueur dental evaluations prior to head and neck radiotherapy or stem cell transplants, serve as a model for the podiatric evaluation of patients receiving agents that result in foot-related adverse events. Most patients, caregivers, podiatrists, other foot-care therapists, and oncology professionals are not aware that cancer treatments may cause foot events. On the other hand, podiatrists and other foot-care workers may not be aware of the complications that their treatments can induce during or after

This training will enable foot therapists to properly screen feet before, during, and after cancer treatment. They will learn to recognize complications and to discuss problems with oncology team members. To ensure patient safety, foot therapists will ask and receive permission from treating oncologists prior to treatment. The need for proper training was evident in the results of a 2013 Dutch survey published in the Dutch publication The Medical Foot. A total of 765 foot therapists responded, indicating that 80% work with cancer patients while they are receiving treatment, 80% of the therapists had little or no knowledge of cancer or complications of cancer treatment, and only

added value to their specialty. To date, two hospitals in the Netherlands have employed trained foot therapists. In June 2015, a newly established association of oncology foot therapists was welcomed as a member of the Dutch Association for Oncology (http://bit.ly/1NsXVIs). This umbrella association covers all cancer professionals striving for optimal cancer care in the Netherlands.

Guidelines In 2014, guidelines were developed for foot therapists on safe foot care for cancer patients in the Netherlands. After questioning several national European cancer foundations, it appeared that

Systematic and evidence-based foot care in oncology commands attention, given the wide range of agents resulting in adverse events that affect the feet. Moreover, complications may develop at a faster pace in cancer patients in the setting of immunosuppression and comorbidities. —Mischa P. M. Nagel, David J. Kopsky, MD, Fiona Damstra, MD, Mario E. Lacouture, MD, and Barrie Cassileth, MS, PhD (left to right)

cancer treatment. Medical professionals, patients, and caregivers should be aware of potential foot complications and how to prevent and treat them.

International Developments In 2012, the Netherlands “medical foot” academy developed an educational program for foot therapists, who are analogous to podiatrists in the United States. The main goal of the program was to encourage awareness of potential complications and screening, providing appropriate guidance to patients and keeping the feet of cancer patients in optimal condition during and after treatment. This effort also aimed to stimulate communication between foot therapists and oncology professionals. In 2015, at the French University of Toulouse, under the guidance of dermatologist Vincent Sibaud, MD, training will be provided to nurse oncologists and foot therapists concerning relevant complications.

10% received information about cancer during foot therapy training. This survey also revealed a complete absence of communication between foot therapists and members of an oncology team. In 2014, an education initiative in the Netherlands led to the successful training of 200 foot therapists who now specialize in cancer patient foot care. A survey of this group revealed that 33% now work with patients referred by oncology team members (previously 0%), 70% of foot therapists now work as part of the oncology team, and 70% work with written approval. Unfortunately, 30% of trained foot therapists do not get a response to their treatment request from the oncology team, and the patient, therefore, does not receive foot care. However, two-thirds of Dutch oncology departments offer foot therapists a 2-day observation of inpatient and outpatient care. Many oncology team members acknowledge foot care as an

no such guidelines existed previously. In 2015, a second version was published. The need for guidelines is clear, and hopefully they will be further developed by the newly established international foundation for oncology foot care (mischa@sup.nl). n

Disclosure: Mr. Nagel is owner and Director of Supplement BV/Medical Foot and Director of Van Dooren Advice, Amsterdam. Drs. Kopsky, Damstra, Lacouture, and Cassileth reported no potential conflicts of interest.

References 1. Miller KK, Gorcey L, McLellan BN: Chemotherapy-induced hand-foot syndrome and nail changes: A review of clinical presentation, etiology, pathogenesis, and management. J Am Acad Dermatol 71:787-794, 2014. 2. McLellan B, Ciardiello F, Lacouture ME, et al: Regorafenib-associated hand-foot skin reaction: Practical advice on diagnosis, prevention, and management. Ann Oncol 26:2017-2026, 2015. 3. Macdonald JB, Macdonald B, Golitz

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Integrative Oncology LE, et al: Cutaneous adverse effects of targeted therapies: Part I: Inhibitors of the cellular membrane. J Am Acad Dermatol 72:203-218, quiz 219-220, 2015. 4. Gomez P, Lacouture ME: Clinical presentation and management of hand-foot skin reaction associated with sorafenib in combination with cytotoxic chemotherapy: Experience in breast cancer. Oncologist 16:15081519, 2011. 5. Lacouture ME: Dermatologic Principles and Practice in Oncology: Conditions of the Skin, Hair, and Nails in Cancer Patients. Hoboken, NJ, Wiley-Blackwell, 2014. Suggested Reading Capriotti K, Capriotti JA, Lessin S, et al: The risk of nail changes with taxane chemotherapy: A systematic review of the literature and meta-analysis. Br J Dermatol 173:842-845, 2015. Dranitsaris G, Vincent MD, Yu J, et al:

Development and validation of a prediction index for hand-foot skin reaction in cancer patients receiving sorafenib. Ann Oncol 23:2103-2108, 2012. Lacouture ME, Reilly LM, Gerami P, et al: Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib. Ann Oncol 19:1955-1961, 2008. Park HJ: Chemotherapy induced peripheral neuropathic pain. Korean J Anesthesiol 67:4-7, 2014. Piano V, Schalkwijk A, Burgers J, et al: Guidelines for neuropathic pain management in patients with cancer: A European survey and comparison. Pain Pract 13:349357, 2013. von Moos R, Thuerlimann BJ, Aapro M, et al: Pegylated liposomal doxorubicin-associated hand-foot syndrome: Recommendations of an international panel of experts. Eur J Cancer 44:781-790, 2008.

GUEST EDITOR

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 Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www. 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 offers 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.

News Technology

A Blueprint for Drug/Diagnostic Development: Expansion and Use of Curated Genetic Databases By Margot J. Fromer

n a continuation of a 2014 conference that explored regulatory considerations and strategies for nextgeneration sequencing, the Friends of Cancer Research, with support from Alexandria Real Estate Equities, Inc, Pasadena, California, met to discuss

lytes and can help predict patients’ risk of developing certain cancers and how they might respond to therapies. “There are many advantages of high-throughput sequencing over that of a single analyte, but demonstrating its adequacy for clinical use is challenging, particularly the

There are many advantages of highthroughput sequencing over that of a single analyte, but demonstrating its adequacy for clinical use is challenging, particularly the tension between the need to ensure validity and the practical limitations of submitting data for every possible variant. —Ellen V. Sigal, PhD

the issues and problems of coordinating drug and diagnostic development, specifically the use of curated databases. Ellen V. Sigal, PhD, Chair and Founder of Friends of Cancer Research, introduced the gathering by noting that high-throughput genomic technologies, including next-generation sequencing, allow for rapid assessment of many ana-

tension between the need to ensure validity and the practical limitations of submitting data for every possible variant.” She added that in 2011, the U.S. Food and Drug Administration (FDA) released a draft guidance on the codevelopment of targeted therapies and companion diagnostics. The next year, Friends of Cancer Research identified the aspects of code-

velopment that would most benefit from increased clarity in such a guidance. But much work remains to be done. “This is a really big deal,” Dr. Sigal said. “Patients always come first, so we have to get it right.” A curated genetic database focuses on genomes that have been completely sequenced and that are associated with an active research community to contribute and oversee gene-specific data. Information includes nomenclature, chromosomal localization, gene products and their attributes (eg, protein interactions), associated markers, phenotypes, and interactions, as well as links to citations, sequences, variation details, maps, expression reports, homologs, protein domain content, and external databases. A significant stumbling block to this work is that there are as yet no evidencebased guidelines about sample collection, preparation, analysis, clinical reporting, or data storage and protection, said Lynne Zydowsky, PhD, President and Cofounder, Alexandria Summit, and Chief Science Advisor to the CEO, Alexandria Real Estate Equities, Inc.

Minimum Core Data Elements The two sets of panelists agreed that a significant problem arises from

Matthew Marton, PhD

defining minimum core data elements required to interpret the clinical significance of variants. In other words, how is information collected and processed to capture functional consequences of variants and other clinical details? Matthew Marton, PhD, Director, Sr. Principal Scientist, Translational Biomarkers, Merck & Co, talked about the relationship between genotypes and phenotypes. “Both germline and somatic variants can be detected in tumors. The latter are the usual targets of cancer therapy, although some germline variants also are targetable (eg, BRCA1/2 variants with PARP inhibitors.)” Zivana Tezak, PhD, Associate Director for Science and Technology, Office of In Vitro Diagnostics and Radiologic Health, FDA Center for Devices continued on page 112

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IMBRUVICA® (ibrutinib) capsules 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. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The safety of IMBRUVICA has not been evaluated in patients with hepatic impairment. Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) [see Dosage and Administration (2.5) and 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]. Plasmapheresis: Management of hyperviscosity in patients with WM may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required. 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, weakness, confusion) 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]. • Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [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 LLC 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 LLC © Pharmacyclics LLC 2015 © Janssen Biotech, Inc. 2015

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The ASCO Post | DECEMBER 10, 2015

News Genetic Databases continued from page 107

and Radiologic Health, added that risk variants for hereditary cancer are classified in the same way as those for other inherited diseases: benign, likely benign, unknown, likely pathogenic, and pathogenic. Moreover, somatic variants need

Zivana Tezak, PhD

a different classification system from germline variants, for example somatic variants are classified as cancer “driver” or “passenger” mutations—or unknown whether variant is involved in treatment response, etc.. Driver variants should be included in genetic databases; however, because they are affected by factors such as clonal vs subclonal status and the level of copy number a mplification.

Roman Yelensky, PhD

Dr. Marton added that biomarkers or variants can be grouped into classes and interpreted on the basis of clinical or preclinical data (eg, all EGFR exon 19 deletions). Variant groups with clinically relevant phenotypes are associated with factors such as diagnosis, prognosis, prediction of response to therapy, adverse events, and demography (age, gender, ethnicity). All this would appear to be part of a significant move forward, he said. But there’s a big hitch: ensuring the validity and comparability of the data, such as sequencing technology, sample type (blood, tissue, etc), and analytic performance parameters. In addition, there are as yet no assay- and platform-specific standards to ensure adequate analytic performance for different variants, such as small or large deletions, insertions, rearrangements, and genomic context. Roman Yelensky, PhD, Vice President, Biomarker and Companion Diagnostic Development, Foundation Medicine, Cambridge, Massachusetts, said that if these parameters are captured when a

variant is submitted, a database would be consistent and accurate. Some variants fall into clear categories of driver or passenger mutations, but others have conflicting classifications among researchers, clinicians, and laboratories. This happens for a variety of reasons, but the fact that it happens at all means that a mechanism must be created to adjudicate variants, particularly those with clinical implications, those that affect regulatory and reimbursement decisions, and those that affect treatment and/or prognosis. One way to do this, he said—and other panelists agreed—is to establish a group of subject matter experts to arbitrate inconsistent results and finalize the variant assignment based on the most current evidence. Such efforts are already underway for germline variant classification where groups of scientists have been organized to apply standards. They are trying to develop a “master” classification for an individual or group of variants by reviewing pertinent literature. The classification system is regularly updated, with an ultimate goal of creating standards that can be applied broadly among databases to minimize variability. There are, however, still significant discrepancies. Jeff Allen, PhD, Friends of Cancer Research Executive Director, put it succinctly: “Since there is such enormous variability in gene panels, what is their ultimate use?” “Anthem health plans do cover individual gene tests when clinically indicated, regardless of the testing methodology used,” said Jennifer Malin, MD, PhD, Staff Vice President, Clinical Strategy, Anthem, Inc. “However, entire panels that include tests that are investigational and not medically necessary are not covered.” The Centers for Medicare & Medicaid Services (CMS) echoed that sentiment. “We need analytical and clinical validity, and we, as a public health agency, support this type of research,” said Tamara Syrek Jensen, JD, Director for the Coverage and Analysis Group at CMS.

Framework to Evaluate Strength of Evidence Girish Putcha, MD, PhD, Director, Laboratory Science, Palmetto GBA,

Girish Putcha, MD, PhD

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News

Mya Thomae, RAC, CQA

Columbia, South Carolina, said that assessing levels of evidence for genotype and phenotype associations is essential to the appropriate application of any proposed database. He suggested a grading system based on preclinical evidence. “Classification for a given variant is not intended to be static and will change as new evidence becomes available. Therefore, we have to continually re-evaluate it.”

• Level 3B: Preclinical data demonstrating that a biomarker predicts cell-based response to a drug Panelists noted several problems with the system. First, words like “robust” or “adequate” are essentially meaningless. Second, “statistically significant” is always a tricky phrase but most especially in rare diseases where there are too few cases to mean much,” said Mya Thomae, RAC, CQA, Vice President of Regulatory Affairs, Illumina, Inc. Third, levels of evidence may not be mutually exclusive. Fourth, clinical validity has never been adequately defined. Finally, characterization of the variants is not clear.

Database Use in Context What actual good are these databases, and what can be done with them? asked Dr. Yelensky. Even if all challenges are

Nonrandomized trials have led us down the garden path many times in the past, so now we need additional ways to generate large-scale knowledge. Variability is rife, and data can differ depending on the tests used. We need similar answers to the same questions posed in different ways. —Janet Woodcock, MD

The system he proposed: • Level 1A: FDA-approved for a patient’s tumor type with indication and outcomes associated with a specific biomarker • Level 1B: Adequately powered prospective study with biomarker selection/stratification or a meta-analysis, demonstrating that biomarker predicts tumor response (or resistance) to a drug or that a drug is clinically more or less effective • Level 2A: Robust demonstration that a biomarker is associated with tumor response or resistance to a drug in a patient’s tumor type • Level 2B: Single or few unusual responders showing a biomarker associated with response or resistance to a drug • Level 3A: Available clinical data demonstrating that a biomarker predicts tumor response to drug in a different tumor type

databases that meet FDA requirements but contain discordant results, how will they be resolved? How will products that relied on these data be affected, and how would the FDA resolve the discrepancy? Larry Norton, MD, Deputy Physician-in-Chief, Breast Cancer Programs and Medical Director, Evelyn H. Lauder Breast Center, Memorial Sloan Kettering Cancer Center, said, “If you don’t

addressed and met, how can the data be used? There are three possibilities, all of which have problems: scientific research (including publication), regulatory approval, and reimbursement. “Associations with level 3 evidence could be used for further investigation and early clinical trials. Level 2 associations could support clinical validity, although FDA review would be required to assess the need for and feasibility of additional studies. Associations with level 1 evidence may possibly not require additional FDA review, rather only analytic validation of variant detection. They are sufficient for diagnosis and reimbursement,” he said. Still such database use remains a very iffy proposition. For example, is a level-based framework appropriate to guide regulatory approval, and how could it translate to other contexts such as reimbursement decisions? Even more problematic, if there are multiple

Larry Norton, MD

have prospective randomized trials, you don’t really have data.” He then immediately acknowledged the impracticality of large trials in the current climate of individual and small-number mutations for any given cancer. Janet Woodcock, MD, Director, FDA Center for Drug Evaluation and Research, agreed in a slightly different way: “Nonrandomized trials have led us down the garden path many times in the past, so now we need additional ways to generate large-scale knowledge. Variability is rife, and data can differ depending on the tests used. We need similar answers to the same questions posed in different ways.”

Data Sharing and Publicly Available Databases Shashikant Kulkarni, MS, PhD, Director, Cytogenetics and Molecular Pathology, Washington University School of Medicine, noted that a significant amount of data generated from genetic testing is not publicly available for two major reasons. First, clinical laboratories have limited resources to

Shashikant Kulkarni, MS, PhD

collate and upload their findings. Second, sponsors who build proprietary databases are reluctant to go public. “Given that accurate interpretation of genomic data is essential to patients, developing incentives to help all laboratories [large and small, public and private] to share data should make it easier for everyone to perform more effective diagnostic tests,” he said. To this end, he suggested the following measures: • Establish or upgrade databases to include the costs of creating pipelines to facilitate data transfer. • Give contributors to public databases access to priority review paths to assist in intensive development and accelerated review. • Provide competitive protection (similar to patenting) that provides a time-bound competitive advantage. • Share data published in peer-reviewed literature with at least one publicly available database. Dr. Kulkarni noted that recent FDA programs to expedite development and review of new drugs (Fast Track designation, Breakthrough Therapy designation, accelerated approval, and priority review) have been a boon to the treatment of serious and life-threatening diseases—especially oncology, where targeted therapy is highly dependent on codevelopment of central data exchanges, which cannot be accomplished within the sped-up time frame of faster development tracks. However, an expedited review path could be created to ensure that the drug and central data exchanges would reach the market at close to the same time. To this end, aggregated publicly available databases to support the clinical relevance of variants in the central data exchange genes may enable cleared or approved products to reach the market quickly. Simultaneous inclusion of data submission requirements as a qualifying criterion for expedited review can help to establish a feedback loop and provide sponsors with the framework they need to share proprietary data sources. n Disclosure: Drs. Sigal, Zydowsky, Tezak, Yelensky, Allen, Malin, Putcha, Norton, Woodcock, and Kulkarni reported no potential conflicts of interest. Dr. Marton is an employee and stock owner of Merck. Ms. Thomae is an employee of Illumina, Inc.

The ASCO Post | DECEMBER 10, 2015

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Announcements

City of Hope Provost Steven T. Rosen, MD, Honored by Israel Cancer Research Fund

teven T. Rosen, MD, Provost and Chief Scientific Officer for City of Hope, has received a Lifetime Achievement Award from the Israel Cancer Research Fund (ICRF). The award recognizes Dr. Rosen’s longstanding commitment to advancing science and medicine and providing extraordinary patient care.

American Cancer Society, Leukemia & Lymphoma Society of America, and Multiple Myeloma Research Foundation have funded Dr. Rosen’s research. He’s also served as an adviser for several of these or-

ganizations and on the external advisory boards of more than a dozen NCI-designated comprehensive cancer centers. The ICRF, the largest organization in North America devoted solely to

supporting cancer research in Israel, has funded cancer research breakthroughs in gene therapy, bone marrow transplant techniques, molecular process, and drug therapies. n

Steven T. Rosen, MD

Dr. Rosen sets the scientific direction of City of Hope, shaping the research and educational vision for the independent biomedical research institution and cancer treatment center. Working closely and collaboratively with City of Hope’s scientists, clinicians, and administrative leaders, he develops strategies that help the organization quickly turn breakthrough discoveries into practical benefit for cancer patients around the world. “This Lifetime Achievement Award is a remarkable honor, especially coming from the ICRF, an organization that advances scientific understanding of cancer and supports innovations that are transforming lives,” said Dr. Rosen, who serves as Director of City of Hope’s Comprehensive Cancer Center, Beckman Research Institute, and Irell & Manella Graduate School of Biological Sciences. He also holds the Irell & Manella Cancer Center Director’s Distinguished Chair. “I am extremely proud and humbled to be the recipient of such an honor.”

Earlier Career Prior to joining City of Hope in 2014 as its first Provost and Chief Scientific Officer, Dr. Rosen served for 24 years as Director of Northwestern University’s Robert H. Lurie Comprehensive Cancer Center. He was also Northwestern’s Genevieve Teuton Professor of Medicine at the Feinberg School of Medicine, providing care for hundreds of patients with blood cancers and overseeing a basic science laboratory and clinical research team. The National Cancer Institute (NCI),

Scanning electron micrograph of T-cell lymphocytes attacking a cancer cell

ASCOPost.com | DECEMBER 10, 2015

PAGE 115

Announcements

Alexandra M. Levine, MD, MACP, Honored by LA County Medical Association

he Los Angeles County Medical Association (LACMA) awarded the Hospital Physician Leadership Award to Alexandra M. Levine, MD, MACP, Chief Medical Officer of City of Hope. Dr. Levine received the award in recognition of her exemplary

contributions to the medical profession, including her leadership in professional organizations, her compassion and devotion to patients, and a career dedicated to pursuing clinical research. Dr. Levine is responsible for all

of City of Hope’s clinical and hospital care programs, which encompass quality of service, patient safety, clinical research, clinical information management, and professional education. She serves as the primary liaison with the City Medical TRIM: 15.15”ofXHope 10.575”

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Alexandra M. Levine, MD, MACP

Dr. Levine is also Professor at City of Hope’s Hematologic Malignancies and Stem Cell Transplantation Institute. She served as Chief of the University of Southern California (USC) School of Medicine’s Division of Hematology from 1991 to 2006, where she was Distinguished Professor of Medicine, Medical Director of the USC/Norris Cancer Hospital, and Past Executive Associate Dean of the Medical School. The National Institutes of Health consistently funded her research as a principal investigator from 1982 to 2012.

HIV Research

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Group and its physician members to promote collaboration across disciplines and ensure staff recruitment and retention. “I am honored and humbled to be recognized by a professional association that represents so many of our medical colleagues in Los Angeles County,” Dr. Levine said. “It is truly a great distinction to be among such accomplished health leaders and visionaries whom LACMA honors each year.”

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Dr. Levine was among the first to recognize the epidemic of lymphoma and other cancers among HIV-infected persons in the United States and has been a strong advocate for HIVinfected patients over the years. Internationally, she served as a consultant on HIV/AIDS programs for the health departments of Chile, Russia, India, and China. In 1995, former President Bill Clinton appointed Dr. Levine to the Presidential Advisory Council on HIV/AIDS, where she served as the Chair of the Research Committee. She was honored by appointment to the National Cancer Institute’s Board of Scientific Counselors from 1996 to 1999 and again from 2010 to 2015. Dr. Levine was elected a Master of the American College of Physicians in 2009. n

The ASCO Post | DECEMBER 10, 2015

PAGE 116

Expert’s Corner International Oncology

A Swiss Psychotherapist Gives Her Perspective on Optimal Palliative Care A Conversation With Monika Renz, PhD By Ronald Piana

Monika Renz, PhD

ver the past few decades, the oncology community has incorporated new evidence-based therapies to address the psychosocial needs of patients with cancer, especially those with advanced disease. To bring a global perspective to this evolving discipline, The ASCO Post recently spoke with Monika Renz, PhD, a palliative care psychotherapist at the Cantonal Hospital in St. Gallen, Switzerland.

Early and Later Influences Please tell the readers about your background, where you grew up, and whether there were any early influences in your decision to enter the palliative care field? I grew up in Zurich. My father was a business leader; my mother was a psychologist. Since childhood, I have been

interested in the human condition, particularly health and spirituality. I was first influenced by my father’s focus on efficiency, and as a psychotherapist, I began looking for efficient therapy methods. A second early influence was music: My mother told me that I had begun singing before speaking. Since I was 5 years old, my hobby has been piano improvisation. Without reading notes, I played whatever I heard and as a child discovered the healing effect of music. When I was a teenager, research on intrauterine hearing had just come to the fore. I was fascinated and became interested in music therapy. At the University of Zurich, I studied educational psychology, psychopathology, and ethnomusicology. The deepest influences on my therapeutic work with dying patients came from several accidents and longer periods of personal illness. As a patient, I experienced what I later called a transformation of perception. I discovered two different states of being: In one, I suffered great pain, and in the other state, I had none. In the one state, I was present and in control, and in the other painless state, I was somehow far away from time and space but very clear. I looked deeper into this phenomenon when writing

my doctoral dissertation on primordial trust and primordial fear under Professor Heinz Stefan H erzka. This was the very beginning for my later research on perception and development of consciousness. Years

cology of the Cantonal Hospital of St. Gallen, feeling that my keen interest in crisis intervention would be useful here. At that time (1998), the hospital did not offer psycho-oncology therapy yet, just music therapy. I was

Understanding the transformation of perception as a key to many other symptoms, such as increasing fear and total pain, may improve care. Thus, pain medication and sedation can be reduced and used selectively, when needed. —Monika Renz, PhD

later, I studied theology to better understand patients’ spiritual distress. My theologic dissertation dealt with redemption from early behavioral imprinting.

From Music Therapy to Palliative Care How did you become involved in palliative care at Cantonal Hospital? Before I entered the field of psychooncology, I had a private practice and worked as a music therapist with children and adults. I felt that the long-term therapies were unsatisfying and inefficient. I closed my practice and applied for a position in the Department of On-

entrusted with building the Psychooncology Department; I developed a multidimensional therapy approach for cancer inpatients and outpatients. The approach combines illness-coping strategies, dream interpretation, family support, spiritual care, trauma therapy, and music therapy. My special focus is music-assisted relaxation combined with active imagination. Over the years, my therapeutic approach has been so successful that there has been a fourfold increase in demand for this therapy at our hospital. Meanwhile, we have developed a whole team including a psychiatrist. We use multidimensional approaches, but each

Don’t Miss These Important Reports in This Issue of The ASCO Post Massimo Cristofanilli, MD, FACP, on Combining Molecular Driven Approach and Immunotherapy in Inflammatory Breast Cancer see page 3

Rudolph M. Navari, MD, PhD, on Olanzapine and CINV Reduction see page 5

Lorenzo Cohen, PhD, and Janet Kahn, PhD, LMT, on Cancer Care Through Nonpharmacologic Symptom Management see page 14

Visit The ASCO Post online at ASCOPost.com

Jennifer S. Temel, MD, on Anamorelin and Cachexia Improvement in Advanced NSCLC see page 12

Paula R. Pohlmann, MD, on Tumor Profiling of Geriatric Breast Tumors see page 15

ASCOPost.com | DECEMBER 10, 2015

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Expert’s Corner

member has his or her own focus. In regular intervision meetings, we discuss casework; thus, everyone in the team learns several techniques. For end-of-life care and support of dying patients, I have developed an educational program together with the Head of Palliative Medicine at our hospital, Dr. Daniel Bueche. As a result, I supervise members of the palliative care nursing team to support dying patients psychologically and spiritually.

An Author’s Insights Please tell the readers about your recently published book. Dying: A Transition introduces readers to the “inside” of dying processes. During the dying process, all automated ego-based thinking and ego-centered perception fall away. The process brings us to another state of consciousness, a different state of sensitivity, and an alternative dimension of spiritual connectedness. This transformation of perception, called transition, seems to be the main mental and emotional process in dying and often the background of visible changes, such as from fear to trust, from struggle to peace, from denial to acceptance. The transformation of perception can also explain why family problems and the need for reconciliation are urgent at first but gradually fade. Understanding the transformation of perception as a key to many other symptoms, such as increasing fear and total pain, may improve care. Thus, pain medication and sedation can be reduced and used selectively, when needed. Dying: A Transition is based on 17 years of work with terminally ill cancer patients and research with 680 dying patients.

Past and Current Research Please describe your current research. Our current study, “Dying Trajectories,” investigates dying processes of 80 terminal cancer patients, whether from a phenomenological perspective, dying is a structured process with periods of crises and peace. It addresses the following themes: fear, pain, denial, and spiritual experiences. Are there any interrelations between them? When do they erupt or subside? Based on our former research, we hypothesize a correlation between fear, pain, and denial. And we expect that spiritual experiences (eg, seeing a light) occur in stages of peace and may facilitate the ongoing process. We also observe alterations in time, space, body awareness, and social connectedness as pos-

sible indicators of a transformation of perception. In addition to our former research, we now include a parameter pain scale. We are also involving the whole palliative care team of two palliative units. Members of the team first have short sensitivity training. We are assessing patients’ previous spiritual attitudes and current fears followed by participant observation of the dying process over a period of 2 to 28 days. We will analyze our data by interpretative phenomenological analysis. A panel of international experts of several disciplines will then discuss the results.

The Swiss National Cancer Strategy Please tell the readers a bit about the state of palliative care in Switzerland. Communication skills training has become mandatory for all Board-certified oncologists. Further, cancer palliative care interventions—delivered by both oncologists and palliative care teams—are increasingly integrated into routine clinical care. Both of these clinical approaches represent an achievement. National oncology services are on a high level, but equal access to optimal care still depends on where people live. Therefore, the Swiss National Cancer Strategy is establishing more quality and efficiency by fostering networks in all major fields of cancer and prevention throughout Switzerland.

Closing Thoughts Any closing thoughts you’d like to share with our readers? I would like to point out the importance of a particular “hearing sensitivity” in the dying process. Even a small noise can be overwhelmingly loud. Next, I would like to bring into the clinical discussion a new approach to spiritual care. Spirituality includes more than just giving a response to a patient’s spiritual attitude. Spiritual needs as well as patients’ consciousness and communication are changing during the dying process. Spirituality in dying, as perhaps in near-death experiences, has to do with an altered connectedness and consciousness. Spiritual experiences are powerfully independent from religious attitudes, as our second study with 251 palliative cancer patients shows. Last but not least, I think that by understanding the phenomenon of primordial fear, we could reduce pain management and sedation therapy. n Disclosure: Dr. Renz reported no potential conflicts of interest.

2016 ASPIRE Breast Cancer Research Awards Pfizer is proud to announce the Advancing Science through Pfizer – Investigator Research Exchange (ASPIRE) Breast Cancer Research Awards, a competitive, peer-reviewed grants program sponsored by Pfizer for investigators in the United States

Call for Research Proposals For complete information on the scope of research, please visit ASPIRE website at www.aspireresearch.org Mission The mission of the ASPIRE Awards is to support clinical research of a Pfizer compound in advanced breast cancer through a competitive grants program to advance knowledge in the treatment and disease management of advanced breast cancer. Awards 2016 ASPIRE Breast Cancer Research Awards program intends to fund four to six clinical studies within scope, for a total of approximately 4 million US dollars. It is open to US investigators. Selection of research proposals will be performed by an independent external review panel of breast cancer experts. Submissions are due March 31, 2016

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The ASCO Post | DECEMBER 10, 2015

PAGE 118

Reflections

Lung Cancer: Hope From Science By Paul A. Bunn, Jr, MD

Choosing a Career Path The following essay by Paul A. Bunn, Jr, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon.com and thebigcasino.org.

grew up in upstate New York and was heavily influenced by my parents and my high school sweetheart, who became my wife of 45 years. My father, an infectious disease physician, developed tuberculosis while he was in medical school, as did most of his classmates, and dedicated his life to the elimination of tuberculosis as a medical scourge worldwide. He was largely successful. Ironically, he died at a young age in part due to his generation’s smoking habits, diet, and lack of physical activity. I graduated from Amherst College after majoring in biology. My mentors were most interested in teaching students how to think. I was disappointed by my first 2 years at Cornell University Medical College, where the emphasis seemed to be on how to memorize rather than how to think. However, my second 2 years were much more rewarding. I was exposed to unbelievable clinicians like Rees Pritchett, MD, and Martin Gardy, MD, who taught me how to put patients first; and to scientists like Walter F. Riker, MD, who taught me many of the principles of medical research.

Dr. Bunn is Distinguished Professor, Division of Medical Oncology, University of Colorado Boulder, and James Dudley Chair, Lung Cancer Research, University of Colorado Cancer Center, Aurora.

This was in the 1960s. The Vietnam War had a major influence on my career. Nearly all medical students were being drafted and sent to Vietnam. This happened to my cousin, who was also an internist and developed tuberculosis while checking for rats on the ships. He told me that unless I wanted to become a surgeon, it might be best to avoid being drafted. So, like thousands of other students, I applied to the National Institutes of Health (NIH) for a fellowship after medical residency and was accepted into the Leukemia Branch of the National Cancer Institute (NCI). During my internship at the University of California, San Francisco, I was assigned to the NCI’s Pediatric Branch. Since I was most interested in adult medicine, I was reassigned to the Medicine Branch. During my residency, many of the early combination chemotherapy regimens were showing improved results in lymphomas, adult leukemias, and breast cancer. Because the NIH Clinical Center was not a complete hospital, we had to draw all the blood; start patient IVs; complete all procedures, including pleural, liver, and lymph node biopsies; and perform laparoscopies, and even dialysis procedures, ourselves. The combination of preclinical, clinical, patho-

ter, because there were a large number of patients with lung cancer in treatment there. At the time, the treatment for lung cancer was very unsatisfactory. Very little was known about lung cancer biology, and nothing was known about the molecular biology or molecular pathogenesis of the disease. Several drugs had shown activity in small cell lung cancer, but each had considerable toxic side effects, and complete remissions were rare. To address the issues of biology and molecular biology, the group attempted to establish cell lines from every patient’s tumor biopsy. They were called human tumor cell lines and numbered sequentially (the first was human tumor cell 1, and so on). Much of what we know of lung cancer biology and molecular biology today originated from these lines. Some of our earliest observations were that the cell lines produced their own growth factors, they had frequent losses of portions of human chromosomes and tumor suppressor genes, and they expressed antigens to which monoclonal antibodies could be produced.

Strength and Hope of Patients Drugs that inhibited cell line growth frequently produced responses in pa-

The fact that these men and women would choose to spend 6 weeks in a hospital under treatment with the most toxic of chemotherapies is a testament to their strength and hope. —Paul A. Bunn, Jr, MD

logic, staging, and therapeutic trials, especially in Hodgkin and non-Hodgkin lymphoma, led to improved outcomes and cures for many patients with cancer. My experience there taught me the importance of having a multidisciplinary approach, combination therapy, and well-conducted clinical trials in the treatment of cancer. By the completion of my fellowship, the NCI had decided to dedicate one of its branches to lung cancer, which was—and still is—the leading cause of cancer death. The branch was located at the Washington DC VA Medical Cen-

tients with lung cancer. They could be grown in laboratory mice to test new therapies in vivo. Our initial trials in small cell lung cancer included a threedrug chemotherapy regimen containing cyclophosphamide, methotrexate, and lomustine. Unfortunately, it was so toxic that all patients developed severe neutropenia, and all were hospitalized for a minimum of 6 weeks. The fact that these men and women would choose to spend 6 weeks in a hospital under treatment with the most toxic of chemotherapies is a testament to their strength and hope.

Years later, I was recruited to the University of Colorado School of Medicine, where I continued my lung cancer studies. One of my early patients was a physician who had bilateral lung metastases (he had never smoked) but was asymptomatic. Convinced that chemotherapy would only decrease his quality of life, he elected to avoid any therapy. I followed him for 11 years, observing his slowly progressive nodules. When he became symptomatic, he agreed to platinum-based chemotherapy. He suffered considerable toxicity and had some response, but he died within a year.

Prolonging the Duration and Quality of Life This patient taught me that our goal as oncologists is to prolong both the duration and the quality of life, which is something the patient decides with support from the physician. His case also illustrated the variability in outcomes, our inability to predict an outcome, and the importance of science in making advances in cancer treatment. At the time, there was an odd perception that patients with lung cancer were somehow morally suspect—tobacco addicts or worse—rather than victims of a devastating disease. When this doctor presented with lung cancer, this was the prevailing view: Lung cancer was associated with the stigma of guilt associated with tobacco, and treatments were solely unscientific poisons. The past decade has changed this view. We have witnessed profound new possibilities in the treatment of lung cancer with molecularly tailored therapies and checkpoint immune therapies. These new therapies provide much higher response rates and much longer responses, and they do so with considerably less toxicity than cytotoxic chemotherapy. It’s now clear that patients should have their tumors tested for the presence of molecular drivers and biomarkers associated with improved outcomes. These therapies are providing new hope and meaningful prolongation of life with more acceptable levels of toxicity. The promise that rational combinations may further improve outcome and lead to some cures may now justify the long periods of research. And yes hope. n

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Announcements

Valerie W. Rusch, MD, FACS, Elected Chair of ACS Board of Regents

alerie W. Rusch, MD, FACS, was elected Chair of the Board of Regents of the American College of Surgeons (ACS) during the College’s Annual Clinical Congress, held October 4–8 in Chicago. In her role as Chair of the Board of Regents, Dr. Rusch will work closely with the ACS Executive Director and will chair the Regents’ Finance and Executive Committees. The College’s 23-member Board of Regents formulates policy and is ultimately responsible for managing the affairs of the College.

Valerie W. Rusch, MD, FACS

Dr. Rusch is the Vice Chair of Clinical Research and Attending Surgeon in Thoracic Service in the Department of Surgery, as well as Miner Family Chair in Intrathoracic Cancers at Memorial Sloan Kettering Cancer Center. She is also Professor of Surgery at Weill Cornell Medical College.

Leader in Thoracic Surgery As a thoracic surgeon, Dr. Rusch specializes in the diagnosis and treatment of patients with cancers of the lungs, trachea, bronchi, esophagus, mediastinum, chest wall, and pleura (malignant pleural mesothelioma). She was among the first women in the country to be board certified in thoracic surgery. Dr. Rusch has been a Fellow of the American College of Surgeons (FACS) since 1986 and served a leadership role on several prominent ACS Committees. Dr. Rusch has been a leader in national clinical trials for the treatment of thoracic malignancies, and in 2007, received the Thoracic Surgery Foundation for Research and Education Socrates Award. In 2012, the Association of Women Surgeons awarded her The Nina Starr Braunwald Award, for lifetime contributions to the advancement of women in surgery. She has held 25 visiting professorships and lectureships and given nearly 300

major lectures on thoracic cancers at medical conferences around the world. Dr. Rusch has also been Chair of the American Board of Thoracic Surgery, Chair of the Lung and Esophagus Task Force of the American Joint Commission on

Cancer, and is currently Chair of the Mesothelioma Subcommittee of the International Association for the Study of Lung Cancer Staging Committee. Dr. Rusch received her medical degree from the Columbia University

College of Physicians and Surgeons, and completed surgical residency training in general surgery and thoracic surgery at the University of Washington, Seattle, followed by a fellowship at the University of Texas MD Anderson Cancer Center. n

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In the Clinic Thoracic Oncology

Osimertinib for Metastatic EGFR T790M–Mutant Non–Small Cell Lung Cancer After EGFR Inhibitor Therapy 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 November 13, 2015, osimertinib (Tagrisso) was granted accelerated approval for the treatment of patients with metastatic EGFR T790M–mutant (as detected by a U.S. Food and Drug Administration [FDA]approved test) non–small cell lung cancer (NSCLC) who have had disease progression on or after EGFR tyrosine kinase inhibitor therapy.

Supporting Efficacy Data Approval was based on response rates observed in two single-arm openlabel trials in patients who had disease progression on prior systemic therapy, including an EGFR tyrosine kinase inhibitor. All patients were required to have EGFR T790M mutation–positive NSCLC as detected by the cobas EGFR mutation test and received oral osimertinib at 80 mg once daily.

OF NOTE Osimertinib is an EGFR tyrosine kinase inhibitor that binds irreversibly to some mutant forms of EGFR at approximately ninefold lower concentrations than to wild-type EGFR.

Patients with a history of interstitial lung disease or radiation pneumonitis that required steroid treatment, serious arrhythmia, or baseline QTc interval > 470 ms were excluded from the studies. Overall, patients had a median age of 63 years (13% ≥ 75 years), 68% were female, 60% were Asian and 36% white, 39% had brain metastases (39%), World Health Organization (WHO) performance status was 0 in 37% and 1 in 63%, and 69% had received at least two prior lines of therapy. Objective response rates on independent review were 57% (all partial responses; 95% confidence interval [CI] = 50%–64%) in study 1 (N = 201) and 61% (complete response in 1%; 95% CI = 54%–68%) in study 2 (N = 210).

Overall, 96% of responding patients in both trials had ongoing responses at the time of primary analysis. Median duration of response had not been reached, with duration of ongoing responses ranging from 1.1 to 5.6 months after a median duration of follow-up of 4.2 months (study 1) and 4.0 months (study 2).

Osimertinib for EGFR T790M–Mutant NSCLC ■■ Osimertinib (Tagrisso) was granted accelerated approval for the treatment of patients with metastatic EGFR T790M–mutant non–small cell lung cancer who have had disease progression on or after EGFR tyrosine kinase inhibitor therapy. ■■ The recommended dose of osimertinib is 80 mg once daily until disease progression or unacceptable toxicity.

How It Works Osimertinib is an EGFR tyrosine kinase inhibitor that binds irreversibly to some mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at approximately ninefold lower concentrations than to wild-type EGFR. In vitro and in animal models, osimertinib exhibited antitumor activity against NSCLC lines with EGFR mutations (T790M/L858R, L858R, T790M/ exon 19 deletion, and exon 19 deletion) and, to a lesser extent, those with wildtype EGFR amplifications. Two pharmacologically active metabolites (AZ7550 and AZ5104, circulating at approximately 10% of parent compound levels) with inhibitory profiles similar to osimertinib have been identified in plasma after oral administration of osimertinib. AZ7550 showed a similar potency to osimertinib, whereas AZ5104 showed greater potency against exon 19 deletion and T790M mutants (approximately eightfold) and wild-type EGFR (approximately 15-fold). In vitro, osimertinib also inhibited the activity of HER2, HER3, HER4, ACK1, and BLK at clinically relevant concentrations.

How It Is Used The recommended dose of osimertinib is 80 mg once daily until disease progression or unacceptable toxicity. Recommended osimertinib dose modifications include the following: For cardiac adverse reactions, patients with a QTc interval > 500 ms on two or more separate electrocardiograms should have treatment withheld until the QTc interval is < 481 ms or there is recovery to baseline if baseline was ≥ 481 ms, with treatment resumed at 40 mg/d. Treatment should be permanently discontinued in those with QTc interval prolongation and signs/symptoms of life-threatening arrhythmia. Treatment should be withheld for up to 4 weeks in patients with an asymptomatic absolute decrease in left ventricular ejection fraction of 10% from baseline and below

50% and resumed if there is improvement to baseline left ventricular ejection fraction or permanently discontinued if there is not improvement to baseline. Treatment should be permanently discontinued in patients with symptomatic congestive heart failure. Treatment should be permanently discontinued in patients with interstitial lung disease or pneumonitis. For other adverse reactions, treatment should be withheld for

OF NOTE Osimertinib carries warnings/precautions for interstitial lung disease/pneumonitis, QTc interval prolongation, cardiomyopathy, and embryofetal toxicity.

up to 3 weeks for grade 3 or 4 events, resumed at 80 or 40 mg/d for improvement to grade 0 to 2 within 3 weeks, and permanently discontinued in those with no improvement within 3 weeks. Concomitant administration of osimertinib with strong CYP3A inhibitors, including macrolide antibiotics (eg, telithromycin), antifungals (eg, itraconazole), antivirals (eg, ritonavir), and nefazodone should be avoided. In addition, concomitant administration with strong CYP3A inducers (eg, phenytoin, rifampicin, carbamazepine, St. John’s wort) should be avoided.

Safety Profile Among 411 patients in studies 1 and 2, the most common adverse events of any grade were diarrhea (42%), rash (41%), dry skin (31%), nail toxicity (25%), eye disorders (18%), nausea (17%), decreased appetite (16%), and constipation (15%). The most common grade 3 or 4 adverse events were venous thromboembolism (2.4%) and pneumonia (2.2%). Interstitial lung disease/pneumonitis occurred in 3.3% of patients, and cardiomyopathy occurred in 1.4%. The most common grade 3 or

4 laboratory abnormalities were hyponatremia (3.4%), neutropenia (3.4%), and lymphopenia (3.3%). Adverse events led to dose reductions in 4.4% of patients, with the most common reasons being QTc prolongation (2.2%) and neutropenia (1.9%), and to discontinuation in 5.6%, with the most common reasons being interstitial lung disease/pneumonitis (2%) and cerebrovascular accident (1%). Overall, cerebrovascular accident occurred in 2.7%. Serious adverse events reported in ≥ 2% of patients were pneumonia and pulmonary embolus. Fatal adverse events occurred in 3.2% of patients, including four patients (1%) with interstitial lung disease/pneumonitis attributed to osimertinib; four patients died from pneumonia and two from cerebrovascular accident/cerebral hemorrhage. Osimertinib carries warnings/precautions for interstitial lung disease/ pneumonitis, QTc interval prolongation, cardiomyopathy, and embryofetal toxicity. ECGs and electrolytes should be monitored in patients with a history of or predisposition for QTc prolongation or who are taking medications known to prolong QTc interval. Left ventricular ejection fraction should be assessed before treatment and then every 3 months. Women should be advised of potential risk to the fetus and to use effective contraception during treatment and for 6 weeks after the final dose. Men should be advised to use effective contraception for 4 months after the last dose. n References 1. U.S. Food and Drug Administration: Osimertinib. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm472565.htm. Accessed November 24, 2015. 2. Tagrisso (osimertinib) tablets prescribing information, AstraZeneca Pharmaceuticals, November 2015. Available at www.azpicentral.com/tagrisso/tagrisso. pdf. Accessed November 24, 2015.

The Evolving Understanding of

THE VEGF PATHWAY IN RCC Medical Commentary Contributor: Thomas Hutson, DO, PharmD, FACP | Dallas, TX

RCC Overview More than 60,000 new cases of kidney and renal pelvis cancer are diagnosed in the United States annually.1 Renal cell carcinoma (RCC) is the most common type of kidney cancer, representing more than 90% of all kidney tumors.2-4 Approximately 20% of patients present with metastatic disease.5

Histologic Subtypes of RCC6-8 75%—clear cell 15%—papillary 5%—chromophobe 5%—oncocytoma

Although there are a number of different histologic subtypes of RCC, each with a different genetic basis and clinical course, the clear-cell subtype is the most common.6-8 In a high percentage of sporadic clear-cell RCC cases, defects exist in the von HippelLindau (VHL) tumor-suppressor gene, which plays a role in angiogenesis.9,10

The VEGF Pathway Vascular endothelial growth factors (VEGFs) regulate vascular development, blood vessel function, and lymphatic vessel function.10 The VEGF pathway is a primary driver of the pathogenesis of RCC due to defects in the VHL gene.9 In the absence of functional VHL genes, hypoxia-inducible factor (HIF) builds up and leads to overproduction of many different gene products, including VEGF and other signaling proteins.9 The Defects in the VHL increased transcription of VEGF and other gene have been factors may explain why tumors such as identified in up to clear-cell RCC are so vascular.11 75% of sporadic

VHL-deficient RCC tumor cells in pre-clinical mouse models, it was found that use of an antibody targeting VEGFR-2 led to a reduction in the density of tumor pericytes and lymphatic vessels in addition to a reduction in tumor blood vessel density.12 VEGFRs play a role in neoangiogenesis and have also been linked to the immune system.18-20 The immune system is constantly trying to detect and destroy cancer cells throughout the body21; however, cancer cells may be able to evolve and evade the immune system through a variety of different mechanisms.21 Interference with VEGFR binding may impact the immune system by altering regulatory T-cell populations and other immune cells in peripheral blood and the tumor microenvironment (Figure 1).18-20 Following interference with the VEGFR binding, there are also increases in many types of immune cells, including cytotoxic cancer-killing T lymphocytes, at the site of the tumor.19,20,22 Together, these data suggest that VEGFRs are linked to the immune system’s ability to induce anti-tumor effects.

Figure 1. Tumor microenviroment

clear-cell RCC cases.9

VEGF binds to and activates 3 vascular endothelial growth factor receptors (VEGFRs) located on endothelial cells of blood vessels and lymphatic vessels.10,12,13 Activation of VEGFR-1, -2, and -3 results in complicated signaling.10,13,14 Increased production of VEGF can cause endothelial cells to change, multiply, and spread abnormally, which can lead to tumor angiogenesis and tumor growth.10,13-15

The VEGF Pathway Beyond Angiogenesis Activation of VEGFR-1, -2, and -3 may also lead to lymphangiogenesis in RCC.10,12 The exact role of lymphangiogenesis is unclear, but some studies suggest that the creation of additional lymphatic channels facilitates metastasis.14,16,17 A correlation was seen between the presence of intratumoral lymphatic vessels and lymph nodes and distant metastases, in RCC patient samples (N=60).17 In another study using

Not drawn to scale

What if the VEGF Signals Were Blocked? Data exist showing that blocking VEGF signals may impact tumor angiogenesis.23 Directly blocking all 3 VEGF receptors may delay the effects of VHL-mediated VEGF overproduction, which plays an important role in tumor angiogenesis, the immune response to the tumor, and RCC progression.9,10,19,20

References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29. 2. American Cancer Society. Cancer Facts & Figures 2015. Atlanta, GA: American Cancer Society; 2015. 3. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010;7(5):245-257. 4. Simard EP, Ward EM, Siegel R, Jemal A. Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin. 2012;62(2):118-128. 5. SEER stat fact sheets: kidney and renal pelvis cancer. Surveillance, Epidemiology, and End Results Program Web site. http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed October 1, 2015. 6. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol. 2003;170(6, pt 1):2163-2172. 7. Kovacs G, Akhtar M, Beckwith BJ, et al. The Heidelberg classification of renal cell tumours. J Pathol. 1997;183(2):131-133. 8. Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol. 2003;27(5):612-624. 9. Pfaffenroth EC, Linehan WM. Genetic basis for kidney cancer: opportunity for disease-specific approaches to therapy. Expert Opin Biol Ther. 2008;8(6):779-790. 10. Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2012;2(7):a006502. 11. Hanrahan AJ, Iyer G, Solit DB. Intracellular signaling. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff’s Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier Saunders; 2014:22-39. 12. Duignan IJ, Corcoran E, Pennello A, et al. Pleiotropic stromal effects of vascular endothelial growth factor receptor 2 antibody therapy in renal cell carcinoma models. Neoplasia. 2011;13(1):49-59. 13. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039-2049. 14. Longo DL. Cancer cell biology and angiogenesis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s™ Principles of Internal Medicine. Vol 1. 18th ed. New York, NY: The McGraw-Hill Companies, Inc.; 2012:672-688. 15. Tannock IF. The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer. 1968;22(2):258-273. 16. Dębiński P, Dembowski J, Kowal P, et al. The clinical significance of lymphangiogenesis in renal cell carcinoma. Med Sci Monit. 2013;19:606-611. 17. Ozardili I, Guldur ME, Ciftci H, Bitiren M, Altunkol A. Correlation between lymphangiogenesis and clinicopathological parameters in renal cell carcinoma. Singapore Med J. 2012;53(5):332-335. 18. Finke JH, Rini B, Ireland J, et al. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res. 2008;14(20):6674-6682. 19. Du Four S, Maenhout SK, De Pierre K, et al. Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model. Oncoimmunology. 2015;4(4):e998107. 20. Ozao-Choy J, Ma G, Kao J, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 2009;69(6):2514-2522. 21. Manipulation of the immune response. In: Murphy K. Janeway’s Immunobiology. 8th ed. New York, NY: Garland Science; 2012:684-687. 22. Liu XD, Hoang A, Zhou L, et al. Resistance to antiangiogenic therapy is associated with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma. Cancer Immunol Res. 2015;3(9):1017-1029. 23. Eichten A, Adler AP, Cooper B, et al. Rapid decrease in tumor perfusion following VEGF blockade predicts long-term tumor growth inhibition in preclinical tumor models. Angiogenesis. 2013;16(2):429-441.

Oncology

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Through the Lens of Oncology History

A Century of Progress The text and photographs on this page are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photographic History, by Stanley B. Burns, MD, FACS. The photos below are from the volume titled “The Anesthesia Era 1845-1875.” To view additional photos from this series of books, visit burnsarchive.com.

The Anesthesia Era 1845-1875 Parotid Tumor Excision, Albumen Print, Paris, February 1872

low-growing benign parotid gland tumors were highly visible lesions only brought to a surgeon’s attention when complications arose. Successful removal of these tumors was often recorded and photographed to verify the competence of the surgeon and enhance his reputation. This series documents one such case and is one of the first cases published with pre- and postoperative photographs. The case report included tipped-in photographs and was presented in Revue Photographique des Hôpitaux de Paris, volume 4, 1872. This was the world’s first medical journal to illustrate cases with photographs. It was published from 1869 through 1874. The photographs accompanying the articles were pasted on separate pages. Dr. Cauchois, interne des Hôpitaux de Paris, reported the case: On February 8, 1872, Mr. P... a 48-year-old man who was in good general health, reported to the service of

Professor Verneuil at the Hospital Lariboisière. He noted the development of a large tumor on the left side of his face over the past 10 years. It started as a nut-sized movable lesion. It did not cause pain or hemorrhage nor impair his health. About 5 months prior, the tumor began to ulcerate. Two small purulent areas developed in the mass. On examination, the tumor, a typical parotid gland “vegetation,” measured 42 cm in circumference at the base. The skin was “friable” in areas. No odor was evident. The tumor pushed the ear back, and the left side of the face was paralyzed, except for the upper eyelid. At operation, an attempt was made to avoid hemorrhage by not using a scalpel but a galvanic cautery knife, special clamps, and hot iron cautery. The external carotid and other arteries were ligated with sutures and cauterized. A 2-cm wide margin was made at the base. The tumor was removed with

little blood loss by using two clamps across the dissected base and then using the cautery knife and a large hot iron cautery. No trace of the tumor could be seen in the base after removal. The wound was dressed and changed three times a day for 6 days. The temperature didn’t rise by ½ degree, which meant there was no “trauma fever.” The wound was dressed with a water and phenol solution gauze dressing daily. In the month of March, the patient left the hospital to recuperate at home. On June 29, the patient returned to the hospital, and the postoperative photograph was taken. The patient remained with left facial paralysis, but the upper lid functioned so well that the eye was covered. In summation, Dr. Verneuil declared he had never operated on such a large tumor. He believed the tumor was not malignant because of the slow growth, so surgery was possible for a cure. He discussed the concept of a two-stage

operation, with tying off the carotid arteries as a preliminary procedure. He emphasized his use of a galvanic knife, hot iron, and clamps, which resulted in a blood loss of only 200 g. Using his technique allowed slow careful dissection in a bloodless field, making only a single-stage operation necessary for removal of these tumors. Dr. Verneuil’s surgical operative recommendations were ultimately elaborated upon and refined by America’s master surgeon William Halsted, MD. He emphasized that a dry field allowed slow, careful, thoughtful dissection in any operation and was especially important in cancer procedures because of the aberrant and aggressive vessel and tissue growth. n Excerpted from Oncology: Tumors & Treatment, A Photographic History, The Anesthesia Era 1845-1875 by Stanley B. Burns, MD, FACS. Photographs courtesy of Stanley B. Burns, MD, and The Burns Archive.

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In the Clinic Hematology

Daratumumab in Previously Treated Multiple Myeloma 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 November 16, 2015, daratumumab injection (Darzalex) was granted accelerated approval for treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.1,2 Daratumumab is the first monoclonal antibody approved for the treatment of multiple myeloma. The manufacturer, Janssen, is required to conduct a multicenter randomized trial establishing the superiority of daratumumab over standard therapy and has several ongoing multicenter randomized trials in patients with multiple myeloma with a primary endpoint of progressionfree survival.

Supporting Efficacy Data Approval was based on response rate in a multicenter open-label study in which 106 patients with relapsed or refractory multiple myeloma received daratumumab monotherapy via intravenous infusion at 16 mg/kg once every week for 8 weeks followed by once every 2 weeks for 16 weeks and once every 4 weeks until unacceptable toxicity or disease progression.2 Treatment was administered with pre- and postinfusion medication. Study patients had a median age of 63.5 years (range = 31–84 years), 51% were female, and 79% were white. Patients had received a median of five prior lines of therapy, 80% had received autologous stem cell transplantation, and prior therapies included bortezomib (Velcade, 99%), lenalidomide (Revlimid, 99%), pomalidomide (Pomalyst, 63%) and carfilzomib (Kyprolis, 50%). The objective response rate was 29% (95% confidence interval = 21%–39%), including stringent complete response in 2.8%, very good partial response in 9.4%, and partial response in 17.0%. Median time to response was 1 month (range = 0.9–5.6 months) and median duration of response was 7.4 months (range = 1.2– 13.1+ months).

How It Works The transmembrane glycoprotein CD38 is expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types and tissues, and has multiple functions, including receptor-mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody that binds to CD38 and inhibits the growth of CD38-expressing tumor cells by inducing apoptosis directly through Fc-mediated cross-linking, as well as inducing immune-mediated tumor cell lysis through complementdependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis. Myeloid-derived suppressor cells and a subset of regulatory T cells (CD38-posi-

there were no grade ≥ 1 infusion reactions during the first 3 hours of the first infusion. For subsequent infusions, the dilution volume should be 500 mL, infusion rate 100 mL/h, and rate increment 50 mL/h every hour, with escalation only if there were no grade ≥ 1 infusion reactions during a final infusion rate of 100 mL/h in the first two infusions. Treatment should be immediately interrupted for infusion reactions of any grade. For grade 1 or 2 reactions that resolve and for the first two occurrences of a grade 3 reaction that improves to grade ≤ 2, infusion may be resumed at no more than half the rate at which the reaction occurred. If the patient does not experience any further reaction symptoms, infusion rate escalation may resume at the specified increments and intervals. Treatment

Daratumumab for Multiple Myeloma ■■ Daratumumab (Darzalex) was granted accelerated approval for treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent. ■■ The recommended dose of daratumumab is 16 mg/kg via intravenous infusion weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, and every 4 weeks from week 25 until disease progression.

tive Tregs) express CD38 and are susceptible to daratumumab-mediated cell lysis.

How It Is Used The recommended dose of daratumumab is 16 mg/kg via intravenous infusion weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, and every 4 weeks from week 25 until disease progression. Pre- and postinfusion medication must be given.

OF NOTE Daratumumab carries warnings/precautions for infusion reactions and interference with cross-matching and red blood cell antibody screening.

The maximum infusion rate for all infusions is 200 mL/h. For first infusion, the dilution volume should be 1,000 mL, with an infusion rate during the first hour of 50 mL/h and a rate increment of 50 mL/h every hour. For the second infusion, infusion volume should be 500 mL, infusion rate 50 mL/h, and rate increment 50 mL/h every hour, with escalation occurring only if

should be permanently discontinued for the third occurrence of a grade 3 reaction and for grade 4 reactions. Preinfusion medications should be given about 1 hour prior to every infusion as follows: intravenous corticosteroid (methylprednisolone at 100 mg or equivalent dose of an intermediate-acting or longacting corticosteroid), oral antipyretics (acetaminophen at 650 to 1,000 mg), oral or intravenous antihistamine (diphenhydramine at 25 to 50 mg or equivalent). After the second infusion, the corticosteroid dose may be reduced (methylprednisolone at 60 mg intravenously). Postinfusion medication should be given as follows: oral corticosteroid on the first and second days after each infusion. Postinfusion medications such as short- and longacting bronchodilators and inhaled corticosteroids should be considered in patients with a history of obstructive pulmonary disorder. These additional medications can be discontinued if no major infusion reaction occurs during the first four infusions. Antiviral prophylaxis to prevent herpes zoster reactivation should be given within 1 week of starting treatment and continued for 3 months following treatment.

OF NOTE Daratumumab is an IgG1κ human monoclonal antibody that binds to CD38 and inhibits the growth of CD38-expressing tumor cells by inducing apoptosis and immunemediated tumor cell lysis through a variety of mechanisms.

Safety Profile Safety data are from 156 patients who received daratumumab at 16 mg/kg in three open-label trials. The most common adverse events of any grade were infusion reaction (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). The most common grade 3 or 4 adverse events (all grade 3) were pneumonia (6%), hypertension (5%), and infusion reaction (3%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia, neutropenia, anemia, and thrombocytopenia. Serious adverse events occurred in 33% of patients, with the most common being pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Adverse events resulted in treatment delay in 15%, most frequently for infections, and treatment discontinuation in 4%. The incidence of infusion reactions was 46% with the first infusion, 5% with the second infusion, and 4% with subsequent infusions; all reactions with second or subsequent infusions were grade ≤ 2. Severe infusion reactions included bronchospasm, dyspnea, hypoxia, and hypertension (< 2% each). Median time to onset of reaction was 1.5 hours. The incidence of infusion interruptions due to reactions was 37%. Systemic antiviral medication was used in 73% of patients. Daratumumab carries warnings/precautions for infusion reactions and interference with cross-matching and red blood cell antibody screening. n References 1. U.S. Food and Drug Administration: Daratumumab injection. Available at www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472904.htm. Accessed December 2, 2015. 2. Darzalex (daratumumab) injection, prescribing information. Janssen Biotech, November 2015. Available at www.accessdata.fda.gov/ drugsatfda_docs/label/2015/761036s000lbl. pdf. Accessed December 2, 2015.

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In the Clinic

Ixazomib in Previously Treated Multiple Myeloma 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 November 20, 2015, ixazomib (Ninlaro) was approved by the U.S. Food and Drug Administration (FDA) for use in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.1,2 Ixazomib is the first FDAapproved oral proteasome inhibitor.

Supporting Efficacy Data Approval was based on improvement in progression-free survival in a phase III double-blind trial.2 In the trial, 722 patients who had received one to three prior lines of therapy were randomly assigned to receive ixazomib at 4 mg (n = 360) or placebo (n = 362) on days 1, 8, and 15 plus lenalidomide (25 mg) on days 1 through 21 and dexamethasone (40 mg) on days 1, 8, 15, and 22 of 28day cycles until disease progression or unacceptable toxicity.

OF NOTE Ixazomib is a reversible proteasome inhibitor that induces apoptosis of multiple myeloma cell lines in vitro and exhibits cytotoxicity against myeloma cells from patients relapsing after prior therapies.

Patients had a median age of 66 years, 56% to 58% were male, 83% to 86% were white, 87% to 88% had stage I or II disease, 60% to 62% had one prior line of therapy, 77% had relapsed disease, 23% had light chain disease and 12% had free light chain measurable–only disease, and 17% to 21% had del(17), t(4;14) or t(14;16) and 9% to 10% had del(17). Prior treatments included bortezomib (Velcade, 69%), melphalan (80%–81%), thalidomide (Thalomid, 44%–47%), lenalidomide (12%), and stem cell transplantation (55%–59%). Median progression-free survival was 20.6 months (95% confidence interval [CI] = 17.0 months to not estimable) in the ixazomib group vs 14.7 months (95% CI = 12.9–17.6 months)

in the placebo group (hazard ratio = 0.74, P = .012). The overall response rate was 78% vs 72%, including a complete response in 12% vs 7%.

How It Works Ixazomib is a reversible proteasome inhibitor that preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome. It induces apoptosis of multiple myeloma cell lines in vitro and exhibits cytotoxicity against myeloma cells from patients relapsing after multiple prior therapies including bortezomib, lenalidomide, and dexamethasone.

ing information) and ixazomib at its most recent dose. For first recurrence, both drugs should be withheld until recovery and lenalidomide resumed at its most recent dose and ixazomib at its next lowest dose. For additional recurrences, dose modifications of lenalidomide and ixazomib should be alternated. For grade 2 or 3 rash, lenalidomide should be withheld until recovery to grade ≤ 1 and then resumed at the next lower dose. For recurrence, ixazomib and lenalidomide should be withheld until recovery to grade ≤ 1, with ixazomib resumed at the next lower dose and

Ixazomib for Multiple Myeloma ■■ Ixazomib (Ninlaro) was approved for use in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. ■■ The recommended starting dose of ixazomib is 4 mg orally once a week on days 1, 8, and 15 of a 28-day treatment cycle.

The combination of ixazomib and lenalidomide showed synergistic cytotoxic effects in multiple myeloma cell lines. The agent has shown antitumor activity in a mouse multiple myeloma tumor xenograft model.

How It Is Used The recommended starting dose of ixazomib is 4 mg orally once a week on days 1, 8, and 15 of a 28-day treatment cycle. The recommended starting dose of lenalidomide is 25 mg/d on days 1 to 21 and the recommended starting dose of dexamethasone is 40 mg/d on days 1, 8, 15, and 22. Prior to initiating a new cycle of therapy, absolute neutrophil count should be ≥ 1,000/mm3, platelet count ≥ 75,000/ mm3, and nonhematologic toxicities should, at the physician’s discretion, generally be recovered to baseline condition or grade ≤ 1. Ixazomib dose reduction should be to 3 mg for first reduction and to 2.3 mg for the second reduction, with discontinuation thereafter. For decrease in platelet count to < 30,000/mm3 or neutrophil count to < 500/mm3, ixazomib and lenalidomide should be withheld until recovery back to these levels, with granulocyte colony-stimulating factor considered for neutropenia. With recovery, lenalidomide should be resumed at its next lowest dose (according to its prescrib-

lenalidomide at the most recent dose. For peripheral neuropathy of grade 1 with pain or grade 2, ixazomib should be withheld until recovery to grade ≤1 and resumed at the most recent dose. For peripheral neuropathy of grade 2 with pain or grade 3 and for other nonhematologic grade 3 or 4 reactions, ixazomib should be withheld and toxicities should, at the physician’s discretion, generally be recovered to baseline condition or grade ≤ 1 before resuming ixazomib; ixazomib can be resumed at the next lowest dose. Treatment should be discontinued for grade 4 rash or peripheral neuropathy. Concomitant administration with strong CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, and St. John’s Wort) should be avoided. The starting dose of ixazomib should be reduced to 3 mg in patients with moderate or severe hepatic impairment and in patients with severe renal impairment or end-stage renal disease requiring dialysis. Ixazomib is not dialyzable and can be administered without regard to the timing of dialysis.

Safety Profile In the phase III trial, the most common adverse events of any grade occurring with a frequency ≥ 5% higher in the ixazomib group were diarrhea (42% vs 36%, grade 3 in 6% vs 2%), constipation (34% vs 25%, grade 3 in < 1% vs < 1%), peripheral neuropathy (28% vs 21%, grade 3 in 2% vs

OF NOTE Ixazomib carries warnings/precautions for thrombocytopenia, gastrointestinal toxicity, peripheral neuropathy, peripheral edema, cutaneous reactions, hepatotoxicity, and embryofetal toxicity.

2%), nausea (26% vs 21%, grade 3 in 2% vs 0%), peripheral edema (25% vs 18%, grade 3 in 2% vs 1%), vomiting (22% vs 11%, grade 3 in 1% vs < 1%), back pain (21% vs 16%, grade 3 in < 1% vs 3%), and rash (19% vs 11%, grade 3 in 3% vs 1%). Any grade thrombocytopenia and neutropenia occurred in 78% vs 54% and 67% vs 66% and was of grade 3 or 4 in 26% vs 11% and 26% vs 30%. The most common serious adverse events in ixazomib patients were thrombocytopenia (2%) and diarrhea (2%). Eye disorders occurred in 26% of the ixazomib group vs 16% of the placebo group (grade 3 in 2% vs 1%), with the most common being blurred vision (6% vs 3%), dry eye (5% vs 1%), and conjunctivitis (6% vs 1%). Serious adverse reactions reported at a frequency of < 1% in patients receiving ixazomib outside of the phase III trial include acute febrile neutrophilic dermatosis (Sweet’s syndrome), StevensJohnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura. Ixazomib carries warnings/precautions for thrombocytopenia, gastrointestinal toxicity, peripheral neuropathy, peripheral edema, cutaneous reactions, hepatotoxicity, and embryofetal toxicity. Platelet counts should be monitored at least monthly during treatment, and hepatic enzymes should be monitored during treatment. Women of reproductive potential should be advised of the potential risk to a fetus and to use effective contraception. n References 1. U.S. Food and Drug Administration: Ixazomib. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm473804.htm. Accessed December 2, 2015. 2. Ninlaro (ixazomib) capsules prescribing information, Millennium Pharmaceuticals, Inc, November 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/ label/2015/208462lbl.pdf. Accessed December 2, 2015.

In Previously Treated Metastatic NSCLC:

Change Expectations, Start With

INDICATION OPDIVO速 (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

SELECT IMPORTANT SAFETY INFORMATION OPDIVO is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, other adverse reactions; infusion reactions; and embryofetal toxicity.

Please see additional Important Safety Information on the following page.

For Previously Treated Metastatic NSCLC Regardless of PD-L1 Expression

OPDIVO is the First and Only PD-1 Inhibitor Approved NON-SQUAMOUS: Overall Survival1,2 Half of Patients Were Alive at 1 Year 2 Median OS was 12.2 months with OPDIVO (95% CI: 9.7-15.0) vs 9.4 months with docetaxel (95% CI: 8.0-10.7); HR=0.73 (95% CI: 0.60-0.89); P=0.0015.1

100 90

PROBABILITY OF SURVIVAL

Objective response rate with OPDIVO was 19% (56/292; 4 complete responses, 52 partial responses) [95% CI: 15-24] vs 12% (36/290; 1 complete response, 35 partial responses) with docetaxel [95% CI: 9-17] (P=0.02). The median duration of response was 17 months in the OPDIVO arm and 6 months in the docetaxel arm.1

51%

95% CI: 45-56

50 40

39%

95% CI: 33-45

Median progression-free survival with OPDIVO was 2.3 months vs 4.2 months with docetaxel; HR=0.92 (95% CI: 0.77–1.11; P=0.39).1

10 0 0

Number at risk OPDIVO DOCETAXEL

292 290

232 244

194 194

169 150

12 OS (Months) 146 111

123 88

62 34

32 10

9 5

0 0

Refer to Figure 2 in the Full Prescribing Information for data on censored patients. CI=confidence interval; HR=hazard ratio; IV=intravenous; OS=overall survival; PD-1=programmed death-1.

Results were based on the prespecified interim analysis conducted when 413 events (93% of the planned number of events for final analysis) were observed (190 in the OPDIVO arm and 223 in the docetaxel arm).1

Study design: OPDIVO was evaluated in a randomized (1:1), open-label, phase 3 study of OPDIVO 3 mg/kg IV every 2 weeks (n=292) vs docetaxel 75 mg/m2 IV every 3 weeks (n=290) in patients with metastatic non-squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Appropriate prior targeted therapy may have been given to patients with known EGFR mutation or ALK translocation. The primary endpoint of the study was OS. Secondary endpoints included ORR and PFS.1,2

Serious Adverse Reactions In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure.

Common Adverse Reactions In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%).

ADDITIONAL IMPORTANT SAFETY INFORMATION Immune-Mediated Pneumonitis Immune-mediated pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred in 0.5% (5/978) of patients receiving OPDIVO as a single agent. In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients receiving OPDIVO including five Grade 3, two Grade 2, and three Grade 1 cases. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold until resolution for Grade 2.

Based on Superior Overall Survival vs Chemotherapy*1 SQUAMOUS: Overall Survival1,3 The First and Only PD-1 Inhibitor to Nearly Double 1-Year Overall Survival Rate vs Chemotherapy*1,3 Median OS was 9.2 months with OPDIVO (95% CI: 7.3-13.3) vs 6.0 months with docetaxel (95% CI: 5.1-7.3); HR=0.59 (95% CI: 0.44-0.79); P=0.00025.1 Results were based on the prespecified interim analysis conducted when 199 events (86% of the planned number of events for final analysis) were observed (86 in the OPDIVO arm and 113 in the docetaxel arm).1 Study design: OPDIVO was evaluated in a randomized (1:1), open-label, phase 3 study of OPDIVO 3 mg/kg IV every 2 weeks (n=135) vs docetaxel 75 mg/m2 IV every 3 weeks (n=137) in patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doubletbased chemotherapy regimen. The primary endpoint of the study was OS.1,3 *Docetaxel. Refer to Figure 1 in the Full Prescribing Information for data on censored patients. PD-L1=programmed death ligand 1.

Start Now: The Only FDA Approved PD-1 Inhibitor That Does Not Require PD-L1 Testing.1

ADDITIONAL IMPORTANT SAFETY INFORMATION (cont'd) Immune-Mediated Colitis Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients including three Grade 3, two Grade 2, and two Grade 1 cases.

Please see additional Important Safety Information on the following page.

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IMPORTANT SAFETY INFORMATION (cont’d) Immune-Mediated Hepatitis

́ Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis.

Immune-Mediated Endocrinopathies ́ Hypophysitis, adrenal insufficiency, and thyroid disorders can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, and thyroid function prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Adrenal insufficiency occurred in 1% (n=555) of patients receiving OPDIVO as a single agent. In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated TSH occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients.

Immune-Mediated Nephritis and Renal Dysfunction ́ Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO. In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients.

Immune-Mediated Rash ́ Immune-mediated rash can occur with OPDIVO treatment. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 rash. In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including 4 Grade 3 cases.

Immune-Mediated Encephalitis ́ Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. Across

clinical trials of 8490 patients receiving OPDIVO as a single agent or in combination with ipilimumab, <1% of patients were identified as having encephalitis. In Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO.

Other Immune-Mediated Adverse Reactions ́ Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone replacement therapy. The following clinically significant immune-mediated adverse reactions occurred in <2% (n=555) of single-agent OPDIVO-treated patients: uveitis, pancreatitis, abducens nerve paresis, demyelination, polymyalgia rheumatica, and autoimmune neuropathy. Across clinical trials of OPDIVO as a single agent administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: facial nerve paralysis, motor dysfunction, vasculitis, diabetic ketoacidosis, and myasthenic syndrome.

Infusion Reactions ́ Severe infusion reactions have been reported in <1% of patients in clinical trials of OPDIVO. In Checkmate 057, Grade 2 infusion reactions occurred in 1% (3/287) of patients receiving OPDIVO. Discontinue OPDIVO in patients with severe or lifethreatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions.

Embryofetal Toxicity ́ Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO-containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation ́ It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Please see brief summary of Full Prescribing Information on the following pages.

References: 1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. 2. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. doi:10.1056/NEJMoa1507643. 3. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med. 2015;373(2): 123-135.

OPDIVO® (nivolumab) injection, for intravenous use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO [see Clinical Studies (14.2) in full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of corticosteroids and no clear alternate etiology, including fatal cases, occurred with OPDIVO treatment. Across clinical trial experience with solid tumors receiving OPDIVO as a single agent, fatal immune-mediated pneumonitis occurred in 0.5% (5/978) of patients. All five fatal cases occurred in a dose-finding study with OPDIVO doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2) or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration (2.3) in full Prescribing Information]. In Trial 3, pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients receiving OPDIVO. Of these 10 patients, there were five patients with Grade 3, two patients with Grade 2, and three patients with Grade 1 immunemediated pneumonitis. The median time to onset was 7.2 months (range: 2.7 to 13.1 months). All five patients with Grade 3 and one of two patients with Grade 2 pneumonitis received high-dose corticosteroids and permanently discontinued OPDIVO; two of these seven were documented radiographically to have complete resolution of pneumonitis. One patient with Grade 2 pneumonitis had OPDIVO temporarily withheld, received low-dose corticosteroids, experienced complete resolution and was retreated without recurrence of pneumonitis. Immune-Mediated Colitis Immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology, can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold OPDIVO for moderate or severe (Grade 2 or 3) colitis. Permanently discontinue OPDIVO for life-threatening (Grade 4) or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.3) in full Prescribing Information]. In Trial 3, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: three patients with Grade 3, two patients with Grade 2, and two patients with Grade 1. The median time to onset in these seven patients was 2.7 months (range: 4 weeks to 19 months). All seven patients received corticosteroids, six of these seven received high-dose corticosteroids for a median duration of 2.9 weeks (range: 1 week to 2.1 months). One patient with Grade 3 colitis permanently discontinued OPDIVO. All seven patients experienced complete resolution. Five of the seven patients were retreated after complete resolution without recurrence of diarrhea or colitis. Immune-Mediated Hepatitis Immune-mediated hepatitis, defined as requiring use of corticosteroids and no clear alternate etiology, can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2) or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis [see Dosage and Administration (2.3) in full Prescribing Information and Adverse Reactions]. In Trial 3, one patient developed immune-mediated hepatitis (0.3%) after 7.8 months of OPDIVO exposure. The event resolved following temporary withholding of OPDIVO and high-dose corticosteroid therapy. Immune-mediated hepatitis recurred following resumption of OPDIVO, resulting in permanent discontinuation.

Immune-Mediated Endocrinopathies Hypophysitis Hypophysitis can occur with OPDIVO (nivolumab) treatment. Monitor patients for signs and symptoms of hypophysitis. Administer corticosteroids at a dose of 1 mg/kg/day prednisone equivalents for moderate (Grade 2) or greater hypophysitis. Withhold OPDIVO for moderate (Grade 2) or severe (Grade 3) and permanently discontinue OPDIVO for life-threatening (Grade 4) hypophysitis [see Dosage and Administration (2.3) in full Prescribing Information]. Adrenal Insufficiency Adrenal insufficiency can occur with OPDIVO treatment. Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency [see Dosage and Administration (2.3) in full Prescribing Information]. In Trials 1 and 3 (n=555), 1% of OPDIVO-treated patients developed adrenal insufficiency. Hypothyroidism and Hyperthyroidism Thyroid disorders can occur with OPDIVO treatment. Monitor thyroid function prior to and periodically during treatment. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of OPDIVO for hypothyroidism or hyperthyroidism. In Trial 3, Grade 1 or Grade 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) of patients receiving OPDIVO and 0% (0/268) of patients receiving docetaxel, while elevated TSH occurred in 17% of patients receiving OPDIVO and 5% of patients receiving docetaxel. The median time to onset of hypothyroidism/ thyroiditis was 2.9 months (range: 1.4 to 11.8 months). All 20 patients received levothyroxine. Two patients received corticosteroids; one of whom received high-dose corticosteroids. Complete resolution of hypothyroidism occurred in one patient. OPDIVO was temporarily withheld due to hypothyroidism/thyroiditis in three patients; no patients discontinued OPDIVO due to hypothyroidism/thyroiditis. Grade 1 or Grade 2 hyperthyroidism occurred in 1.4% (4/287) of patients. The median time to onset was 2 months (range: 4.1 weeks to 2.8 months). Two of four patients received methimazole and one patient also received treatment with high-dose corticosteroids. All four patients experienced complete resolution. Immune-Mediated Nephritis and Renal Dysfunction Immune-mediated nephritis, defined as renal dysfunction or ≥Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology, can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Withhold OPDIVO for moderate (Grade 2) or severe (Grade 3) increased serum creatinine, and administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper. If worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue OPDIVO. Permanently discontinue OPDIVO and administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) increased serum creatinine [see Dosage and Administration (2.3) in full Prescribing Information and Adverse Reactions]. In Trial 3, immune-mediated renal dysfunction (Grade 2) occurred in 0.3% (1/287) of patients. The time to onset in this patient was 1.5 months. The patient permanently discontinued OPDIVO, received high-dose corticosteroids, and experienced complete resolution. Immune-Mediated Rash Immune-mediated rash can occur with OPDIVO treatment. Monitor patients for rash. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for severe (Grade 3) or life-threatening (Grade 4) rash. Withhold OPDIVO for severe (Grade 3) rash and permanently discontinue OPDIVO for lifethreatening (Grade 4) rash [see Dosage and Administration (2.3) in full Prescribing Information]. In Trial 3, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO. Grade 3 rash developed in four patients (1.4%), of whom one discontinued treatment. Immune-Mediated Encephalitis Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to serve neurologic deterioration. Evaluation may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. If other etiologies are ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for immune-mediated encephalitis [see Dosage and Administration (2.3) in full Prescribing Information]. Across clinical studies of 8490 patients receiving OPDIVO, less than 1% of patients were identified as having encephalitis. In Trial 3, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO after 7.2 months of exposure. OPDIVO was discontinued; corticosteroids were administered.

Other Immune-Mediated Adverse Reactions Other clinically significant immune-mediated adverse reactions can occur. Immune-mediated adverse reactions may occur after discontinuation of OPDIVO (nivolumab) therapy. For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting OPDIVO after completion of corticosteroid taper based on the severity of the event [see Dosage and Administration (2.3) in full Prescribing Information]. The following clinically significant, immune-mediated adverse reactions occurred in less than 2% of OPDIVO-treated patients in Trials 1 and 3 (n=555): uveitis, pancreatitis, abducens nerve paresis, demyelination, polymyalgia rheumatica, and autoimmune neuropathy. Across clinical trials of OPDIVO administered at doses of 3 mg/kg and 10 mg/kg the following additional clinically significant, immune-mediated adverse reactions were identified: facial nerve paralysis, motor dysfunction, vasculitis, diabetic ketoacidosis, and myasthenic syndrome. Infusion Reactions Severe infusion reactions have been reported in <1% of patients in clinical trials of OPDIVO as a single agent. In Trial 3, Grade 2 infusion reactions occurred in 1% (3/287) of patients receiving OPDIVO. Discontinue OPDIVO in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Embryofetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-Mediated Pneumonitis [see Warnings and Precautions] • Immune-Mediated Colitis [see Warnings and Precautions] • Immune-Mediated Hepatitis [see Warnings and Precautions] • Immune-Mediated Endocrinopathies [see Warnings and Precautions] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions] • Immune-Mediated Rash [see Warnings and Precautions] • Immune-Mediated Encephalitis [see Warnings and Precautions] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions] • Infusion Reactions [see Warnings and Precautions] 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 in the Warning and Precautions section reflect exposure to OPDIVO for clinically significant adverse reactions in 978 patients enrolled in Trials 1, 3, a single-arm trial in NSCLC, or an additional dose finding study (n=306) administering OPDIVO as a single agent at doses of 0.1 to 10 mg/kg every 2 weeks [see Warnings and Precautions]. The data described below reflect exposure to OPDIVO in Trial 3, which is a randomized trial in patients with metastatic non-squamous non-small cell lung cancer (NSCLC). Metastatic Non-Squamous Non-Small Cell Lung Cancer The safety of OPDIVO was evaluated in Trial 3, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies (14.2) in full Prescribing Information]. Patients received 3 mg/kg of OPDIVO (n=287) administered intravenously over 60 minutes every 2 weeks or docetaxel (n=268) administered intravenously at 75 mg/m2 every 3 weeks. The median duration of therapy was 2.6 months (range: 0 to 24.0+) in OPDIVO-treated patients and was 2.3 months (range: 0 to 15.9 months) in docetaxel-treated patients. In this trial, 30% of patients received OPDIVO for greater than 6 months and 20% of patients received OPDIVO for greater than 1 year.

Trial 3 excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. The median age of all randomized patients was 62 years (range: 21 to 85); 37% of patients in the OPDIVO (nivolumab) group were ≥65 years of age and 47% of patients in the docetaxel group were ≥65 years of age, 55% were male, and 92% were white. Twelve percent of patients had brain metastases and ECOG performance status was 0 (31%) or 1 (69%). OPDIVO was discontinued in 13% of patients, and was delayed in 29% of patients for an adverse reaction. Serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In the OPDIVO arm, seven deaths were due to infection including one case of pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, cough, decreased appetite, and constipation. Table 1 summarizes selected adverse reactions occurring more frequently in at least 10% of OPDIVO-treated patients. Table 1:

Selected Adverse Reactions Occurring in ≥10% of OPDIVOTreated Patients and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 3) OPDIVO (n=287)

Adverse Reaction

All Grades

Docetaxel (n=268)

Grades 3-4

All Grades

Grades 3-4

Percentage (%) of Patients Respiratory, Thoracic, and Mediastinal Disorders Cough Metabolism and Nutrition Disorders Decreased appetite Gastrointestinal Disorders Constipation Skin and Subcutaneous Tissue Disorders Pruritus

0.3

1.7

1.5

0.7

1.9

Other clinically important adverse reactions observed in patients treated with OPDIVO and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (49% Grade 1-4, 6% Grade 3-4), musculoskeletal pain (36%), pleural effusion (5.6%), pulmonary embolism (4.2%), urticaria (1.4%), and polymyalgia rheumatica (0.3%). Table 2:

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

Test

Chemistry Hyponatremia Increased AST Increased alkaline phosphatase Increased ALT Increased creatinine Increased TSHb a

OPDIVO

Docetaxel

All Grades

Grades 3-4

All Grades

Grades 3-4

35 28 27

6 2.8 1.1

32 14 18

2.7 0.4 0.4

23 18 17

2.4 0 N/A

15 13 5

0.4 0.4 N/A

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 280 to 287 patients) and docetaxel group (range: 252 to 262 patients); TSH: OPDIVO group n=209 and docetaxel group n=207. b Not graded per NCI CTCAE v4.0.

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Of 532 patients who were treated with OPDIVO (nivolumab) 3 mg/kg every 2 weeks and evaluable for the presence of anti-nivolumab antibodies, 67 patients (12.6%) tested positive for treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies against nivolumab were detected in five patients (0.9%). There was no evidence of altered pharmacokinetic profile or toxicity profile with anti-nivolumab binding antibody development. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to OPDIVO with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) in full Prescribing Information] and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in full Prescribing Information]. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). Nivolumab administration resulted in a non-doserelated increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Lactation Risk Summary It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment with OPDIVO. Females and Males of Reproductive Potential Contraception Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO. Pediatric Use The safety and effectiveness of OPDIVO have not been established in pediatric patients. Geriatric Use Of the 292 patients randomized to OPDIVO in Trial 3, 37% of patients were 65 years or older and 7% were 75 years or older. In this trial, no overall differences in safety or efficacy were reported between elderly patients and younger patients.

Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. OPDIVO (nivolumab) has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There is no information on overdosage with OPDIVO. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of OPDIVO, including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions]. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions]. • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, and hyperthyroidism [see Warnings and Precautions]. • Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions]. • Rash: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions]. • Encephalitis: Advise patients to contact their healthcare provider immediately for neurological signs or symptoms of encephalitis [see Warnings and Precautions]. • Infusion Reactions: Advise patients of the potential risk of infusion reaction [see Warnings and Precautions]. • Females of Reproductive Potential: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions, Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO [see Use in Specific Populations]. • Lactation: Advise women not to breastfeed while taking OPDIVO [see Use in Specific Populations]. Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321663A2

Revised: October 2015 1506US1502380-05-01

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2015-2016 Oncology Meetings December American Society for Cell Biology Annual Meeting December 12-16 • San Diego, Callifornia For more information: http://ascb.org/2015meeting/

European Society for Medical Oncology Asia 2015 Congress December 18-21 • Singapore For more information: www.esmo.org/Conferences/ ESMO-Asia-2015-Congress

Advances in Medical and Surgical Management of Thyroid Cancer January 15-16 • Tempe, Arizona For more information: www.aace.com/meetings/symposia/ january/thyroid-cancer

The Biomarker Conference February 18-20 • San Diego, California For more information: www.mnmconferences.com/thebiomarker-conference-florida.html

14th Oncology Update: Advances and Controversies January 15-18 • Steamboat Springs, Colorado For more information: www.mdanderson.org/educationand-research/education-andtraining/schools-and-programs/ cme-conference-management/ conferences/cme/conferencemanagement-14th-oncology-updateadvances-and-controversies.html

Multidisciplinary Head and Neck Cancer Symposium February 18-20 • Scottsdale, Arizona For more information: www.headandnecksymposium.org

4th AACR-IASLC International Joint Conference: Lung Cancer Translational Science January 4-7 • San Diego, California For more information: www.aacr.org

Gastrointestinal Cancers Symposium January 21-23 • San Francisco, CA For more information: http://gicasym.org

Genitourinary Cancers Symposium January 7-9 • San Francisco, California For more information: http://gucasym.org

Personalized World Medicine Conference January 24-27 • Mountain View, California For more information: http://2016sv.pmwcintl.com/ index.php

Cancer Survivorship Symposium: Primary Care and Oncology Collaboration January 15-16 • San Francisco, California For more information: www.survivorsym.org/

3rd Annual University of Southern California Multidisciplinary Breast Cancer Symposium January 30 • Los Angeles, CA For more information: http://keck. usc.edu/About/Administrative_ Offices/Office_of_Continuing_ Education/Courses/~/media/ Office%20of%20CME/FINAL_ brochure_2016%20breast%20 cancer.pdf

February

January 2016

Breast and Gynaecological International Cancer Society (BGICS) Conference January 14-15 • Cairo, Egypt For more information: www.bgicc.eg.net/Home.aspx

2015-2016

8th Immunotherapeutics & Immunomonitoring Conference January 25-26 • San Diego, CA For more information: https://www.gtcbio.com/ conferences/immunotherapeuticsimmunomonitoring-overview 8th Annual T-Cell Lymphoma Forum January 28-30 • San Francisco, CA For more information: www.tcellforum.com/

4th State of the Science Cancer Survivorship Research Symposium February 4 • Houston, Texas For more information: www.mdanderson.org 18th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 4-6 • San Diego, CA For more information: www.imedex.com/antiangiogenesis-and-immunetherapies/

25th Conference of the Asian Pacific Association for the Study of the Liver February 20-24 • Tokyo, Japan For more information: http://www.apasl2016.org 3rd Annual International Conference on Advances in Cancer Medical Research (ACMR 2016) February 22-23 • Singapore For more information: http://cancerresearch-conf.org/ Cancer Center Business Summit February 24-25 • Phoenix, Arizona For more information: http://cancerbusinesssummit.com

Advances in Systemic Therapy for Breast Cancer 2016 February 12-13 • Ponte Vedra Beach, Florida For more information: https://ce.mayo.edu/node/5816

ASCO Quality Care Symposium February 26-27 • Phoenix, Arizona For more information: http://quality.asco.org

10th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics February 16-20 • Maui, Hawaii For more information: www.aacr.org

Winship Cancer Institute 2016 Melanoma Conference February 27 • Atlanta, Georgia For more information: www. winshipmelanomaconference.com

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2015-2016 Oncology Meetings AACR Precision Medicine Series: Cancer Cell Cycle–Tumor Progression and Therapeutic Response February 28-March 2 • Maui, Hawaii For more information: www.aacr.org/Meetings/Pages/ MeetingDetail.aspx?EventItemID=76#. Vbb2qKTbJjo 6th World Congress on Cell & Stem Cell Research February 29-March 2 • Philadelphia, Pennsylvania For more information: http://stemcell.omicsgroup.com/

March

Society of Surgical Oncology Annual Cancer Symposia March 2-5 • Boston, Massachusetts For more information: www.surgonc.org

Second Annual New Treatments in Oncology March 5-6 • Scottsdale, Arizona For more information: www.cvent.com/events/annualnew-treatments-in-oncologyconference-presented-by-cancertreatment-centers-of-america-/ event-summary-2fb116562f6447cca49 2c89064760b02.aspx ILCA School of Liver Cancer 2016 March 7-8 • Barcelona, Spain For more information: www.ilcaonline.org/sitecore/content/bebruga/ilca-online/School%20of%20 Liver%20Cancer/2016.aspx Moffitt Cancer Center Neuro-Oncology Conference March 10-11 • Clearwater Beach, FL For more information: http://myana.org/events/moffittcancer-center-neuro-oncologyconference

8th Annual Asian Oncology Summit March 3-6 • Kyoto, Japan For more information: www.asianoncologysummit.com Hematology and Medical Oncology Board Review: Contemporary Practice From Memorial Sloan Kettering Cancer Center March 4-7 • New York, New York For more information: www.mskcc.org/event/hematologyand-medical-oncology-boardreview-contemporary-practice

40th Annual American Society of Preventive Oncology (ASPO) Conference March 12-15 • Columbus, Ohio For more information: https://aspo.org/annual-meeting 2016 Methods in Clinical Research Workshop for Minority Physicians March 17-20 • Fort Lauderdale, Florida For more information: www.roswellpark.edu/education/ diversity-clinical-researchworkshop The 16th Multidisciplinary Management of Cancers: A Case-Based Approach March 18-20 • Napa, California For more information: https://med.stanford.edu/cme/ courses/2016/multicancer2016.html

Society of Gynecologic Oncology Annual Meeting on Women’s Cancer March 19-22 • San Diego, California For more information: www.sgo.org

33rd Annual Miami Breast Cancer Conference March 10-13 • Miami, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/33rd-Annual-MiamiBreast-Cancer-Conference 2016 ASTRO Annual Refresher Course March 11-13 • La Jolla, California For more information: www.astro.org/Meetings-andEvents/2016-Annual-RefresherCourse/Index.aspx Annual European Association of Urology Congress March 11-15 • Munich, Germany For more information: http://eaumunich2016.uroweb.org

Gastrointestinal Cancer Multidisciplinary Symposium 2016: Current Update on State of the Art Screening, Diagnosis and Treatment April 9 • Columbus, Ohio For more information: https://ccme.osu.edu/

26th Annual Interdisciplinary Breast Cancer Center Conference April 9-13 • Las Vegas, Nevada For more information: http://www2.breastcare.org/ welcome-to-the-24th-annualnational-interdisciplinary-breastcenter-conference/ European Lung Cancer Conference April 13-16 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2016-Lung-Cancer

3rd St. Gallen International Gastrointestinal Cancer Conference March 10-12 • St. Gallen, Switzerland For more information: www.oncoconferences.ch/dynasite .cfm?dsmid=500294

22nd Annual Blood-Brain Barrier and Neuro-oncology Meeting March 3-5 • Stevenson, Washington For more information: www.ohsu.edu/bbb 4th Annual UC San Diego Essentials and Advances in Apheresis Therapies March 3-5 • San Diego, California For more information: https://cme.ucsd.edu/apheresis/

2015-2016

International Conference on Pancreatic and Colorectal Cancer March 29-30 • Atlanta, Georgia For more information: http://pancreatic-colorectal .cancersummit.org NCCN 21st Annual Conference: Advancing the Standard of Cancer CareTM March 31-April 2 • Hollywood, Florida For more information: www.nccn.org

April New Frontiers in Diagnosis, Screening, and Management of Inherited Cancer Syndromes April 8-9 • Chicago, Illinois For more information: https://cme.uchicago.edu/NFD2016

American Society for Colposcopy and Cervical Pathology (ASCCP) Annual Meeting April 13-16 • New Orleans, Louisiana For more information: www.asccp.org/2016annualmeeting Clinical Immunology Society Annual Meeting April 14-17 • Boston, Massachusetts For more information: www.clinimmsoc.org/education/ meetings/2016-annual-meeting American Association of Cancer Research Annual Meeting April 16-20 • New Orleans, Louisiana For more information: www.aacr.org 16th Pan Arab Cancer Conference April 28-30 • Cairo, Egypt For more information: www.pacc16.org 2016 Head and Neck Cancer Symposium Fifth Annual April 30 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx continued on page 134

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2015-2016 Oncology Meetings Meetings Calendar continued from page 133

May Markers in Cancer Diagnostic Development Tutorial May 2-3 • Bethesda, Maryland For more information: http://markersincancer.org Palliative Care Education and Practice (PCEP) May 4-10 • Cambridge, Massachusetts For more information: www.hms.harvard.edu/pallcare/ PCEP/PCEP.htm 19th SIS World Congress on Breast Healthcare May 5-8 • Warsaw, Poland For more information: www.siscongress.org 14th CIMT Annual Meeting: Mechanisms of Efficacy in Cancer Immunotherapy May 10-12 • Mainz, Germany For more information:www.meeting. cimt.eu IMPAKT 2016 Breast Cancer Conference May 12-14 • Brussels, Belgium For more information: www.esmo.org/Conferences/ IMPAKT-2016-Breast-Cancer Lymphoma: State-of-the-Art in Biology, Therapy, and Patient Care May 13-14 • New York, New York For more information: www.mskcc.org/event/lymphomastate-art-biology-therapy-andpatient-care

AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer May 16-19 • Miami, Florida For more information: www.aacr.org/Meetings/ Pages/MeetingDetail. aspx?EventItemID=78#.Vbel9qTbJjo

June

2015-2016

IARC: Emerging Issues in Oncogenic Virus Research June 15-19 • Puglia, Italy For more information: www.iarc.fr/oncogenicviruses2016/ 2016 ASH Meeting on Lymphoma Biology June 18-21 • Colorado Springs, CO For more information: www.hematology.org/ Lymphoma-Biology/ Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology Annual Meeting on Supportive Care in Cancer June 23-25 • Adelaide, Australia For more information: www.mascc.org

2016 ASCO Annual Meeting June 3-7 • Chicago, Illinois For more information: http://am.asco.org IARC: Global Cancer: Occurrence, Causes, and Avenues to Prevention June 7-10 • Lyon, France For more information: http://iarc-conference2016.com WCIO 2016 June 9-12 • Boston, Massachusetts For more information: www.wcioevents.org The Society of Nuclear Medicine & Molecular Imaging Annual Meeting June 11-15 • San Diego, California For more information: www.snmmi.org/AM/

Best of ASCO® Chicago June 24-25 • Chicago, Illinois For more information: http://boa.asco.org

July 24th Biennial Congress of the European Association for Cancer Research (EACR24) July 9-12 • Manchester, United Kingdom For more information: www.ecco-org.eu/EACR Best of ASCO® Washington, DC July 15-16 • Washington, DC For more information: http://boa.asco.org AHNS 9th International Conference on Head and Neck Cancer July 16-20 • Seattle, Washington For more information: www.ahns2016.org/

Pan Pacific Lymphoma Conference July 18-22 • Koloa, Hawaii For more information: www.unmc.edu/cce/catalog/ clinicmed/panpacificlymphoma/ index.html Best of ASCO® Los Angeles July 22-23 • Los Angeles, California For more information: http://boa.asco.org Mayo Clinic Oncology Review 2016 July 23 • Minneapolis, Minnesota For your information: https://ce.mayo.edu/hematologyand-oncology/content/mayo-cliniconcology-review-2016 Japanese Society of Medical Oncology Annual Meeting July 28-30 • Kobe, Japan For more information: http://www2.convention.co.jp/ jsmo2016/english/index.html

August The 33rd World Congress of Internal Medicine (WCIM) August 22-25 • Bali, Indonesia For more information: www.wcimbali2016.org

September 2nd World Congress on Controversies in Breast Cancer (CoBrCa) September 8-11 • Barcelona, Spain For more information: http://congressmed.com/cobrca/

November 3-6, 2016 Washington, DC

Gaylord National Hotel | National Harbor, MD

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR TREANDA® (bendamustine hydrochloride) injection, for intravenous use TREANDA® (bendamustine hydrochloride) for injection, for intravenous use 1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established. 2 DOSAGE AND ADMINISTRATION 2.1 Selection of TREANDA Formulation to Administer TREANDA is available in two formulations, a solution (TREANDA Injection) and a lyophilized powder (TREANDA for Injection). Do not use TREANDA Injection if you intend to use closed system transfer devices (CSTDs), adapters and syringes containing polycarbonate or acrylonitrilebutadiene-styrene (ABS) prior to dilution in the infusion bag [see Dosage and Administration (2.4)]. If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a polypropylene syringe with a metal needle and polypropylene hub to withdraw and transfer TREANDA Injection into the infusion bag. Polypropylene syringes are translucent in appearance. TREANDA Injection and the reconstituted TREANDA for Injection have different concentrations of bendamustine hydrochloride. The concentration of bendamustine hydrochloride in the solution is 90 mg/mL and the concentration of bendamustine hydrochloride in the reconstituted solution of lyophilized powder is 5 mg/mL. Do not mix or combine the two formulations. TREANDA Injection must be withdrawn and transferred for dilution in a biosafety cabinet (BSC) or containment isolator using a polypropylene syringe with a metal needle and a polypropylene hub. If a CSTD or adapter that contains polycarbonate or ABS is used as supplemental protection prior to dilution, only use TREANDA for Injection, the lyophilized powder formulation [see How Supplied/Storage and Handling (16.1)]. 2.2 Dosing Instructions for CLL Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [see Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. 2.4 Preparation for Intravenous Administration TREANDA is a cytotoxic drug. Follow applicable special handling and disposal procedures. TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) TREANDA Injection must be diluted in a biosafety cabinet (BSC) or containment isolator. • When preparing and transferring the concentrated TREANDA Injection solution into the infusion bag, do not use devices that contain polycarbonate or ABS. However, after dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used. TREANDA Injection contains N,N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices, including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA which is present in the product. This incompatibility leads to device failure (e.g., leaking, breaking, or operational failure of CSTD components), possible product contamination, and potential serious adverse

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

health consequences to the practitioner, including skin reactions; or to the patient, including but not limited to, the risk of small blood vessel blockage if they receive product contaminated with dissolved ABS or polycarbonate. Devices that are compatible for use in dilution of TREANDA Injection are available. • If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a polypropylene syringe with a metal needle and a polypropylene hub to withdraw and transfer TREANDA Injection into the infusion bag. • Each vial of TREANDA Injection is intended for single dose only. • Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution using a polypropylene syringe with a metal needle and a polypropylene hub. • Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.7 mg/mL. • After dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used. • Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear colorless to yellow solution. Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder) If a closed system transfer device or adapter that contains polycarbonate or ABS is to be used as supplemental protection during preparation, only use TREANDA for Injection, the lyophilized formulation. • Each vial of TREANDA for Injection is intended for single dose only. • Aseptically reconstitute each TREANDA for Injection vial as follows: ◦ 25 mg TREANDA for Injection vial: Add 5 mL of only Sterile Water for Injection, USP. ◦ 100 mg TREANDA for Injection vial: Add 20 mL of only Sterile Water for Injection, USP. • Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag. • Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear and colorless to slightly yellow solution. Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. General Information Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. 2.5 Admixture Stability TREANDA Injection and TREANDA for Injection contain no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.

TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature (15°-30°C or 59°86°F) and room light. Administration of diluted TREANDA Injection must be completed within this period. TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder) Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (3647°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of reconstituted and diluted TREANDA for Injection must be completed within this period. 4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [see Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [see Dosage and Administration (2. 2)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection. 5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)]. 5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports,

TREANDA® (bendamustine hydrochloride) Injection TREANDA® (bendamustine hydrochloride) for Injection

including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. 5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. 6.1 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. Chronic Lymphocytic Leukemia The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. Non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class All Grade All Grade Preferred term Grades 3/4 Grades 3/4 Total number of 121 (79) 52 (34) 96 (67) 25 (17) patients with at least 1 adverse reaction Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class All Grade All Grade Preferred term Grades 3/4 Grades 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study Laboratory TREANDA Chlorambucil Abnormality N=150 N=141 All Grade All Grade Grades 3/4 Grades 3/4 n (%) n (%) n (%) n (%) Hemoglobin 134 (89) 20 (13) 115 (82) 12 (9) Decreased Platelets 116 (77) 16 (11) 110 (78) 14 (10) Decreased Leukocytes 92 (61) 42 (28) 26 (18) 4 (3) Decreased Lymphocytes 102 (68) 70 (47) 27 (19) 6 (4) Decreased Neutrophils 113 (75) 65 (43) 86 (61) 30 (21) Decreased In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [see Warnings and Precautions (5.5)]

7 DRUG INTERACTIONS No formal clinical assessments of pharmacokinetic drug-drug interactions between TREANDA and other drugs have been conducted. Bendamustine’s active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma concentrations of bendamustine and decrease plasma concentrations of active metabolites. Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites. Caution should be used, or alternative treatments considered if concomitant treatment with CYP1A2 inhibitors or inducers is needed. The role of active transport systems in bendamustine distribution has not been fully evaluated. In vitro data suggest that P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may have a role in bendamustine transport. Based on in vitro data, bendamustine is not likely to inhibit metabolism via human CYP isoenzymes CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or to induce metabolism of substrates of cytochrome P450 enzymes. 8.6 Renal Impairment No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild or moderate renal impairment. TREANDA should not be used in patients with CrCL < 40 mL/min. 8.7 Hepatic Impairment No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild hepatic impairment. TREANDA should not be used in patients with moderate (AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 X ULN) or severe (total bilirubin > 3 X ULN) hepatic impairment. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal TREANDA is a cytotoxic drug. Follow applicable special handling and disposal procedures. Care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection and TREANDA for Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If gloves come in contact with TREANDA Injection prior to dilution, remove gloves and follow disposal procedures. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. 16.3 Storage TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) TREANDA Injection must be stored refrigerated between 2°-8°C (36°-46°F). Retain in original package until time of use to protect from light. TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder) TREANDA for Injection may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2015 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates. All rights reserved. Brief Summary of TREANDA Prescribing Information TRE-011

TRE-40554

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Book Review

The Highs and Lows of a Transplant Surgeon By Ronald Piana

urgery has a distinct place in medicine. Surgeons cut deep into our bodies amid clusters of nerves and ligaments and pulsing organs; a slight mishap brings blood. And the scalpel—the tool of the trade—is just a specially designed knife, as is a butcher knife and a bayonet. And surgeons begin their work as we drift far away on a cloud of propofol. Organ transplant is one of the most difficult surgical procedures—not just technically but with the emotions swirling around waiting for someone to die so that another may live. Bud Shaw, MD, captures the emotion, heartache, and drama of organ transplant and more in his gritty memoir, Last Night in the OR: A Transplant Surgeon’s Odyssey.

el, and the author is clearly a fan of terse Hemingwayesque prose, which, given the sensitivity of his life-and-death profession, sometimes feels a bit too clipped. That said, Dr. Shaw’s writing style is obviously tailored to capture the grittiness of liver transplantation and the men who got their hands dirty. Yes, at the time, this profession was gender-centric—the operating room of Dr. Shaw’s surgical adventures was scented with testosterone.

University of Pittsburgh Dr. Shaw sold his wife’s car, loaded up their belongings, and schlepped across the country to the University of Pittsburgh Medical Center, where Dr. Starzl had his transplant clinic. Although there’s

Like many professionals who care deeply for their patients, I lived every day of my career with the horrible reality that more than half of the people awaiting an organ will never get them. —Bud Shaw, MD

In his author’s note, Dr. Shaw sums up the emotional roller coaster of his profession. He writes: “Like many professionals who care deeply for their patients, I lived every day of my career with the horrible reality that more than half of the people awaiting an organ will never get them.” His book, sometimes rough around the edges, is a fast-paced chronicle of the early 1980s, when the field of organ transplantation was pushing into uncharted medical territory, which was fraught with fear and ethical taboos. Dr. Shaw was on the front lines. “I was desperate to show how good I was that night,” he writes in his opening line, spoken like a true surgeon.

A Daring Profession The book begins on Dr. Shaw’s last day as a surgery resident at the University of Utah in 1981. The 31-year-old doctor aspired to be a transplant surgeon, and, with pluck and good fortune, he was granted a training position on the surgical team of Thomas E. Starzl, MD, PhD, the “father of liver transplantation” and perhaps the most renowned transplant surgeon of that time. Besides Dr. Shaw’s burning desire to become part of this daring transplant profession, the reader also learns of his passion for football and thrill seeking. More important, the cadence and voice of the book are established. It reads like a nov-

no shortage of drama in Dr. Shaw’s life, there is, however, a shortage of his wife’s presence in his life in the book. Upon arriving in Pittsburgh, Dr. Shaw immediately gets embroiled in a scheduling brouhaha that almost cost him his position; inadvertently, dates were mixed up, and he was 2 weeks late. In some rather course language, Dr. Starzl’s assistant barked into the phone, “Get your butt here as soon as possible or else!”

A Closer Look at Surgeons For readers looking for detailed medical descriptions of the nascent field of transplantation, they should look elsewhere. Instead, Last Night in the OR is textured with the internal workings of, what was at the time, a rough-andtumble foray into the lives of surgeons who drop f-bombs, smoke, hang-glide, and hold football as a sacred pastime. It makes for an exciting read but sometimes a bit ham-handed in the delivery. For example, on Dr. Shaw’s first day, Sandee, a nurse on the transplant team, grabbed him by the arm and showed him around the hospital. As they moved through the intensive care unit, a medical student with a clipboard approached and asked Dr. Shaw to sign a petition banning liver transplants on ethical grounds. When Dr. Shaw explained that he’s the new transplant fellow, the medical student responded firmly, “Then you

should definitely sign it.” After some rather staged barbs between Sandee and the medical student about the net worth of liver transplantation, the outgunned medical student resorted to a crass sports analogy to make her point. To this Sandee retorted, “This ain’t baseball, sweetie.”

Questionable Anecdotes Dr. Shaw fills in his backstory with lively excursions into the past: some work, some do not. This book’s story, according to the title, is located largely in the organ transplant operating room, and there’s enough there to fill several books. However, somehow, perhaps to lace his book with dicey commercial anecdotes, the author recalls past events that don’t relate to the captivating theme of his profession. For example, during his stint on the psychiatric ward in his third-year surgery rotation, a 40-year-old man named Ike with erectile dysfunction threatens suicide by gunshot if Dr. Shaw can’t help him. This is pre–little-blue-pill days, so Dr. Shaw’s prescription pad proved impotent for Ike’s issue. So, Dr. Shaw made the doctor’s cardinal sin: He got personally involved with a patient, no less one who is suicidal. Ike didn’t kill himself, but it got pretty messy, and Dr. Shaw explained his medical faux pas like this: “I felt so stupid. I felt like I should have known better, that my supervisor had taught us about this sort of thing and I’d dozed off.” Last Night in the OR is structured in three parts, with each one broken into short chapters with catchy titles and an arresting opening. This format is stock and trade for commercial nonfiction. Dr. Shaw is a capable writer, but at times, he tries too hard to impress the reader with visceral prose. For example, in a chapter called “Good Opera,” he unleashed this beaut: “On the table lay a man from Kansas. He had a wife, two daughters under five, and a bad liver. He had a belly full of fluid, skin glowing like a pumpkin, and a nest of veins like snakes between my knife and his liver.” Snakes? Knife? Dr. Shaw’s images invoke a Tarzan-like death struggle, instead of a risky and highly technical surgical procedure with a person’s life in the balance.

Much of the Story Left Untold At times, Last Night in the OR is a rollicking read, but Dr. Shaw made several mistakes when taking pen to paper, beginning with the title’s subhead: “A Transplant Surgeon’s Odyssey.” The

Bookmark Title: Last Night in the OR: A Transplant Surgeon’s Odyssey Author: Bud Shaw, MD Publisher: Plume, division of Penguin Group Publication date: September 15, 2015 Price: $16.00; paperback, 304 pages

reader learns little about the intriguing science and techniques of organ transplantation; immune system rejection and HLA markers are absent from Dr. Shaw’s narrative. And the last several chapters are flashbacks about his mother’s losing battle with lung cancer while Dr. Shaw was an adolescent. His mother was a heavy smoker, and there were some anger and guilt issues between Dr. Shaw and his father. OK, this was an important chapter in his life, but what does it have to do with last night in the operating room or a transplant surgeon’s odyssey? By all accounts, Dr. Shaw is a skilled and dedicated surgeon who has saved countless lives. However, too little of that story was left untold. Instead, he attempted to write a commercial product, and to that end, he succeeded; Last Night in the OR is the equivalent of a medical beach read. For readers of The ASCO Post vacationing in Turks and Caicos or some other tropical destination, this book is recommended. For those in the clinic and elsewhere in the oncology community, it may not be. n

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Book Review

Racial Issues on the Road to Medicine By Ronald Piana

trained race relations over issues whose foundation is based on inequality remain a persistently difficult social problem. Inequality in health care has palpable social consequences. As Martin Luther King, Jr famously said, “Of all forms of inequality, injustice in health is the most shocking and the most inhumane.” ASCO, for one, has been at the forefront of engaging the challenges associated with disparities of cancer care among economically challenged populations. These are complicated issues, with no simple solution in sight. However, our ability to make the U.S. healthcare system more equitable relies, in part, on our insight into the social phenomena that create disparities. In his recently published memoir, Black Man in a White Coat: A Doctor’s Reflections on Race and Medicine, Damon Tweedy, MD, takes the reader inside the personal experiences of an African American’s journey into the medical profession, some of which are uncomfortable to read.

in lecture, my stomach twisted. I knew where this was heading. Seated in a sea of mostly white and Asian faces, I wondered how this information affected their views of black people, whether they already had biases against us, and whether they impacted the way they saw me.” In a very straightforward manner, Dr. Tweedy lets the reader know that even though he was a well-educated person studying to be a doctor at one of the nation’s most honored medical schools, he suffered insecurities based on his race. And in doing that, he tacitly renders a more somber picture of the health-care system he is about to join: If he, an African American doctor, is inhibited by a system that largely does not look like him, what chance does a poor, undereducated black person have in accessing equitable care? This question, in various permutations, is central to our ongoing healthcare debate.

Title: Black Man in a White Coat: A Doctor’s Reflections on Race and Medicine Author: Damon Tweedy, MD Publisher: Picador, Macmillan Publishing Publication date: September 8, 2015 Price: $26.00; hardcover, 304 pages Dr. Tweedy’s serious arguments about disparities of care. Although illustrating the larger point of inequality with anecdotal stories from his medical school

At least once a day during my rotations, my race would come up in an interaction with [white] patients. The racial conversation was usually implied, rather than explicit….

A Must-Read Introduction Dr. Tweedy received his medical degree from the prestigious Duke University School of Medicine, “as one of a half dozen black students on scholarship.” As a psychiatrist, he brings the introspection of a discipline centered on the inner workings of the human mind to the pages of his thoroughly honest book. Dr. Tweedy’s introduction is a must read. In economic prose, he lets the reader know exactly where he is coming from—make no mistake, this book is about race. And, according to the author, during his early medical schooling, the subject was thrust on him. His original goal was to make his parents proud and set himself up for a good career. In fact, race-based concerns were low on his priority list. He writes, “But my professors could not stop talking about race. During my early months, as they taught us about diseases both common and rare, they inevitably cited the demographics about one racial group or another…. They spoke about Asians, Hispanics, and Native Americans, but invariably, as it always seems in America, their analyses always came down to comparing blacks and whites.” Then it gets personal. “Each time demographics of a new disease came up

Bookmark

—Damon Tweedy, MD

However, a book about medical care needs more than one conflict or argument to properly fill its pages and keep an audience like the readers of The ASCO Post engaged. To that end, with a few exceptions, Dr. Tweedy succeeds and does so admirably.

Different Phases of Medical Life Smartly, he divided his book into three sections, corresponding to the different phases of his medical life. Giving a complicated set of subjects a modular framework results in a pleasant-toread symmetry. Part 1 examines Dr. Tweedy’s medical school years; part 2, looks at the grueling 12 months of medical internship as a newly minted doctor; and section 3 gives a rolling overview of his years in psychiatry training and early clinical practice.

Disparities Part 1, titled “Disparities,” has a reader-friendly narrative style that livens up

years—including his own compelling health drama with hypertension—linking multiple case histories runs the risk of becoming episodic. And here, Dr. Tweedy flirts with that danger. It is well documented that poverty is the biggest predictor of poor health-care outcomes, and although Dr. Tweedy does elucidate real access issues faced by poor patients, he tends to blame the medical system’s inherent racism for the woes of economically challenged African Americans. Burdened as it is with fiscal troubles, however, the health-care system cannot overcome what is essentially a socioeconomic problem.

Barriers Section 2, titled “Barriers,” is where Dr. Tweedy vents his frustration with what he deems our system’s underlying race problem. If what he related were not true, it would sound like crude clichés. As he writes, “At least once a day during my rotations, my race would come up in an interaction with [white]

patients. The racial conversation was usually implied, rather than explicit…. One person after another, usually white, took one look at me, being a tall black man, and inquired about my basketball skills…. Others offered advice, ‘your wasting your time in school. You should be playing in the NBA.’” As astoundingly ignorant as these comments are, Dr. Tweedy perhaps goes overboard in relating one moronic comment after another. He then says, “Nor were stereotypes restricted to the South…. Otis Brawley has recounted similar experiences of patient and family prejudice.” Dr. Tweedy recounts experiences that are bruising to read and often difficult to endure. He highlights the problems in a very humanistic manner, but he offers no solutions. This is a memoir after all.

Perseverance In the final section, “Perseverance,” Dr. Tweedy offers his most balanced and reasoned exposition about race and medicine. Broken into several chapters, he ends with a cogent chapter called, “Beyond Race,” in which he deconstructs the Affordable Care Act, pros and cons, and gives the reader a physician’s take on how it affects overall health-care outcomes. Black Man in a White Coat is an unvarnished look at what it means to be black in medicine. Most doctors are white. Perhaps more black doctors would make our health system better for all Americans. It is something to strive for, and Dr. Tweedy’s fine, well-written book speaks eloquently to the issue. n

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Book Review

Yet Another Reason Why Dogs Are Our Best Friends By Ronald Piana

omparative oncology, a fairly recent addition to the ever-evolving world of cancer research, studies the naturally developing cancers in animals as models for human disease. Various institutions are looking at this intriguing line of inquiry, most notably the National Cancer Institute (NCI), which launched the NCI Comparative Oncology Program in 2003. Science writer Arlene Weintraub explores the challenges and promise of comparative oncology in her new book Heal: The Vital Role of Dogs in the Search for Cancer Cures. The author uses a lay-friendly writing style that is conversational but never chatty. Unlike some authors in this genre, Ms. Weintraub knows the difference between solid, informationdriven content and filler that is used to beef up a book’s word count to meet a publisher’s criterion. Plus, she’s done

seed for this highly readable book. The trial was part of an international effort to recruit dogs with cancer for research designed to yield new avenues for drug development to treat human cancers. That was also the first time she had ever heard the term comparative oncology. As she describes, researchers at the University of California at Davis led the phase trial III trial that was looking at oral toceranib phosphate, a receptor tyrosine kinase inhibitor used in dogs with recurrent mast cell tumor following surgical excision. The trials successful outcomes resulted in Palladia and Sutent, the first-ever FDA-approved drugs to treat cancer in dogs. Readers of The ASCO Post know that for 30 or more years, drug development using mouse modeling in bench research has been problematic, because so many drugs that cure cancer in these

The regulation of genes is overall more similar between dogs and humans than between mice and humans… —Arlene Weintraub

her research, backing up every scientific point with data and input from experts in the respective fields.

Early Comparative Oncology Ms. Weintraub’s interest in oncology was driven, in part, by the loss of her sister to gastric cancer. In 2001, working as a science reporter, Ms. Weintraub heard of an unusual phase III clinical cancer trial involving 206 dogs, which planted the

mice fail to help humans. Dog models could markedly improve cancer drug development. Ms. Weintraub explains that most mammals have about 20 thousand genes, and most of them are similar across species…, but it is the nucleotide overlap that’s key to determining how closely related one creature is to another. “And the regulation of genes is overall more similar between dogs and

Bookmark Title: Heal: The Vital Role of Dogs in the Search for Cancer Cures Author: Arlene Weintraub Publisher: ECW Press Publication date: October 13, 2015 Price: $16.95; paperback, 240 pages

humans than between mice and humans…. So if you have a drug that’s supposed to interact with a certain portion of a protein, it’s likely that protein will have exactly the same structure and composition in dogs as it does in humans, which means that the dog is much more likely to provide an accurate picture of how that drug will work in people,” writes the author.

True Case Histories However, while integrating the dog model into cancer research is super exciting—Ms. Weintraub does a superb job explicating the genetics and biology—the subject might run a bit thin for a book, perhaps better suited for an article in a science magazine. Ms.

Weintraub addresses that quam by unspooling a series of related chapters that culminate beautifully, ending the book with a chapter titled “Banking on a Cure for Gastric Cancer”—the malignancy that killed her sister. Ms. Weintraub weaves true case histories of cancer patients throughout the narrative to remind readers that the central aim of using dog models is to advance research that will ultimately result in better treatments for humans. That said, there are many well-drawn descriptions about our canine friends enduring the side effects of cancer treatment, such as a good-natured Golden Lab with breast cancer suffering from chemotherapyinduced nausea and alopecia.

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

www.ASCOPost.com

Phone: 631.692.0800 Fax: 631.692.0805

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

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Book Review A Clinical Partnership The readers of The ASCO Post will find something of interest in each of the eleven chapters, especially those in which the veterinarian world intersects with oncology. For instance, in chapter three, “Do Dogs Get Melanoma?” Philip Bergman, PhD, is a veterinarian specializing in canine cancer. Dr. Bergman did his fellowship at MD Anderson Cancer Center, where he studied human cancer biology to give him a better understanding of the disease he planned to treat in dogs. In 1999, Dr. Bergman was attending a dinner for cancer researchers at the Princeton Club in New York when a man at his table turned and asked, “Do dogs get melanoma?” The man behind the question was Jedd Wolchok, MD, an oncology researcher at Memorial Sloan Kettering Cancer Center—no stranger to the readers of The ASCO Post. At the time, Dr. Wolchok was working on an immunologic approach to treating melanoma called xenogeneic plasmid DNA vaccination, which used human tyrosinase to initiate an immune response to kill melanoma cells. The approach had produced surprisingly good results in mouse models, and now he wanted to test his immunotherapy in dogs. After a brief discussion, Drs. Bergman and Wolchok entered a clinical partnership, which was capped by a successful trial using dogs with melanoma as its subjects. Both intrepid researchers were honored for their contributions. Dr. Wolchok summed up the partnership: “We were both considered bright young investigators who trained at prominent institutions and we had every reason to be egomaniacal. But that was not part of our DNA…. We were not in this to make a name for ourselves; we were committed to the bigger goal of helping patients and advancing science.” Readers will find this and other veterinarian-oncologist partnerships interesting and rewarding. This moderately sized book is chock-full of thought-provoking data-backed stories, in which experts in canine and human cancer weigh in. Moreover, their quotes add to the legitimacy of the content, never feeling like they were injected as celebrity window dressing.

A Rescue Dog With Mammary Cancer One chapter in this fine book, called “Cali’s Total Mastectomy,” deserves a special mention. It tells the story and clinical history of a rescue dog named Cali, who

at 6 years old was diagnosed with latestage mammary cancer, which is the most prevalent tumor in female dogs. “Mammary cancer bears a remarkable resemblance to breast cancer. For example, mammary tumors in dogs are often driven by estrogen, and BRCA1 and BRCA2 genetic mutations have been found in English Springer Span-

iels with mammary tumors. The dog provides us a snapshot of the entire continuum from benign to malignant…offering incredible possibilities for the development of new drugs,” writes the author. Cali’s journey from diagnosis to mastectomy and adjuvant therapy into survivorship is done without overarch-

ing sentimentality. The dog and her care team would make the oncology community proud. Ms. Weintraub has produced a fine book about the hope and possibilities that abound in today’s era of cancer research and treatment. This book is highly recommended for the readers of The ASCO Post, especially dog lovers. n

NOW ENROLLING Rociletinib Expanded Access Program For patients with previously treated EGFR mutation– positive NSCLC and the T790M resistance mutation Access for eligible patients in the US who have no other available rociletinib clinical trial options Key inclusion criteria • Documented evidence of a tumor with the T790M mutation • Prior treatment with an approved or experimental EGFR-directed therapy • Central nervous system metastases, other than leptomeningeal disease, are permitted if asymptomatic and stable • Prior chemotherapy is permitted if the last treatment occurred >14 days prior to the ﬁrst dose of rociletinib

Key exclusion criteria • EGFR exon 20 insertion activating mutation • Prior participation in a rociletinib clinical trial or eligibility for a current rociletinib clinical trial Upon FDA approval of rociletinib, patients will be transitioned to the commercially available drug. Visit TIGERtrials.com to learn more

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Art of Oncology You’ve Lived A Good Life By Brendan F. Curley, DO

ur aging population places a strain on all aspects of the health-care system, including oncology services. In an article published in The ASCO Post, Holland and Greenstein1 discussed the need to prepare younger oncologists to care for much older patients. I typically prepare for new patients by reviewing their pathology, radiology, and comorbid conditions. Age is always listed, and although it is something I think about, I need to see the patient to truly get a feeling for his or her performance status, level of social support, and comorbid conditions. We have all seen patients who appear their stated age and patients who do not. Sometimes, we can obtain useful information from performance status or the descriptor of frail included in the medical record; however, the accurate decisions are made in the examination room, whether the patient is 59 or 89 years of age.

tron emission tomography/CT) and July (CT) showed that the mass was growing. Ted continued to live his lifebut wondered, “Why is no one going after this?” He saw his pulmonologist and was told that the mass was likely lung cancer, but testing for lung cancer was so hard—biopsy, more scans, chemotherapy. Who wants that? Well, Ted wanted that. He was 89 years old, but he felt much younger. Older patients are often excluded from clinical trials in oncology, either because of rigid eligibility criteria or because of bias on the part of enrolling oncologists. The problem with the older patient is the other things that come with them, such as frailty, multiple medical comorbidities, and worsening social support systems, all of which may interfere with the patient’s ability to withstand anticancer therapy. So what is the oncologist to do? Back to Ted. He followed up again in October, 9 months after the mass was initially identified. The scan now showed that the primary mass had continued to grow and that there were enlarged lymph nodes and bone lesions suggestive of metastatic disease. There was now little doubt that he had progressive lung cancer and that his window of opportunity for curative therapy had closed. Finally, Ted put his foot down and demanded a biopsy. It was, as expected, primary non–small cell adenocarcinoma of the lung. Magnetic resonance imaging of the brain was negative, and he was evaluated by radiation oncology, but no therapy was offered, because what had been localized disease was now metastatic. He saw a medical oncologist and was offered singleagent chemotherapy, not a standard platinum-based doublet. Why? He was too old. He was told by his oncologist, “You’ve lived a good life.”

More Than Chronologic Age

Who Should Receive Treatment?

Several months ago, I met Ted, an 89-year-old patient who was in fantastic shape. He liked to tinker around the house, tend his garden, and spend time with his girlfriend. He did his own grocery shopping, liked a glass (or two) of wine with his lunch, and had a great social support system. He presented to his primary care physician in January after an abnormal chest x-ray and computed tomography (CT) scan showed a 3-cm mass, noted by radiology to likely be lung cancer. “Wait and see,” he was told. Well, he waited, and it grew. Repeat scans in March (CT and posi-

There is always a debate in an oncologist’s mind about who should receive chemotherapy and who should not. We have predictive models, guidelines, Eastern Cooperative Oncology Group performance status requirements, and geriatric assessment tools that allow us to estimate an individual’s ability to tolerate chemotherapy, but in the end, it is frequently a gut decision. I always tell my patients with advanced disease that my goal is to optimize their quantity and quality of life. If one of them is compromised, we need to re-evaluate our goals of care.

The ASCO Post is pleased to reproduce installments of the “Art of Oncology” as published previously in the Journal of Clinical Oncology ( JCO). These articles focus on the experience of suffering from cancer or of caring for people diagnosed with cancer, and they include narratives, topical essays, historical vignettes, poems, and photographic essays. To read more, visit http://jco. ascopubs.org/ and search “Art of Oncology.” For information on how you can submit your own essay for consideration in JCO’s Art of Oncology, visit http:// jco.ascopubs.org/site/ifc/ determine-my-article-ty pe. xhtml#art-of-oncology

I met Ted 3 days before Christmas for his initial consultation, a full 11 months since the first CT of his chest showed probable lung cancer. He was still sharp as a tack, and I was a little embarrassed to admit that he was dressed much more sharply than I was. All of his records and scans were available for my review. I was interested in his functional status and asked my office staff if he had walked in by himself. Did he come alone? Ted was interactive, gregarious, and entertaining. He brought his A game to see me and was ready to fight. I spoke with his daughter via cell phone, and she confirmed that he was extremely active at home. His girlfriend

egory about which I had no data to give him, no randomized trial to fall back on to guide our treatment decision. I gave him information, and we would meet again in a few days with a final decision. I presented his case at our local tumor board, where the consensus opinion was that this was a gray area. I recommended starting platinum-based doublet therapy (carboplatin and pemetrexed [Alimta]). And I held my breath.

A Seat at the Table Ted was ecstatic. Someone believed in him. He had seen multiple physicians who had made decisions for him and not decisions with him. He believed he

He believed he could handle treatment and was ready to fight. Who was I to say no, based on a number, his age? —Brendan F. Curley, DO

was with him. He told me he wanted someone to believe in him. I consulted my former fellowship classmates and my partner in the office next door for advice. Opinions were divided about what to do. The overwhelming recommendation was to trust my instincts, and I was conflicted. How aggressive should I be? I shared my dilemma with Ted and presented it in the following way: “I don’t want to kill you, but I want to give you a chance.” We discussed the benefits and risks of each treatment option: no treatment vs single-agent therapy vs a platinumbased doublet. I discussed with him that platinum-based doublet therapy had long been administered to those younger than 70 years of age; in years past, monotherapy had been considered for those older than age 70 years. However, that had changed with the Intergroupe Francophone de Cancérologie Thoracique 0501 trial, which showed that patients older than age 70 years had a survival advantage when administered platinum-based doublet chemotherapy as opposed to monotherapy. I dove further into that report2 with Ted and showed him the harsh reality—he was older than the oldest participant (by 3 years), falling into a cat-

could handle treatment and was ready to fight. Who was I to say no, based on a number, his age? We talked extensively about all routes of care. We had a roadmap of the pace of the disease, because it had been untreated for almost a year. We discussed not proceeding with any treatment at length; he had already lived a year with this disease. Ted did not want to die without trying to fight this, and I believe I was the first person who truly listened to what he was saying. He was not an unrealistic man; he knew that treatment or no treatment, the lung cancer was likely going to be how he was going to die. We talked about everything before starting. I felt I knew why he wanted to try, even one cycle—he had been told he could not, he should not, and physicians would not give him the treatment. However, Ted had never been told why. The Institute of Medicine report3 on delivering high-quality cancer care discusses engaging patients in their medical decisions as part of providing that level of care. It goes on to address patients with advanced cancer; we as physicians need to address their needs, values, and preferences. Ted had all of those choices planned and knew what he was willing to accept and what he was not; he wanted a seat at the table to decide. He knew that

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Art of Oncology starting one cycle of chemotherapy did not mean he would get a second cycle, but our road ahead was written in pencil, easily changed based on how he responded and his preferences. He tolerated cycle one with absolutely no problems. I am pretty sure he did not want to give me a reason to stop, and I did not. He received three cycles, followed by a positron emission tomography/CT scan, which showed a great response. He completed his induction regimen, and with two subsequent scans

showing continued response, he is now receiving maintenance therapy (pemetrexed based on PARAMOUNT trial4). He celebrated his 90th birthday, one that he did not think he would live to see. They will not all be success stories like this. Ted still is likely to die as a result of his lung cancer, but I feel satisfied with the counsel I provided him, and he certainly seems happy with his decision. Ted smiles and hugs me and thanks me for giving him a chance to continue living his good life. It was a tough decision, one I know I

will struggle with many more times. But for now, Ted’s smiling face tells me that I got this one right. n References 1. Holland J, Greenstein M: Preparing for the “silver tsunami” and the impact of an aging population on cancer care. The ASCO Post 7:40-41, 2015. 2. Quoix E, Zalcman G, Oster JP, et al: Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-

cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet 378:1079-1088, 2011. 3. Ganz PA, Cohen HJ, Eberlein TJ, et al: Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. Washington, DC, National Academies Press, 2013. 4. Paz-Ares LG, de Marinis F, Dediu M, et al: PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed vs placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous NSCLC. J Clin Oncol 31:2895-2902, 2013.

News Oncology Worldwide

Cancer Survival Improves in Europe, With Wide Regional Variations By Alice Goodman

UROCARE-5, the latest in a series of comprehensive reports on the state of cancer survival in Europe, shows an improvement in 5-year survival from

1998 to 2007, with large variations among regions of Europe, according to a presentation at the European Cancer Congress.1 Furthermore, although

5-year survival rates have improved in Eastern European countries, that region has the lowest rates of survival, whereas Northern European countries fare the

EXPERT POINT OF VIEW

artine Piccart, MD, PhD, Professor of Oncology at the Université Libre de Bruxelles, Belgium, and President of the European Cancer Organisation, said she found it “distressing” to see such large variations in 5-year survival across European countries. “I would like to stress the fact that

We need to consider the complexity of the concept of survival. Many factors influence incidence and cancer-related mortality. Survival is a conglomerate between mortality and incidence. —Philippe Autier, MD

A Note of Caution

Martine Piccart, MD, PhD

these cancer registries are incredibly important, but they are not sufficiently funded in many, many countries. So the data that the scientists there are able to put together are very often not standardized from one cancer registry to another, not detailed enough to allow full understanding of the reasons behind the variations,” said Dr. Piccart, speaking at a press briefing she moderated. “We need to get the message out about how important it is to support cancer registries. This is the only way we can monitor how well or how poorly we are treating cancer patients,” she added.

Formal discussant of this study, Philippe Autier, MD, of the University of Strathclyde Institute of Global Public Health, Lyon, France, had some concerns about the report. “I would like to inject a note of caution. We need to consider the complexity of the concept of survival. Many factors influence incidence and cancer-related mortality. Survival is a conglomerate between mortality and incidence.” “Overdiagnosis makes a huge difference in incidence of common cancers—mainly breast, prostate, thyroid cancers, and melanoma. These increases are mainly at early stages, many of which would not become clinically apparent during the patient’s lifetime,” Dr. Autier told listeners. “We should bear this in mind when interpreting cancer survival statistics, particularly for these

cancers where screening plays a role.” In hematologic cancers, screening is not associated with overdiagnosis. In colorectal, cervical, and pancreatic cancers, the risk of overdiagnosis is minimal. Survival is specific to stage at diagnosis. There are changes in stage over time, great variability in staging procedures between and within medical institutions. These factors can affect reporting of survival, Dr. Autier said. n Disclosure: Dr. Piccart has a consulting or advisory role with Amgen, Astellas Pharma, AstraZeneca, Bayer, Invivis, Lilly, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi, Symphogen, Synthon, and Verastem; and honoraria from Amgen, Astellas Pharma, AstraZeneca, Bayer, Invivis, Lilly, MSD, Novartis, Pfizer, Roche/Genentech, Sanofi, Symphogen, Synthon, and Verastem. Dr. Autier reported no potential conflicts of interest.

best, with the notable exception of the UK and Denmark, where survival was lower than in other countries with comparable income and health systems. Overall survival gains in some hematologic cancers are particularly impressive. “Five-year survival adjusted for causes of death other than cancer increased steadily over time in Europe, particularly Eastern Europe, for most cancers. In general, there is a remarkable increase in survival for all hematologic malignancies,” said Milena Sant, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. “Despite the increases in survival, the most dramatic geographical variations were observed for hematologic cancers, where there have been recent advances in treatment, such as chronic myeloid and lymphocytic leukemias [CML and CLL), non-Hodgkin lymphoma [NHL], two NHL subtypes—follicular and diffuse large B-cell lymphoma—and multiple myeloma. Hodgkin lymphoma was the exception, with smaller regional variations and a fairly good prognosis in most countries,” she continued. In Dr. Sant’s view, the major contribution of this and other EUROCARE publications is to highlight regions at poor survival where actions are needed to better organize care and reduce its fragmentation in order to improve the outcome of cancer patients. EUROCARE-5 is a massive undertaking. “This is the largest study of cancer patient survival in Europe, representing more than 50% of the European population. We have survival data on more than 20 million adult patients over age 15 from 31 countries followed from 2008 or later,” Dr. Sant said. continued on page 147

ARE YOU TESTING FOR RAS ? Amgen is committed to the integration of RAS testing into routine clinical practice, which may help oncologists select an appropriate first-line treatment plan for their patients with mCRC.

KRAS and NRAS are part of the RAS family of oncogenes1

KRAS

EXON 2

NRAS

EXON 2

EXON 3 59

EXON 4 117 146

• A mutation on the RAS gene can continuously activate intracellular signaling, leading to increased cell growth and proliferation. The EGFR pathway is always “turned on,” and the cell keeps growing and dividing regardless of anti-EGFR therapy2 • Patients with mutant-type RAS tumors should not be treated with Vectibix®2 • In addition, in an exploratory subgroup analysis of Study 3,* overall survival was shorter in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone2

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy Limitation of Use Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

Important Safety Information WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. • In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

• Vectibix® is not indicated for the treatment of patients with colorectal

cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as“RAS”.

• Retrospective subset analyses across several randomized clinical trials

were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR- related adverse reactions without clinical benefit from these agents.

• Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors

received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01–1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone.

Important Safety Information (continued) • Progressively decreasing serum magnesium levels leading to severe

(grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of

patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe

diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal

and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.

• In

patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

• Exposure

to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis

and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• In

an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients

with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). • NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate

in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

• As

a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

• Advise patients of the need for adequate contraception in both males

and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

• Because

many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®.

• Women

who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

• In Study 1, the most common adverse reactions (≥ 20%) with Vectibix®

were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction.

• In

Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix® -treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

Visit Vectibix.com to learn more

*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.2 EGFR = epidermal growth factor receptor; mCRC = metastatic colorectal cancer; Q2W = every two weeks. References: 1. Douillard J-Y, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–1034. 2. Vectibix® (panitumumab) prescribing information, Amgen. Please see Brief Summary of full Prescribing Information on adjacent pages.

KING SIZE (6 pt condensed type) S:9.25”

Vectibix® (panitumumab) BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

VECT15CDLA0437_B_Vectibix_BS_9.25x13_v23_Mar2015_r11_MBS.indd 1

Study 1

SYSTEM ORGAN CLASS Preferred Term

Vectibix® Plus Best Supportive Care (N = 229)

Best Supportive Care (N = 234)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

1 (< 1)

EYE DISORDERS Growth of eyelashes

13 (6)

GASTROINTESTINAL DISORDERS Nausea

52 (23)

2 (< 1)

37 (16)

Diarrhea

49 (21)

4 (2)

26 (11)

Vomiting

43 (19)

6 (3)

28 (12)

Stomatitis

15 (7)

2 (< 1)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue

60 (26)

10 (4)

34 (15)

Mucosal inflammation

15 (7)

1 (< 1)

2 (< 1)

57 (25)

4 (2)

7 (3)

INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea

41 (18)

12 (5)

30 (13)

Cough

34 (15)

1 (< 1)

17 (7)

Erythema

150 (66)

13 (6)

2 (< 1)

Pruritus

132 (58)

6 (3)

4 (2)

Acneiform dermatitis

131 (57)

17 (7)

2 (< 1)

Rash

51 (22)

3 (1)

2 (< 1)

Skin fissures

45 (20)

3 (1)

1 (< 1)

Exfoliative rash

41 (18)

4 (2)

Acne

31 (14)

3 (1)

Dry skin

23 (10)

Nail disorder

22 (10)

Skin exfoliation

21 (9)

2 (< 1)

Skin ulcer

13 (6)

1 (< 1)

8 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

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) Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

58 (18)

5 (2)

10 (3)

Diarrhea

201 (62)

59 (18)

169 (52)

29 (9)

Stomatitis

87 (27)

15 (5)

42 (13)

1 (< 1)

EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inflammation

82 (25)

14 (4)

53 (16)

1 (< 1)

Asthenia

79 (25)

16 (5)

62 (19)

11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

Anorexia

116 (36)

14 (4)

85 (26)

6 (2)

INFECTIONS AND INFESTATIONS Paronychia

Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 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)

24 (7)

1 (< 1)

10 (3) 4 (1)

14 (4) 13 (4) 14 (4) 1 (< 1) 30 (9) 1 (< 1) 4 (1)

30 (9)

4 (1)

9 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

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: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) 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)]

INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Hypomagnesemia

96 (30)

21 (7)

26 (8)

1 (< 1)

Hypokalemia

68 (21)

32 (10)

42 (13)

15 (5)

Dehydration

26 (8)

8 (2)

10 (3)

5 (2)

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

46 (14)

30 (9)

This brief summary is based on the Vectibix ® Prescribing Information v23, 03/15. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2015 Amgen Inc. All rights reserved. v23 03/15

4/27/15 6:12 PM

S:13”

INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)]. Limitation of Use Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)]. DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as “RAS ” [see Indications and Usage (1.1), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents [see Indications and Usage (1.1), and Clinical Pharmacology (12.1)]. Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone [see Indications and Usage (1.1)]. Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.1) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)]

• Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an openlabel, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

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News Cancer Survival continued from page 143

“Between 1998–2001 and 2005– 2007, the largest increases in 5-year survival were observed in CML [from 32% to 54%], prostate cancer [73% to 82%], and rectal cancer [from 52% to 58%],” she continued.

Geographic Variation Regional variation is high for cancers with a relatively good prognosis—breast, prostate, and colorectal cancers—but relatively low for poor-

ern Europe to 49% in Eastern Europe. Survival in rectal cancer currently ranges from 59.5% in Northern Europe to 44.6% in Eastern Europe, and it is even lower than the regional mean in Latvia and Bulgaria. Cancers that are detected by screening have large increases in 5-year and 10-year survival, Dr. Sant said. For example, breast cancer 5-year survival is now 70% in Eastern Europe, and melanoma has an 87.7% survival in Northern Europe and 74.6% in Eastern Europe. Dr. Sant attributed this improvement in

Between 1998–2001 and 2005–2007, the largest increases in 5-year survival were observed in CML [from 32% to 54%], prostate cancer [73% to 82%], and rectal cancer [from 52% to 58%]. —Milena Sant, MD

prognosis cancers, such as lung, pancreatic, and esophageal cancers. The largest geographical variation for all hematologic cancers was observed in CML. Overall 5-year survival is now up to 54%, but the variability ranges from 56.1% for Northern Europe to 33.4% for Eastern Europe. For NHL, the average 5-year survival is 59.4%, ranging from 63.3% in North-

part to educational campaigns regarding risk factors for melanoma leading to patient awareness of the need for screening and earlier stage at diagnosis. “The large increment in survival for prostate cancer is related to a concomitant increase in incidence, which points to the problem of overdiagnosis with PSA [prostate-specific antigen] testing,” she noted.

Update From EUROCARE-5 Study ■■ Although overall 5-year survival from the time of cancer diagnosis is on the rise, there are large variations in different regions of Europe. ■■ In general, Northern Europe has the highest survival rates, whereas Eastern Europe has the lowest survival rates. ■■ Some of the improvement in survival could be related to overdiagnosis of cancers at early stages, which may never become clinically apparent. ■■ Results point to the need to improve access to care and coordination of care.

Investing in Health Care Survival correlated with gross domestic product and total national expenditure on health, with the exception of Denmark and the UK, “which continue to perform worse than expected for their level of total national expenditure on health and are in the lowest tertile for 5-year survival,” noted Dr. Sant. This phenomenon is also seen in the United States, which spends more per capita on health care than most other countries but lags behind for several health-care outcomes. In an interview, Dr. Sant attributed this lackluster showing for Denmark and the UK to fragmentation of care and lack of coordination. “This problem—in the UK and Denmark—has been repeatedly highlighted. In 2000, EUROCARE published similar results with strong reactions and skepticism from people in those countries.” Dr. Sant continued: “Our reports raised the consciousness, and now the

UK government is investing 500 million pounds to improve services and shorten delays for referral to oncologists. Also, Denmark, Nordic countries, and the UK are collaborating on a recently launched project to understand disparities in care called the International Cancer Benchmarking Project,” she said. “Further studies are needed to help reduce survival inequalities and improve cancer care, reduce the fragmentation of services, and promote comprehensive multidisciplinary care,” concluded Dr. Sant. n

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

Reference 1. Sant M, Francisci S, Minicozzi P, et al: Is Europe doing better in cancer care since the 90s? The latest findings from the EUROCARE-5 study. 2015 European Cancer Congress. Abstract 1LBA. Presented September 26, 2015.

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The ASCO Post | DECEMBER 10, 2015

PAGE 148

News Gastrointestinal Cancer

Selective Internal Radiation Therapy Impacts Liver Metastases in Colorectal Cancer By Caroline Helwick

novel interventional approach to treating liver metastases associated with colorectal cancer improved control of liver metastases, according to the SIRFLOX study presented at the 2015 ASCO Annual Meeting.1 The addition of selective internal radiation therapy to first-line chemotherapy extended median progressionfree survival in the liver by almost 8 months in patients with liver-dominant metastases, compared with the control arm, although outcomes in the overall population were not improved, according to Peter Gibbs, MD, of The Royal Melbourne and Western Hospitals in Melbourne, Australia. SIRFLOX, which evaluated the benefit of yttrium-90 (Y-90) resin microspheres as an adjunct to chemotherapy, is the largest randomized controlled trial of an interventional radiology procedure to date, he said.

‘An Ongoing Impact’ “Our key message is that we saw a major impact on control of liver metastases with the addition of Y-90 resin microspheres to standard first-line systemic chemotherapy in patients with metastatic colorectal cancer limited to the liver or small-volume extrahepatic

Chemoradiotherapy for Liver Metastases

he phase III SIRFLOX trial showed that selective internal radiation therapy delivered to liver metastases in patients with colorectal cancer, plus chemotherapy, improved local control, although median progression-free survival for the whole population was not affected. Median progression-free survival of liver metastases was approximately 10 months overall in the study of 530 patients. In patients with liver-only or liver-predominant metastases, however, median progression-free survival was improved by almost 8 months with the addition of selective internal radiation therapy. Toxicity was slightly increased with the additional treatment modality. n

disease,” revealed Dr. Gibbs. “This finding matters a great deal,” he commented, “because the liver is typically the organ where colorectal cancer spreads to first…. Hopefully, this will translate to an improvement in overall survival.” Selective internal radiation therapy, which is administered by an interventional radiologist, employs Y-90–labeled resin microspheres into the hepatic artery, releasing a single, large dose of radiation directly to the tumor. “It’s the single dose which is important,” emphasized Dr. Gibbs. “Most treatments we use in medical oncology are repeat dosing every 2 to 3 weeks—often for many months at a time. Selective internal radiation therapy is important because it’s a one-off treatment that has an ongoing impact over a long period of time.”

SIRFLOX Trial Details The prospective, open-label, randomized controlled SIRFLOX trial enrolled 530 chemotherapy-naive patients with nonresectable liver-only or liver-dominant metastatic colorectal cancer. The primary tumor had not been removed in about 45% of patients, and 40% had extrahepatic disease, either low volume lung or lymph node metastases. Patients were randomized to receive either modified FOLFOX6 (folinic acid, fluorouracil, oxaliplatin) with or without bevacizumab (Avastin; n = 263) or the same treatment with selective internal radiation therapy administered once with cycle 1 or 2 with or without bevacizumab until disease progression (n = 267). The primary endpoint was overall progression-free survival in the intent-to-treat population.

Benefit Restricted to the Liver The analysis of overall median progression-free survival showed no difference between the two arms. Median progression-free survival was 10.2 months in the control arm and 10.7 months with the addition of selective internal radiation therapy (P = .43). However, major changes were observed within the liver, Dr. Gibbs reported. For patients with liver metastases, “with systemic therapy alone, the median progression-free survival was 12.6 months. With the addition of selective internal radiation therapy, this increased to 20.5 months, a difference of 7.9

We saw a major impact on control of liver metastases with the addition of Y-90 resin microspheres to standard first-line systemic chemotherapy in patients with metastatic colorectal cancer limited to the liver or smallvolume extrahepatic disease. —Peter Gibbs, MD

months (hazard ratio = 0.69; P = .002),” he reported. “Another way of saying this, is we saw a 31% reduction in the risk of disease progression within the liver.” The hepatic response rate was 78.7% in selective internal radiation therapy– treated patients, compared with 68.8% in controls (P = .042). Although this difference may appear to mean little clinically, Dr. Gibbs noted that the rate of complete responses in the liver of selective internal radiation therapy–

treated patients (6.0%) was more than triple that of patients treated with chemotherapy alone (1.9%; P = .02). Rates of hepatic resection were similar: 14.2% with selective internal radiation therapy and 13.7% with modified FOLFOX alone (P = .857).

Toxicity Selective internal radiation therapy–treated patients experienced a continued on page 149

EXPERT POINT OF VIEW

icky A. Sharma, MA, MB, BChir, PhD, of Gray Institute for Radiation Oncology and Biology at the University of Oxford, United Kingdom, formally discussed the paper. He disclosed that he is a co-principal investigator for the FOXFIRE study, which is currently evaluating selective internal radiation therapy. Dr. Sharma commented on the need to treat colorectal cancer with more than just drugs. “How many modalities are enough? I can tell you, it’s not Ricky A. Sharma, MA, MB, BChir, PhD one,” he said. Despite the approval of more than 70 drugs to treat cancer in the past 15 years, overall progression-free survival has increased only by 2.5 months and overall survival by 2.1 months, he pointed out. “To improve cure rates, we shouldn’t just think about drugs. The curative modalities for cancer tend to be combinations of treatment,” he added.

Clinical Implications Dr. Sharma raised the possibility that in SIRFLOX, the lack of a progression-free survival benefit is related to the 40% of patients with metastatic disease outside the liver. “Perhaps because of that burden of extrahepatic disease, we don’t see a signal in progression-free survival, but there is an impressive change in local control. This is a robust result,” he offered, “but it comes at a cost—more neutropenia, thrombocytopenia, and ulcerations or radiation-induced liver complications.” “Selective internal radiation therapy does have the capacity to improve local control, in combination with FOLFOX, but with slightly higher toxicity,” concluded Dr. Sharma. “We anticipate the subgroup analyses and combined analyses to tell us which patients will benefit most from selective internal radiation therapy.” n Disclosure: Dr. Sharma reported no potential conflicts of interest.

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Expert’s Corner Psycho-oncology

Integrating Spirituality Into Palliative Care Services A Conversation With Christina Puchalski, MD, MS By Ronald Piana medical education. Dr. Puchalski is the Founder and Director of the George Washington Institute for Spirituality and Health (GWish), and Professor of Medicine at the George Washington University School of Medicine and Health Sciences.

Clinical and Academic Experience

Christina Puchalski, MD, MS

ver the past couple of decades, the oncology community has made great strides in mediating the psychosocial needs of our patients. However, a patient’s spirituality is a subjective and uncomfortable issue for many oncologists, which leaves a gap in the continuum of care. To reach a better understanding of this complex issue, The ASCO Post recently spoke with Christina Puchalski, MD, MS, a pioneer and international leader in the movement to integrate spirituality into the clinical setting and

Please tell our readers about your background. A physician by training, I did my undergraduate work at UCLA and earned my medical degree at The George Washington School of Medicine & Health Sciences. I also have an advanced degree in biochemistry and have done some basic research. I am also a Boardcertified internist and palliative care physician. Besides my clinical work, I am Professor of Medicine and Health at George Washington University.

Bringing Spirituality to the Bedside As Founder and Director of GWish, how would you define its worth within the

Consensus Conference Definition of Spirituality

pirituality is the aspect of humanity that refers to the way individuals seek and express meaning and purpose and the way they experience their connectedness to the moment, to self, to others, to nature, and to the significant or sacred. This Consensus Conference, which was held in February 2009 in Pasadena, California, was based on the belief that spiritual care is a fundamental component of quality palliative care. The recommendations from this Conference build upon prior literature, the National Consensus Project Guidelines, and the National Quality Forum Preferred Practices and Conference proceedings. n

Internal Radiation Therapy continued from page 148

greater number of grade ≥ 3 adverse events, especially neutropenia (40.7% vs 28.5%), febrile neutropenia (6.1% vs 1.9%), and thrombocytopenia (9.8% vs 2.6%). Selective internal radiation therapy–associated events included gastric or duodenal ulcer (3.7%), ascites (2.8%), hepatic failure (1.2%), and radiation hepatitis (0.8%). “Adverse events had no negative impact on duration of systemic therapy and were acceptable and as predicted,” indicated Dr. Gibbs.

Future analyses will include subgroups of interest, particularly liver-only vs liver-dominant disease; the effect of bevacizumab; the depth of response; and quality of life. “Ultimately, however, we’re most interested in overall survival,” Dr. Gibbs said.

Additional Commentary At a press briefing, the principal U.S. investigator of the trial, Navesh K. Sharma, DO, PhD, Associate Professor in the Division of Radiation Oncology at Penn State Hershey Cancer Institute, Pennsylvania, commented:

context of the oncology community? The central mission of GWish is to foster more compassionate and caring health-care systems and restore the heart and humanity to health care. We do this by developing educational

Other studies have shown that spiritual care models also offer a framework for health-care professionals to connect with their patients; listen to their fears, dreams, and pain; collaborate with their patients as partners in their care;

Once we have proof from trials that the spiritual domain is related to the physical domain, people will pay attention. —Christina Puchalski, MD, MS

programs supported by scholarly and research-based initiatives. These courses provide the practical skills and tools needed by clinicians to bring spirituality to the bedside. By creating an academic field of study, we strongly believe we are improving clinical care and ultimately improving the lives of patients and their families.

An Opportunity for Healing Have noted researchers looked at the role of spirituality in palliative care? Yes. There have been numerous studies on the role of spiritualty in the palliative care continuum, such as work by George Fitchett, DMin, PhD, and others who looked at the role of professional chaplains on palliative care teams. Their research has been funded by the National Institutes of Health and published in pastoral, medical, and psychological journals. In short, the data culled from retrospective studies show a statistical correlation between spirituality—more broadly defined as a search for meaning and purpose and connectedness to the significant or sacred—and mental health, with lower levels of depression and anxiety, and even better social functioning skills. “SIRFLOX has shown us, in an unbiased manner, that not only can we deliver high doses of radiation to the liver safely with this approach, but we can do so using concurrent chemotherapy. Concurrent chemoradiation has been one of the most effective ways to treat cancer in general, especially those of gastrointestinal origin.” Combined analysis of overall survival data from SIRFLOX and two additional trials (FOXFIRE and FOXFIRE Global) is expected in 2017. n Disclosure: Dr. Gibbs has received honoraria from Alchemia, Amgen, Bayer, Merck, Roche,

and provide an opportunity for healing through the therapeutic relationship. Healing is distinguished from cure in this context. It refers to the ability of a person to find solace, comfort, connection, meaning, and purpose in the midst of suffering, disarray, and pain.

Steps to Widening Acceptance It was an uphill battle for palliative care to become accepted as an essential component in the delivery of cancer care. The spiritual care of patients is a relatively new addition to oncologic care services. Is there growing acceptance among the field? There have been significant strides in palliative care but it has not been broadly accepted in the palliative care community. That said, I think as more positive data emerge, people become more willing to accept its importance. A lot of our work in this area was initially done back in the 1990s, before GWish was formed. We did one of the first classes on spiritualty and health at our medical school, and after that, we worked with the John Templeton Foundation to give grants to medical schools so that we could integrate spirituality more fully continued on page 150

and Sirtex Medical and research funding (institution) from Pfizer and Roche. Dr. Navesh Sharma has received honoraria from, consulted for, been on the speakers bureau of, and received travel expenses from Sirtex Medical.

Reference 1. Gibbs P, Heinemann V, Sharma NK, et al: SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 ± bevacizumab versus mFOLFOX6 + selective internal radiation therapy ± bevacizumab in patients with metastatic colorectal cancer. 2015 ASCO Annual Meeting. Abstract 3502. Presented May 30, 2015.

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Expert’s Corner Christina Puchalski, MD, MS continued from page 149

in medical school curricula nationwide. Over the years, we taught our students how to assess and attend to their patients’ spiritual needs, but we realized that it was not happening in the general clinical setting. So that’s when I began working with Betty Ferrell, MD, PhD, RN, to develop guidelines that sought to improve the spiritual domain of palliative care. In 2009, we published a paper on the findings from a consensus conference,1 the goal of which was to identify points of agreement about spirituality as it applies to health care and to make recommendations to advance the delivery of quality spiritual care. That work has spawned some policy changes on the global level. For instance, the World Health Organization (WHO) just passed a resolution stressing the need to enhance palliative care on a global level to help relieve the suffering from pain and other problems, whether physical, psychosocial, or spiritual. Recognition of a global health issue by the WHO or other organizations does not solve the problem of undertreated symptoms of disease such as cancer, but it is an important step. To me, these are all markers that palliative care, including the spiritual domain of palliative care, is getting more widely accepted. What did the 2006 palliative care guidelines address? In the 2009 consensus conference mentioned above, an interprofessional model of spiritual care was developed where all members of the team address spiritual issues of patients and families. Specific clinical recommendations include doing a spiritual screening or spiritual history with all patients, identifying spiritual distress, formulating and assessment and treatment plan that includes the psychosocial and spiritual as well as the physical aspects of the patient, working with trained chaplains as the spiritual care experts. Additonally recommendations were made about developing educational programs in spiritual care, integrating spiritual care in Quality Improvement projects in clinical settings and addressing spiritual needs of patients and families in clinical policies and guidelines.

Taking It to the Next Step Guidelines developed among academics provide an actionable framework. However, although there’s a growing awareness of the need for early initiation of palliative care, there are large gaps in its implementation across various demographics. How do we remedy this?

It requires a multipronged approach. We certainly need more and better research. For instance, much of the research in spirituality has been in association studies, which have shown the benefit of patients’ spirituality in their health outcomes. However, we have to take it to the next step and start looking at outcomes of spiritual care interventions.

We have existing models that show the vital role of chaplains in palliative care. That said, we need to aggregate our knowledge and build multidisciplinary programs that attend to the whole person as a patient. We’ve seen incredible advances in the physical treatment of disease; now we have to catch up on the delivery of state-of-the art psychosocial and

spiritual care. I see the healthful benefits in my own patients who have had their spiritual needs addressed. They tend to take better care of themselves and are more engaged in their treatments. The other component is education, which I cannot stress enough. I just returned from Europe, where I attended the European CanCer Organisa-

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Expert’s Corner

tion (ECCO) meeting, and I was very pleased to see the activity and studies presented that looked at cancer patient outcomes within the context of spiritual distress. Much of the work examined whether those who had their spiritual distress managed properly had better outcomes all the way around, even in pain. Once we have proof from trials

that the spiritual domain impacts other domains of care including the physical domain, people will pay attention.

Closing Thoughts Do you have any closing thoughts to share? As health-care professionals, we need to provide dignity to all of our

patients, no matter what stage of disease they are in. We need to reframe the way we look at chronic illness and dying: people can lead meaningful lives; feel they are a gift and not a burden to others; know they still can find meaning in life right up until the end and can be open to the unknown gifts that may happen toward the end of life. n

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

Reference 1. Puchalski C, Ferrell B, Virani R, et al: Improving the quality of spiritual care as a dimension of palliative care: The report of the Consensus Conference. J Palliat Med 12:885-904, 2009.

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Announcements

Elizabeth Blackburn, PhD, Named President of the Salk Institute

lizabeth Blackburn, PhD, has been named President of the Salk Institute for Biological Studies. Dr. Blackburn will join the Salk Institute from the University of California, San Francisco (UCSF), where she is Professor in the Department

of Biochemistry and Biophysics. She will assume her new role effective January 1, 2016. As Salk’s president, Dr. Blackburn will be responsible for leading scientists in fields such as cancer, neuroscience, aging, and plant biology.

“Few scientists garner the kind of admiration and respect that Dr. Blackburn receives from her peers for her scientific accomplishments and her leadership, service, and integrity,” said Irwin M. Jacobs, ScD, Chairman of Salk’s Board of Trustees.

A Career of Discovery and Service Dr. Blackburn won the Nobel Prize in Physiology or Medicine in 2009 for discovering the molecular nature of telomeres and for codiscovering telomerase. Both telomeres and telom-

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Announcements

She has shown an abiding commitment to public service in the scientific, academic, and public policy arenas. She has served as President of both the American Association of Cancer Research (AACR) and the American Society for Cell Biology (ASCB) and has served on the editorial boards of several scientific journals, including Cell and Science.

Dr. Blackburn was a member of the Stem Cell Research Advisory Panel for the California State Legislature, and a member of the President’s Council of Bioethics, an advisory committee to the President of the United States. Since 2001, Dr. Blackburn has served as a Salk nonresident fellow, one of a group of leading scientists who advise

the Institute’s leadership and play key decision-making roles in the appointment and promotion of Salk professors.

erase are thought to play central roles in aging and diseases such as cancer, and her work helped launch entire new fields of research in these areas. Dr. Blackburn is a member of numerous prestigious scientific societies, including the National Academy of Sciences, the National Academy of Medicine, and the Royal Society of London.

Elizabeth Blackburn, PhD

She earned her doctorate in molecular biology from the University of Cambridge in England. She conducted postdoctoral research at Yale University. Dr. Blackburn joined the faculty of the University of California, Berkeley, and then moved to the University of California, San Francisco, where she was a past Chair of the Department of Microbiology and Immunology. n

Contact

The ASCO Post Editorial Correspondence

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Book Review

The Sixth Edition of the Essential Breast Cancer Book By Ronald Piana

or more than 25 years, Dr. Susan Love’s Breast Book has been the best source of information for women with breast cancer. Susan M. Love, MD— with contributions from writers Karen Lindsey and Elizabeth Love—recently published the sixth edition of the book. In the introduction, Dr. Love revisits her first edition with a sober reminder of some of the clinical travails that have paved the road to today’s successes: “[O]ur belief that all breast cancers were the same and should be treated the same was wrong, as was the idea that more aggressive tumors required more aggressive treatments. At the time this had led to high-dose chemotherapy and stem cell rescue in an effort to kill every cancer cell … ultimately this approach proved no better than regular dose chemotherapy.”

continues with nicely drawn subchapters detailing common breast problems. To her credit, she sets the record straight whenever there’s a medical misstep that needs correction—another reason why this book should be the preferred guide on breast health for women of all ages. “Doctors have a tendency to describe all nonmalignant lumps as cysts. They’re not. A cyst is a distinct kind of lump. Typically it occurs in women in their thirties, forties, and early fifties and is most common in women approaching menopause,” writes Dr. Love. Every woman of a certain age has known someone who has had and possibly died of breast cancer. Naturally, women want to know what their chances are of developing the disease and ways to prevent or at least reduce their risk of breast

To her credit, [Dr. Love] sets the record straight whenever there’s a medical misstep that needs correction—another reason why this book should be the preferred guide on breast health for women of all ages. Although this is a valuable read for oncology fellows or medical students toying with the idea of pursuing a career in oncology, Dr. Love’s book is targeted at women with breast cancer. Wisely, she opens with a chapter called, “The Breast,” in which she gives a well-written A-to-Z discussion about “the only organ in your body that you are not born with. You come into the world with a nipple and lots of potential; some cells behind the nipple that, given the right hormonal stimulation, will grow and become a breast.” Clear and accurate writing such as this terrific opening is seen throughout this fine book. It looks easy, but it’s far from that.

Painstaking Process Another strong point in Dr. Love’s approach is her references to previous editions, giving readers a sense of the organic and painstaking process they are participating in. “In the first edition of this book, I wrote about the common use of the term ‘fibrocystic disease,’ which doctors once used to describe a number of symptoms.… The term had no real meaning, even though the symptoms were very real.… Unfortunately some doctors still tell women they have fibrocystic disease, as I have discovered from the comments women have sent to me on Facebook,” writes Dr. Love. She then

cancer. Although this information is constantly being updated, Dr. Love drills down to the most current data, from the types of risk factors to prevention strategies that have been validated by epidemiologists and public health experts. The chapters on risk and prevention are information-dense, and the reader will come away fully informed. However, laypersons without some science reading background will find discussions on lobular involution and ductal lavage quite challenging.

Thorny Issues The relevance of screening remains a point of confusion and contention among women and their breast advocacy groups. Dr. Love tackles the issue with frankness and authority, explaining that when screening was first introduced, the understanding was that cancers grow at a certain rate and “at some point get out into the rest of the body.… Thus, we concluded that if we could find the cancers before this happened, we could prevent people from dying from breast cancer.” Of course, that wasn’t the case, and Dr. Love explains why. She then wades into the thorny issue of the clinical worth of breast self-exam, breast physical exam, and mammography, debunking the myth that early detection saves all lives and the problems of false-

Bookmark Title: Dr. Susan Love’s Breast Book Author: Susan M. Love, MD Publisher: Da Capo Lifelong Books Publication date: September 8, 2015 Price: $24.00; paperback, 704 pages positives and overdiagnosis that lead to overtreatment. The various iterations of the U.S. Preventive Services Task Force on mammography recommendations don’t add comfort. But in the end, after learning about the fallibility of breast cancer screening, women want a clear way forward from the author. She provides just that: “What mammography can do is important.… For now it’s what we have, and it makes sense to use it.” The chapters on diagnosis and treatment are written with firm delicacy, giving an exact description of scanning and biopsy techniques. Dr. Love never lets her detailed clinical discussions stray from the patient as a whole person who has been pushed to the furthest edge of vulnerability by a diagnosis of breast cancer.

Valuable Reading Chapter 10, “What Kind of Cancer Do I Have?” is some of the book’s most valuable reading, and also its most difficult. It is in this chapter that women will truly understand the challenges faced by their oncology team. Sorting out the various types of breast cancers, pathology reports, hormonal relationships, molecular classifications, and the commercial tests that help determine the best treatment strategies can be overwhelming, but this is what a newly diagnosed patient faces. That said, many lay readers will need help decoding this highly scientific section, and it is best used as a partnering tool with a woman’s oncology team. Part Five (“Treatment in the Age of Personalized Medicine”) is the strongest section of the book, and it is here, in treatment, where women need the most guidance and support. Since almost every form of breast cancer involves surgery, Dr. Love uses a steady and even-

handed approach in her narrative, from lumpectomy to mastectomy to reconstructive surgery. Women reading this material will come away better informed and less fearful. Yes, the descriptions of postmastectomy reconstructive surgery will be digested in long pauses, but each section is a gem of information, explaining the difficult decision-making process many women undergo. Moreover, Dr. Love empowers her readers to be strong advocates for their breast health and appearance.

Measured Optimism Moving into the dizzying array of targeted therapies will again prove difficult reading for many women, but the knowledge that these exciting therapeutic options exist adds another layer of measured optimism for breast cancer patients and their caregivers. In chapter 16, Dr. Love deals with lifestyle changes and complementary treatments; her own growth as a clinician and advocate since the first edition of this remarkable series becomes obvious when she talks about the salutary effects of prayer and laughter. Survivorship issues are handled with sensitivity, as are the difficult but necessary sections on end-of-life planning and living with recurrence. Fittingly, Dr. Love’s epilogue is called Eradicating Breast Cancer: Politics and Research,” in which she points out that her first edition made no mention of the politics of the disease, because there were none. The second edition of Dr. Susan Love’s Breast Book chronicled the birth of the breast cancer political movement. And she has been there every step of the way. Dr. Susan Love’s Breast Book is highly recommended for readers of The ASCO Post and their patients. n

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Announcements

Mayo Clinic Names Bobbie Gostout, MD, Vice President

he Mayo Clinic Board of Trustees named Bobbie Gostout, MD, Vice President of the Mayo Clinic. Dr. Gostout will be the physician leader for Mayo’s community practice

the Midwest and the Department of Obstetrics and Gynecology in Rochester, Minnesota, where she has been Department Chair since 2007. Dr. Gostout has been on the Mayo Clinic’s Rochester staff for nearly 20 years. In addition to her roles as a phy-

sician and Chair of the Department of Obstetrics and Gynecology, she is Professor of Obstetrics and Gynecology and has served in various leadership roles at Mayo Clinic, including Vice Chair of the Rochester Personnel Committee and Rochester Clinical Practice

Committee. Dr. Gostout is a member of the Mayo Clinic Board of Governors and Board of Trustees. She is former President of the Western Association of Gynecologic Oncologists and a member of the former Mayo Clinic Health System Board of Directors. n

Bobbie Gostout, MD

in the Midwest, including Mayo Clinic Health System in Iowa, Minnesota, and Wisconsin, and Mayo Clinic’s Minnesota-based community care locations. In her new role, Dr. Gostout, along with her administrative partner, Mark Koch, will lead the integration of Mayo’s specialty and community care practices in the Midwest and guide the implementation of all aspects of Mayo’s strategic and operating plans. Dr. Gostout will transition into her new role through the end of 2015. This will ensure a smooth leadership transition for Mayo’s community practice in

The ASCO Post

News, Advocacy and Analysis on Cancer Policy

YOUR SOURCE FOR

Cancer-Related Policy News ASCO in Action is the American Society of Clinical Oncology’s (ASCO) online information hub for the critical policy issues that affect cancer practice, research, and patient care in the United States today. Updated daily, ASCO in Action is your source for breaking news on developments you most care about:

• Physician reimbursement and payment reform initiatives • Federal funding of clinical cancer research

ASCO Government Relations Committee Leadership Philip Stella, MD, and Blase N. Polite, MD, MPP, with Congressman Tom Price (GA-06), in the middle

• New federal regulations affecting oncology practices • Quality and value-focused initiatives

@ASCOPost

• FDA drug approvals • Implementation of the Affordable Care Act …and much more! Learn how ASCO is advocating on your behalf with policymakers and about opportunities for you to become involved through ASCO’s ACT Network. Also, access advocacy tools to help you get started, including ASCO’s policy agenda, policy statements, and issue backgrounders.

ASCO Leadership and Members of the Government Relations Committee on Capitol Hill

Check out ASCO in Action today! Visit ascoaction.asco.org.

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Patient’s Corner

Starting Over

After a diagnosis of pleural mesothelioma upturned my life and career, I am now learning to adjust to life as a cancer survivor. By Sally Teahan, as told to Jo Cavallo

y diagnosis of pleural mesothelioma early in 2015 couldn’t have been more surprising. In one day, I went from being a healthy, vibrant woman with a busy career and the excitement of launching a promising new business venture to a woman facing the greatest

who ordered a chest x-ray. The test showed fluid buildup in my lungs, but it wasn’t until 2 L of fluid were drained from my pleura that a pulmonologist to whom I had been referred had spotted a mass on my lower left lung.

Although I have asked my thoracic surgeon for a prognosis, he said that, unlike a carton of milk, I don’t have an ‘expiration date,’ and that was comforting to hear. —Sally Teahan

challenge of her life. The fact that my only symptom was shortness of breath, which came on suddenly and was originally diagnosed as being caused by pneumonia, made the news that I had cancer especially difficult to hear. And getting to the correct diagnosis was such an arduous process that it made the experience even more difficult to cope with.

Getting the Diagnosis Soon after my symptom appeared, I saw my primary care physician,

A biopsy of the pleural tissue showed that I had pleural mesothelioma, and a second biopsy was performed to confirm the diagnosis. I then was sent out of state for biopsies of several surrounding lymph nodes and tissue to determine whether the cancer had spread and the stage of the tumor. Although I was never given a disease stage, I was told that the cancer had been caught early and that it was confined to the lower part of my left lung, which was a relief.

Emotional and Physical Impact Still, even now, 9 months after my diagnosis, the aftermath of having cancer and its treatment has been difficult to manage emotionally and physically. I had surgery to remove half of my diaphragm, the pleura, part of my pericardium, and a lower rib, which left me with unrelenting pain for months. Then I underwent four rounds of a combination regimen of pemetrexed (Alimta) and cisplatin to kill any remaining errant malignant cells. I’m hoping now that my treatment has been completed, I’m cured of my cancer, but I know there is a chance it will recur in the future, and I’m learning to live with that fact.

The Unpredictability of Life Although I have asked my thoracic surgeon for a prognosis, he said that, unlike a carton of milk, I don’t have an “expiration date,” and that was comforting to hear. Because the mesothelioma was caught early and the treatment was aggressive, he said he is confident that I have the best chance possible of living a long life, and I am monitored closely for signs of recurrence. So far, I remain cancer-free. Surviving cancer has taught me

Patient Guides Available Through ASCO University Bookstore

many lessons, including how unpredictable life is and the folly of taking anything for granted. It has also renewed my appreciation for the love of family and friends, and I am especially grateful to all the members of my community who bolstered my spirits with offers of prayers. Their good thoughts and well wishes have given me a new appreciation of the generosity of strangers and made me resolve to return that generosity to others I meet who may need an act of kindness during a difficult time.

A New Normal Although I’m still recovering from the emotional and physical shock of having cancer, I’m starting to move on with my life and career. When I was first diagnosed, I had just launched a new business, which had to be put on hold while I received treatment. Now that that part of my cancer experience is behind me, I’m starting to proceed with my business plans. When you have cancer, you become permanently tagged with the word “survivor.” But all I want is to have my normal life back, whatever that means now. n Sally Teahan is an event and wedding planner and lives in Lenexa, Kansas.

The ASCO Post

Wants to Hear From You

• 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.

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

• 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

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In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Shift in Treatment Patterns of Ductal Carcinoma in Situ An evaluation of national treatment trends for ductal carcinoma in

situ from 1991 to 2010 and their impact on survival revealed “a substantial shift in locoregional treatment patterns for ductal carcinoma in situ,” Mathias Worni, MD, of Duke University Medical Center, Durham, North Carolina,

and colleagues reported in the Journal of the National Cancer Institute. “The use of lumpectomy with radiation increased by almost 100%, whereas use of unilateral mastectomy dropped by 60%,” the investigators stated. Overall

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survival was higher for lumpectomy with radiation therapy than for mastectomy, which was higher than for lumpectomy alone. These findings were based on 121,080 patients with ductal carcinoma in situ identified through the Surveillance, Epidemiology, and End Results (SEER) registry from 1991 to 2010. Overall, the greatest proportion of patients was treated with lumpectomy and radiation therapy (43.0%), followed by lumpectomy alone (26.5%) and unilateral mastectomy (23.8%) or bilateral mastectomy (4.5%), and 2.3% had no surgical treatment. There were, however, “significant shifts over time.” The proportion of patients undergoing lumpectomy plus radiation therapy increased from 24.2% in 1991 to 46.8% in 2010. The proportion of patients treated with bilateral mastectomy increased from 0% to 8.5% during those years, which the authors noted was “likely driven by prophylactic contralateral mastectomy rather than by bilateral ductal carcinoma in situ.” The proportion of patients receiving no treatment increased from 1.2% to 3.2%. “In contrast, there was a statistically significant reduction in the rate of unilateral mastectomy (44.9%–19.3%) and lumpectomy alone (29.8%– 22.3%, Ptrend < .001 for all groups),” the investigators reported.

Increase in Sentinel Lymph Node Biopsies For patients undergoing mastectomy, the rate of sentinel lymph node biopsy increased from 9.7% in 1991 to 67.1% in 2010, and axillary dissections dropped from 62.9% to 15.3% < .001 for both comparisons). (P trend For those patients treated with lumpectomy, the rate of sentinel lymph node biopsy increased from 1.4% to 17.8%, whereas the rate of axillary dissections decreased from 14.2% to 2.8% (P < trend .001 for both comparisons). “The low prevalence of node involvement in the setting of ductal carcinoma in situ and minimal impact of lumpectomy on feasibility of subsequent axillary surgery supports a more restrained use of sentinel node biopsy with lumpectomy for ductal carcinoma in situ,” the investigators commented. They pointed out, “current rate of axillary surgery overall, and of axillary continued on page 158

The ASCO Post | DECEMBER 10, 2015

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In the Literature Emerging Clinical Data continued from page 157

dissection specifically, remains higher than indicated based upon the recent ASCO clinical practice guidelines and represents both a source of concern as well as a target for further education.”

Striking Regional Differences The investigators also found “striking differences” by region in the rate of radiation use following lumpectomy. “Reasons for such geographical variation remain unclear and are of concern, as these data suggest that treatment decisions are much more strongly driven by the geography where the diagnosis was made, rather than by ductal carcinoma in situ disease characteristics,” the authors wrote. “Compared with mastectomy, overall survival was higher for lumpectomy with radiation (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.76–0.83, P < .001) and lower for lumpectomy alone (HR = 1.17, 95% CI = 1.13–1.23, P < .001),” the researchers reported. The 10-year inverse probability weight–adjusted disease-specific survival was also highest for lumpectomy with radiation therapy (98.9%), followed by mastectomy (98.5%) and lumpectomy alone (98.4%). The greater differences in overall survival than disease-specific survival were “likely reflecting both a prevailing patient selection bias as well as clinically negligible differences in breast cancer outcomes between groups,” the authors noted. “The choice of locoregional treatment had a strikingly small impact on

breast cancer–specific survival, calling for a more thoughtful and restrained treatment approach for this disease,” the researchers concluded. “Consideration of an individual’s health and life expectancy as well as implementation of less invasive treatment options, including active surveillance in thoughtfully selected patients, could yield the greatest benefit and treatment-related harms for future patients diagnosed with ductal carcinoma in situ.” Worni M, et al: J Natl Cancer Inst. September 30, 2015 (early release online).

DERMATOLOGIC CANCER Increased Risk of Second Nonmelanoma Skin Cancer Among Patients Receiving Immunosuppressive Therapy Patients with rheumatoid arthritis treated with methotrexate had an increased risk of a second nonmelanoma skin cancer, and adding anti–tumor necrosis factor (TNF) may increase that risk, according to results of a retrospective cohort study reported in JAMA Dermatology. A similar association was seen for antiTNFs among patients with inflammatory bowel disease, the investigators noted, although this finding was not statistically significant. Immunosuppressive therapy is the standard of care for rheumatoid arthritis and inflammatory bowel disease, the authors noted, and “both immune dysfunction and therapy-related immunosuppression can inhibit cancer-related immune surveillance

in this population.” Drug-induced immunosuppression is also risk factor for nonmelanoma skin cancer, particularly squamous cell tumors.

‘Exposures of Interest’ Along with methotrexate and antiTNFs, other medications considered “exposures of interest” included abatacept (Orencia), rituximab (Rituxan), and thiopurines. The study looked at 9,460 individuals, 6,672 with rheumatoid arthritis only, 2,619 with inflammatory bowel disease only, and 169 with both rheumatoid arthritis and inflammatory bowel disease. All had an incident nonmelanoma skin cancer diagnosis after enrollment in Medicare from January 1, 2006, through December 31, 2012. “This cohort has been used previously to evaluate the comparative effectiveness and safety of medications used to treat inflammatory bowel disease and rheumatoid arthritis,” the authors explained. Exclusion criteria included any other malignancy before the first diagnosis of nonmelanoma skin cancer, organ transplant, and human immunodeficiency virus, as well as “use of medications thought to affect the risk of nonmelanoma skin cancer before the first nonmelanoma skin cancer diagnosis, such as tacrolimus, cyclosporine, imiquimod, or fluorouracil,” the investigators noted. “A total of 1,291 individuals developed a second [nonmelanoma skin cancer] (910 with [rheumatoid arthritis] only, 359 with [inflammatory bowel disease] only, and 22 with both [rheumatoid arthritis and inflammatory bowel disease]),” the researchers reported. The incidence rate per 1,000 personyears of a second nonmelanoma skin cancer was 58.2 among patients with rheumatoid arthritis (95% confidence interval [CI] = 54.5–62.1) and 58.9 among patients with inflammatory bowel disease (95% CI = 53.2–65.2). In both groups of patients, men were more likely than women to have a second nonmelanoma skin cancer, and those with a second nonmelanoma skin cancer were more likely to have a history of actinic keratosis.

Other Immunosuppressants

“Among patients with [rheumatoid arthritis], methotrexate used in conjunction with other medications was associated with an increased risk of a second [nonmelanoma skin cancer] (hazard ratio [HR] = 1.60; 95% CI = 1.08–2.37). Adjusted for other medications, the risk

of [nonmelanoma skin cancer] increased with 1 year or more of methotrexate use (HR = 1.24; 95% CI = 1.04–1.48),” the researchers reported. “Compared with methotrexate alone, the addition of anti-TNF drugs was significantly associated with risk of [nonmelanoma skin cancer] (HR = 1.49; 95% CI = 1.03–2.16). Abatacept and rituximab were not associated with increased [nonmelanoma skin cancer] risk. The nonsignificant [hazard ratios] for 1 year or more of thiopurine and anti-TNF use for [inflammatory bowel disease] were 1.49 (95% CI = 0.98–2.27) and 1.36 (95% CI = 0.76–2.44), respectively,” the investigators found. “This is the largest study to date, to our knowledge, to examine the effect of commonly used therapies in [inflammatory bowel disease] and [rheumatoid arthritis] on the risk of cancer recurrence,” the authors stated. They cautioned that although the study “found an increased risk of a second [nonmelanoma skin cancer] with methotrexate and possibly antiTNF drugs, we cannot conclude that the other immunosuppressive therapies represent safer alternatives. Further research examining these agents is required.” Scott FI, et al: JAMA Dermatol. October 28, 2015 (early release online).

ANEMIA IN OLDER ADULTS Anemia Prevalent and Independently Associated With Functional Disability in Older Patients With Cancer “Anemia was highly prevalent and independently associated with functional disability” among older adults with cancer, according to an analysis of data conducted by Cynthia Owusu, MD, MS, of Case Western Reserve University, Cleveland, and colleagues. “Older patients with anemia were more than twice as likely to have functional disability than those without anemia,” the investigators reported in the Journal of the National Comprehensive Cancer Network. An assessment of the association between anemia and activities of daily living among older adults with cancer “is clinically relevant,” the authors noted, because Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky performance scale “may underestimate the extent of functional impairment among older adults, and self-reported activities of

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In the Literature

daily living and instrumental activities of daily living present a more comprehensive approach for assessing the functional status of older adults with cancer.” It is in this context that the researchers sought to examine the association between anemia and functional disability (the need for assistance with at least one instrumental activity of daily living) among a cohort of older adults with cancer.

cancer to help in establishing a causal link between anemia and functional disability and randomized controlled trials to evaluate whether treating anemia can improve functional status and treatment tolerance among older adults with cancer. “Although 30% of all anemia in older adults may be unexplained, and therefore is not readily

Needed Assistance With at Least One Activity The researchers conducted a crosssectional analysis of data derived from a multicenter prospective study that identified clinical and biologic predictors of chemotherapy among 500 patients with cancer who were aged 65 years or older. The patients were recruited from ambulatory oncology clinics at seven institutions. The median age of the 491 evaluable patients was 73.1 years (range, 65–91 years); 85% were white, and 56% were female. The most common types of cancer were lung (28.5%), gastrointestinal (27.1%), gynecologic (17.3%), breast (11.4%), and genitourinary (10.2%). Most patients (61.5%) had stage IV disease, and 44% had three or more comorbidities. “The primary outcome was functional disability at chemotherapy initiation, defined as the need for assistance with at least one instrumental activity of daily living. Anemia (using World Health Organization criteria) was defined as a hemoglobin level of less than 12 g/dL in women and less than 13 g/dL in men,” the investigators explained.

‘Consistent and Robust Association’ Functional disability was present in 43% of patients and anemia, in 51%. “On multivariable analysis, adjusting for sex, stage, and unintentional weight loss, patients with anemia were more likely to have functional disability (odds ratio, 2.40; 95% confidence interval, 1.61–3.59),” the researchers found. Patients with anemia also had lower scores for instrumental activities of daily living and other physical functioning scales. “These results demonstrate a consistent and robust association between anemia and physical function, irrespective of whether physical function is patient self-reported or provider-rated,” the investigators stated. The researchers called for longitudinal studies among older adults with

corrected, and the use of erythropoietin in patients with cancer may be associated with increased mortality and is therefore not recommended by current guidelines, a significant proportion of anemia in older adults is caused by nutritional deficiencies and is readily modifiable,” the authors wrote. “Modifiable causes of anemia offer an

opportunity to evaluate whether treating anemia can improve functional status and treatment tolerance among older adults with cancer.” n Owusu C, et al: J Natl Compr Canc Netw 13:1233-1239, 2015. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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Early Stage, Hormone Sensitive, and Screening and Risk Assessment

Genitourinary (GU) Cancers

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Gastrointestinal (GI) Cancers

Gastroesophageal, Localized Rectal, Metastatic Colorectal Cancer, and Pancreatic

Hematologic Malignancies

B-Cell Lymphomas, Chronic Myelogenous Leukemia, and Multiple Myeloma

Lung Cancer

EGFR-Mutation Positive Metastatic NSCLC

Survivorship

Sexual Function in Cancer Survivors and Cancer Pain Management

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Advanced Melanoma, CNS, Hepatocellular Carcinoma, Role of Biosimilars, VTE

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The ASCO Post | DECEMBER 10, 2015

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Book Review

One Long Shift With a Nurse on a Cancer Ward By Ronald Piana

capturing the conversational voices of nurses and doctors as well as their patients, in all shades of emotion. What illuminates Ms. Brown’s story are the moving and sometimes wacky moments that make life in a hospital terrific fodder for storytelling. In one scene, a patient says a weepy goodbye before surgery, knowing there is a fair chance that she won’t survive the risky procedure. Ms. Brown offers her a hug; the patient, instead, kisses Ms. Brown squarely on the lips.

tron, explaining that for an old man, going home to one’s room was not like sitting in a clean, well-lit café. It is a story of loneliness and mortality. Ms. Brown explains Hemingway’s story and then inexplicably writes, “There will come a time when each of us will need a clean, well-lighted place that stays open all day and night, offering shelter from life’s storm—this is a hospital.” Really? Hospitals save countless lives, but it is about the last place anyone wants to go. They are noisy and uncomfortable with middling to bad food, patients groaning through the night, and a place where, according to the Institute of Medicine, about 99,000 Americans die each year from nosocomial infections. The analogy just doesn’t hold water, surprising for a PhD in literature. And because real life, even in a busy hospital setting can also be more dull than fiction, the story sometimes reads like a very busy person’s to-do list, executed in real time. Without a main narrative purpose, its insights can also come off like a collection of clichés, as when Ms. Brown notes of the ward’s survivors: “Their lives will continue to spool out as they each weave the fabric of their own unique existence.”

Writing Style Critique

Hierarchal Struggles

Good writers sometimes fall into the trap of searching for allegory for allegory’s sake, ending up with chunks of well-written narrative, which can be an

The author becomes closely involved with her patients and makes no bones about questioning a doctor’s orders when she feels they aren’t in her

Bookmark Title: The Shift: One Nurse, Twelve Hours, Four Patients’ Lives Author: Theresa Brown, RN Publisher: Algonquin Books Publication date: September 22, 2015 Price: $15.59; hardcover, 272 pages

f health care were looked at through an architect’s eyes, nurses would be the girders holding the structure together. They work 12-hour shifts caring for the needs of sick people, doing intimate things with the bodies of total strangers that would make most laypersons queasy. In her new book, The Shift: One Nurse, Twelve Hours, Four Patients’ Lives, Theresa Brown, RN, a practicing nurse and columnist for The New York Times, invites readers into the heart of her daily experiences on a cancer ward. And she compresses that experience into one shift. Every day, Nurse Brown and her colleagues care for critically sick people, at once being tough and tender and super efficient. By the end of this enjoyable medical story, readers of The Shift will be well acquainted with several patients with cancer and the durable hardworking nurses who care for them. Ms. Brown earned a PhD in English and taught writing at Tufts University before trading academia for hospital scrubs at a Pennsylvania teaching hospital. She explains that nursing was her true calling, although she describes it more as a rewarding job than an enjoyable one. She lets readers know that her career change was motivated by compassion and care.

Moving and Wacky Moments She is a capable writer, at times turning out lovely descriptive sentences. She also has a keen ear for dialogue, deftly

Theresa Brown, RN, a practicing nurse and columnist for The New York Times, invites readers into the heart of her daily experiences on a cancer ward. And she compresses that experience into one shift. uncomfortable fit into the storyline. For instance, Ms. Brown’s prologue is titled “A Clean, Well-Lighted Place,” which is, of course, the title of one of Ernest Hemingway’s best-known short stories. In the story, a lonely old man sits sipping brandy in a café late at night. A young waiter wants to close the café and go home to his wife, whereas an older waiter has empathy for the dawdling pa-

patient’s best interest. To that end, in a pointed critique of yesteryear’s patriarchal medical culture, Ms. Brown notes that vestiges of that Ivory Tower occupied by white male doctors still exists. “Hospital nurses get hired and fired independent of MDs, but from what I see and hear, at a fair number of hospitals no nurse would be protected if an important doctor really wanted her

gone. Doctors are our shadow bosses, the people whose orders we put into action, whose patients we share the care of, even though MDs don’t explicitly supervise us. No wonder we both end up playing games when we communicate at work.” Hierarchal struggles exist in every stratum of life, from marriage to career. Ms. Brown makes some sweeping generalizations about doctor-nurse relationships, derived from personal experience. No doubt male chauvinism still exists in medicine. However, although Ms. Brown is a dedicated nurse working on a cancer ward, her experience does not capture the incredible respect that oncologists and oncology specialist nurses have for each other as they work side by side caring for their cancer patients.

Making Patients Come Alive For readers of The ASCO Post, the hook in The Shift is that the story’s central location is a cancer ward. Ms. Brown weaves the clinical scenarios of four cancer patients into her narrative, and her common touch and genuine humanity—despite some cornball antics—shine through as the patients come alive on the pages. We meet Richard Hampton, a lymphoma patient in his late 70s. She does a superb job describing the rigors of Mr. Hampton’s cancer care and his vital family support systems. However, when Ms. Brown discovers, after a brief secretive conversation with an intern, that Mr. Hampton has been prescribed rituximab by the attending physician, this back and forth ensues: “Are you his nurse? Asks the intern, his voice soft and low. I nod and say my name. “So, it looks like they’re going to give him Rituxan today,” he says. “Rituxan?” I ask, raising my eyebrows. His features collapse, and his face goes blank. “We’ll discuss it on rounds.”

This is not a professional oncology exchange. It adds intrigue where none should exist. Cancer care is not a spy movie. The lay audience looking for a somewhat entertaining hospital story should try The Shift, but readers of The ASCO Post perhaps may want to give it a pass. n

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The ASCO Post | DECEMBER 10, 2015

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In Memoriam

Nationally Regarded Oncology Nurse Practitioner, Mary Pazdur, RN, MSN, Remembered by Friends and Colleagues By Ronald Piana

ncology nurse practitioner Mary Pazdur, RN, MSN, spent her professional life bettering the clinical care and outcomes of cancer patients, culminating in her career at the National Cancer Institute (NCI), in the Laboratory of Tumor Immunology and Biology, working with patients on cancer vaccine protocols. Ms. Pazdur died on November 24, 2015. The cause of death was ovarian cancer. Ms. Pazdur’s life and work in the oncology community had a distinctive history—for 33 years she was married to Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products at the U.S. Food and Drug Administration (FDA). And for more than 3 decades, Ms. Pazdur was intimately involved in some of the most exciting clinical and political advances in oncology.

Bonding in Oncology: A Partnership Flourishes Lung cancer expert Philip D. Bonomi, MD, introduced Ms. Pazdur to her future husband in 1979, when they were both working in the oncology department at Rush-Presbyterian St. Luke’s Medical Center in Chicago. “I had the privilege of working with Mary Pazdur early in her career and the honor of introducing her to Rick. Right from the beginning, we could see that they made a great team. Rick had a penchant for coming up with humorous nicknames, and Mary would sometimes offer her gentle perspective on these new monikers. Mary was also a role model for her nursing colleagues, and she was a great physician partner. I’m sure that she also served as a great sounding board for Rick in his very demanding job. Along with these fond memories, we will remember Mary for her dedication to patients, common sense, and kindness,” Dr. Bonomi told The ASCO Post. Dr. Pazdur recounted his initial encounter with the oncology nurse who would become his wife. “I always joke that our first date was over a bottle of Adriamycin in the exam room, which sounds somewhat peculiar, but that was the truth,” said Dr. Pazdur. According to Dr. Pazdur, it was the common experience of oncology that helped forge their bond. “I look back to all of those early patients who were treated by Mary, myself, and the

people at Rush-Presbyterian St. Luke’s Medical Center, and it really was a special time in our lives.” In 1982, Dr. Pazdur accepted a position at Wayne State University School of Medicine in Detroit. “It was the same year Mary and I were married. Because time and money were tight, we spent our honeymoon in Detroit planning our move from Chicago,” said Dr. Pazdur.

Extraordinarily Skilled and Highly Compassionate After 6 years at Wayne State, Dr. Pazdur was recruited for a position in gastrointestinal oncology at The University of Texas MD Anderson Cancer Center and moved with his wife to Houston. At MD Anderson, Ms. Pazdur’s own career path accelerated. In 1988, she was appointed Clinical Instructor. In 1989, she was named nurse manager of discharge planning, and in 1993, clinical nurse specialist. Ms. Pazdur’s colleagues at MD Anderson recalled her special humanistic and clinical traits that were emblematic of her career. Colleague Ellen V. Sigal, PhD, Chairperson and Founder of Friends of Cancer Research, described Ms. Pazdur’s passing as “a pro-

Mary Pazdur, RN, MSN, with husband Rick Pazdur, MD, and their Maltese, Cleo.

ing—I can’t think of anyone with better communication skills. She will be sorely missed, not only by physicians but by patients as well,” said Dr. Hong in an interview with The ASCO Post.

Simply a Superb Person and Practitioner Roy S. Herbst, MD, PhD, Chief of Medical Oncology at Yale Cancer Center, who cut his oncology teeth with Ms. Pazdur remembers her with fond respect. “I’ve known Mary since 1997, when I was a young attending at

The many patients and families she served during her distinguished career benefited tremendously from her clinical acumen. She also had an exceptional ability to engage patients, and to skillfully incorporate their preferences and values into the plan of care. —Sandra A. Mitchell, PhD, CRNP, FAAN

found loss of an extraordinary woman who devoted her life to helping others. She will be deeply missed.” Waun Ki Hong, MD, Head of MD Anderson’s Division of Cancer Medicine, noted that he had the tremendous privilege and honor to work with Ms. Pazdur side by side. “I must say that she was one of the best advanced nurse practitioners I have ever worked with in my almost 40 years in oncology practice. She was a totally dedicated nurse who always worked for the best interest of her patients. She was extremely compassionate, and her communication skills between physician and patient were absolutely outstand-

MD Anderson. She was a nurse practitioner managing Dr. Waun Ki Hong’s practice. At that time, I was working very closely with Fadlo Khuri, MD; we were the junior attendings who would help Mary with Dr. Hong’s patients, but when Ki wasn’t around, Mary helped us. We loved when Mary was there at the clinic because it meant our patients would get superb care.” He continued, “We once treated some patients from another country, which posed language barriers that made the collection of their clinical information difficult. But Mary would always pull things together and, in the end, no matter who the patients were

or where they came from, Mary made sure they received the best care possible. She was the dean of oncology nurse practitioners, and she helped move the field forward to what it is today. When Rick left MD Anderson for the FDA, we were sad to see him go, but we were even sadder to see Mary go. She was simply a superb person and practitioner.”

Lessons About Living and Dying At a recent National Coalition for Cancer Survivorship meeting, in which her husband was honored for his contributions to cancer patients and their families, Ms. Pazdur reflected on her own career. “I’ve always worked in oncology, even when I was an undergraduate nursing student. I was drawn to oncology because it’s so many different diseases affecting so many body systems and developmentally along the continuum of life. The silver lining is that you learn a lot of existential lessons about living and dying when you’re almost too young to learn those things.” During that same interview, Dr. Pazdur spoke of his wife. “I’ve enjoyed the partnership that I’ve had with Mary during those years. As many of you know, my life had been transformed over the past 3 years with my wife having ovarian cancer, and this gives me a special perspective on the treatment of patients with cancer.” Ms. Pazdur has said that her career as a health-care provider in exam rooms with vulnerable cancer patients actually helped her prepare for her own struggle against cancer. “I’ve had the luxury of

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In Memoriam

some rehearsal, and very few people have that opportunity in their lifetime. I’ve learned a newfound respect for the caregiver’s role, since he [Dr. Pazdur] has had to become a caregiver in addition to the other hats that he wears.”

A Pioneering Leader of the Oncology Nurse Practitioner

Philip D. Bonomi, MD

On Ms. Pazdur’s passing, colleagues across the country paid tribute to her as a special person among many special people. Following MD Anderson, in 2000, she joined NCI as an advanced practice nurse. One of her many associates at the NCI, Sandra A. Mitchell, PhD, CRNP, FAAN, Research Scientist, Outcomes Research Branch, remarked, “Mary was a pioneering leader of the oncology nurse practitioner role at cancer cen-

Ellen V. Sigal, PhD

Waun Ki Hong, MD

ters around the country and at the NCI. Through her expertise, compassion, and continuous striving for optimal patient outcomes, Mary transformed the interprofessional team at NCI, establishing the nurse practitioner role as an essential component in the delivery of patient-centered care. The many patients and families she served during her distinguished career benefited tremendously from her clinical acumen. She also had an exceptional ability to

Roy S. Herbst, MD, PhD

engage patients and to skillfully incorporate their preferences and values into the plan of care.” Ms. Pazdur’s research activities have also included a study of the needs of orthopedic oncology patients at home, funded by the National Association of Orthopedic Nurses, and she has lectured on that and other topics at the Oncology Nursing Society’s Annual Fall Institute and Annual Congress. “Those of us privileged to know

Sandra A. Mitchell, PhD, CRNP, FAAN

Mary as a friend and colleague could always count on her warm and caring spirit, her generosity, and her always-wise perspectives. She is greatly missed, but her legacy of professional excellence blended with deep compassion remains an enduring inspiration for us all,” added Dr. Mitchell. Mary Pazdur represented the truest spirit and dedication of an oncology specialist. She will be dearly missed by her family and many friends. n

 In Memoriam

Mary Pazdur, RN, MSN July 23, 1952 – November 24, 2015 

AACC Elects Michael J. Bennett, PhD, 2017 President, Names New Treasurer and Board Members

he American Association for Clinical Chemistry (AACC) has announced that Michael J. Bennett, PhD, has been elected to serve on the AACC

Michael J. Bennett, PhD

Board as President-Elect beginning in January 2016, followed by successive terms as the Association’s 68th President in 2017 and Past President in 2018. The AACC membership also elected a new treasurer and two new members of the Association’s Board of Directors who will take office at the start of 2016. Dr. Bennett is Professor of Pathology and Laboratory Medicine at the Univer-

sity of Pennsylvania, and Chief of Laboratory Medicine and Director of Clinical Chemistry and the Metabolic Disease Laboratory at The Children’s Hospital of Philadelphia. He also holds the Evelyn Willing Bromley Endowed Chair in Clinical Laboratories and Pathology. An active member of AACC since 1993, he is currently AACC Treasurer, ChairElect of the Association’s Proteomics and Metabolomics Division, and is a Past President of AACC’s Academy, the National Academy of Clinical Biochemistry (NACB). He was also a member of the NACB Education and Scientific Affairs Committee, where he chaired the Laboratory Medicine Practice Guidelines for expanded newborn screening. Dr. Bennett’s research includes investigation of inborn errors of energy metabolism and pediatric neurodegenerative diseases.

AACC Treasurer Corinne Fantz, PhD, will serve a 3-year term as AACC Treasurer.

Dr. Fantz is Director of Scientific Affairs, Point-of-Care Testing at Roche Diagnostics Corporation. She has been an active AACC member for 17 years and in 2015, was Chair of the Association’s Annual Meeting Organizing Committee, which plans the AACC Annual Meeting & Clinical Lab Expo. She has also served as a member of the Patient Safety Focus editorial board for AACC’s flagship magazine, Clinical Laboratory News, in addition to holding a variety of other association positions.

AACC Board Members Linnea M. Baudhuin, PhD, and William Clarke, PhD, MBA, will serve 3-year terms as members of AACC’s Board of Directors. Dr. Baudhuin is Associate Professor of Laboratory Medicine and Pathology at the Mayo Clinic, where she also serves as Codirector of the Personalized Genomics Laboratory, the Clinical Genomics Sequencing Laboratory, and

Cardiovascular Laboratory, and has a joint appointment in the Department of Medical Genetics. An AACC member since 1998, Dr. Baudhuin helped found and currently chairs the Association’s Society for Young Clinical Laboratorians, is Chair of AACC’s Midwest Section, a member of the Clinical Laboratory News editorial board, and an Associate Editor of AACC’s journal Clinical Chemistry. Dr. Clarke is Associate Professor of Pathology and Director of Point-ofCare Testing and Clinical Toxicology at Johns Hopkins Hospital. His involvement with AACC includes serving as Chair of the 2016 AACC Annual Meeting Organizing Committee and as a member of the Association’s Government Relations Committee, in addition to holding leadership positions in AACC’s Capital Local Section, Therapeutic Drug Management and Toxicology Division, and Critical and Point-ofCare Testing Division. n

The ASCO Post | DECEMBER 10, 2015

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Perspective

Important Safety Information for VOTRIENT® (pazopanib) tablets (cont) ® protein avoided due satisfaction to risk of potentially serious effects on organ Wound Healing: VOTRIENT (pazopanib) tablets Chandrakanth Are, MBBS, reform, medical school debts, and(BCRP) the should world. He watched her go cause to school to adverse Fewerbegive you the on the increased exposure to pazopanib. development in pediatric patients, particularly in may impair wound healing. Interruption of therapy MBA, FRCS, FACS learn the ways of the world, gain her legions of uninsured. Buried under- drive back home that you indeed had an

patients younger than 2 years of age. is recommended surgical continued from page 1in patients undergoingindependence, neath all and make something

this lies the true profession, indelible impact on someone’s life that CYP Substrates: Concomitant use of VOTRIENT with procedures; with be a smile can be antreatment enormous featVOTRIENT to ac- should productive of her life. He probably which still at its core is one of the most day. It is not uncommon to be out shopagents with narrow therapeutic windows that are Pregnancy Category D: VOTRIENT can cause fetal stopped days prior to scheduled surgery. complish dueattoleast her 7extreme weakness gave her away at her wedding and was noble and selfless professions. But to ping or at the gym with your family and metabolized by CYP3A4, CYP2D6, or CYP2C8 is harm when administered to a pregnant woman. VOTRIENT should be discontinued in patients with and the hindrance from all the tubes around for the arrival of her children. get to the core, one has to peel away so have someone approach you and mennot recommended. Coadministration may result in Women of childbearing potential should be advised wound A dehiscence. and drains. machine has to breathe It was to come that he would enter the many layers of unwanted paraphernalia. tion to your children “your father saved inhibition of the metabolism of these products and of the potential hazard to the fetus and to avoid for her, and several tubes take care of twilight of his life surrounded by his It is not that there are not enough peo- my life.” Such is the joy of this profescreate the potential for serious adverse events. becoming pregnant while taking VOTRIENT. Hypothyroidism: Hypothyroidism was reported her nutritional and other needs neces- children and her children. ple who ponder entering this profession that it is probably one of those few in 7% (19/290) of patients treated with VOTRIENT sary for survival. The crux the problem lies in the useprofessions Unfortunately,Diarrhea: sickness Diarrhea has snatched actively working to Concomitant of VOTRIENTthat and is simvastatin occurredsion. frequently andofwas in the randomized RCC trial and in no patients fact that how many people are willing to her away from feeding the fruits of filensure that they are notIfforced to work increases the incidence of ALT elevations. a patient predominantly mild to moderate in severity. Patients receiving placebo. Monitoring of thyroid function The Man Standing Beside Her fewer hours. develops ALT elevations, follow dosing guidelines should be advised how to manage mild diarrhea and tests is recommended. Despite the predicament of her illDespite all the complex changes for VOTRIENT, consider alternatives to VOTRIENT, to notify their health care provider if moderate to Despite all the complex changes ness, Proteinuria: for the first Intime, she somehow of the turbulent, extremely unceror consider discontinuing simvastatin. There are severe diarrhea occurs so appropriate management the randomized RCC trial, looked capable of fighting the battle— tain health-care environment, the of the turbulent, extremely uncertain insufficient data to assess the risk of concomitant can be implemented to minimize its impact. proteinuria was reported as an adverse reaction in and only because of the man standing sheer joy of possessing the privilege administration of alternative statins and VOTRIENT. 9% (27/290) of patients receiving VOTRIENT, leading health-care environment, the sheer Lipase Elevations: In a single-arm RCC trial, besidetoher. What madeofit treatment touching in was to mend and extend life as a physidiscontinuation 2 patients. There Drugs That Raise Gastric pH: Avoid concomitant increases in lipase values were observed for 27% joy of possessing the privilege to mend to watch entire of spectrum of infeelcian is what drives us to our desk or werethe no reports proteinuria patients receiving use of VOTRIENT with drugs that raise gastric (48/181) of patients. In the RCC trials of VOTRIENT, ings, emotions, and love that is associoperating room every day.pHThere are placebo. Monitor urine protein at baseline and and extend life as a physician is what (eg, esomeprazole) to the potential decrease clinical pancreatitis was observed in <1% (4/586) ated with a father and child relationfewdue professions that tocan demand so periodically as clinically indicated. Interrupt treatment drives us to our desk or operating room concentrations of pazopanib. Consider short-acting of patients. ship play out in front of us. Even more much of you and take so much of for 24-hour urine protein ≥3 grams, and discontinue antacids in place of proton pump inhibitors (PPIs) touching is to know thatdespite patientdose X isreductions. in your life away from you. At the same for repeat episodes everyTwo day. Pneumothorax: of 290 patients treated with and H2 receptortime, antagonists. antacid and that her mid-40s with teenage children of there isSeparate no other profession —Chandrakanth Are, MBBS, MBA, FRCS, FACS VOTRIENT and no patients on the placebo arm in the pazopanib dosing by several Infection: or without her own, and theSerious fatherinfections standing(with by her rewards youhours. with so much in return. randomized RCC trial developed a pneumothorax. side isneutropenia), in his 80s. some with fatal outcomes, have been These rewards are tangible and inAdverse Reactions in the Randomized RCC Trial: reported. Monitor signs and symptoms, treat to her aging father, when spend a better part of their youth A robust man is hisfor day, I am sure by ialand affection tangible, short term and long term, Bradycardia: In the randomized trial of VOTRIENT for A dosetrying interruption was required for 42% of patients active infection or need it most. As we left the to get to the core of this noble profeslooking at his build,promptly. he is nowConsider stoopedinterruption he would and finally can only be measured on the treatment of RCC, bradycardia based on vital signs on VOTRIENT. The VOTRIENT dose was reduced for discontinuation of the VOTRIENT. and has to hold on to railing of his room after examining sion and enjoy the benefits that it ofpatient X, I saw (<60 beats per minute) was observed in 19% (52/280) 36% of patients.a yardstick of “silent but bountiful” daughter’s bed to stand for long peri- him go back toofher fers? The bedside in with mea-VOTRIENT patients treated andbenefits in 11% cannot be measured gratification, which none other than a Increased Toxicity with Other Cancer Therapy: ods. An honorable man, without any sured steps. Here in monetary they ofwere, in on thethe placebo physician appreciate. The most common adversecan reactions (≥20%) (16/144) patients arm. terms, or on a performance is not indicated for use in combination doubtVOTRIENT as he is of the great generation, same father-daughter world again, re- scale, or on the U.S. News & World ReI dare say it is the best profession for VOTRIENT vs placebo were diarrhea (52% with other agents. Increased toxicity and mortality Drug Interactions: Coadministration withlist strong he did not miss greeting all of us in assuring each other. port ranking of the best vs hospitals in in the world. We knew it coming into 9%), HTN (40% vs 10%), hair color changes have been observed in clinical trials administering CYP3A4 inhibitors (eg, ketoconazole, ritonavir, the group, despite the enormity of the the country. it and still abide by those feelings (depigmentation) (38% vs 3%), nausea (26% vs 9%), and VOTRIENT in combination with lapatinib or with clarithromycin) increases concentrations of pazopanib problem facing his child. A hard-work- A Noble and Selfless Profession The best benefits derived from (22% this vsprinciples. for all(21% thatvswe selfishly anorexia 10%), and So vomiting 8%). pemetrexed. The fatal toxicities observed included should be avoided, if warranted, the in the number took away from this profession, it is This is what and we physicians witnessbut,profession ing man—yes—they did not come in arereduce measured pulmonary hemorrhage, GI hemorrhage, and sudden abnormalities occurring in >10% ofour part to of VOTRIENThuman to 400 mg. Avoidsaved, grapefruit and on Laboratory at work—the any other form. An affectionate and on a regular basisdose of lives the smiles the patients time for each one of us to do A safe and effective combination dose has not patients commonly in patients grapefruit juice.wonder- going home, the thank-you of our lovingdeath. father—they all were. He did and humane aspects notesand of more maintain the(≥5%) viability, glory, and sancbeen established with these regimens. VOTRIENTtity vs placebo included increasesSo in ALT not complain—not many did in his ful profession—and fortunately not all family members, the trust oftaking the patient of our noble profession. for genConcomitant use of strong CYP3A4 inducers (eg, (53% vs 22%), AST (53% vs 19%), glucose (41% vs outcomes are in the same league as padays. Increased He was thankful for all the care in the doctor, the ability to share intierations to come, scores of physicians Toxicity in Developing Organs: The rifampin) should bemedavoidedmate due tomoments the potential topatients 33%), and total bilirubin (36% vs 10%); decreases in tient X. And it is far away from the we were delivering—the honorable with and famican continue to reap the innumerable safety and effectiveness of VOTRIENT in pediatric decrease concentrations of pazopanib. VOTRIENT phosphorus (34% vs 11%), sodium (31% vs 24%), icolegal aspects, the Affordable Care generation. lies, and the shrinking but still present benefits and joy derived from following patients have not been established. VOTRIENT is not should not be used in patients who cannot avoid magnesium 14%),but andstrong glucoseguiding (17% vsprinciple: Act, health Heindicated must have heldin her in hispatients. arms Animal by(26% itsvssimple for use pediatric studiesmaintenance organizations, respect for the profession accorded chronic use of CYP3A4 inducers. 3%); andyou leukopenia (37% vs 6%), concerns whenhave she demonstrated was born, fed her through give “to nurture life. ” n neutropenia pazopanib can severely affect about health-care expendi- some. Not many professions (34% vs 6%), thrombocytopenia (32% vs 5%),no and Disclosure: Dr. Are reported potential tures, pay for performance, Medicare the bottle, put her to sleep, read her the pride of waking up every day to say organ growth and maturation during early postnatal Concomitant treatment with strong inhibitors of lymphocytopenia (31% vs 24%). conflicts of interest. cuts, big-industry influence, health-care tales, development, carried her on his back into this that you will save someone’s life today. and resulted in toxicity to the lungs, P-glycoprotein (PgP) or breast cancer resistance liver, heart, and kidney, and in death. VOTRIENT may

Please see Brief Summary of Prescribing Information, including Boxed WARNING, on adjacent pages. References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GSK; 2015. 2. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Kidney Cancer V.1.2016. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed October 23, 2015. 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. 4. Data on file. Novartis; 2011.

2015 ASH Annual Meeting Watch upcoming issues of The ASCO Post for reports from the ASH Annual Meeting, being held December 5–8, 2015 in Orlando, Florida.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

11/15

VRT-1126150

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)].

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B:14.25”

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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. Patients older than 65 years are at greater risk for hepatotoxicity [see Use in Specific Populations (8.5)]. 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 groups receiving VOTRIENT and placebo, 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 uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (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 postbaseline 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. In a randomized RCC trial of VOTRIENT compared with sunitinib, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared with baseline or a decline in LVEF of ≥10% compared with baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 13% (47/362) of patients on VOTRIENT compared with 11% (42/369) of patients on sunitinib. Congestive heart failure occurred in 0.5% of patients on each arm. 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 (5.11)]. 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 hemorrhage, 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 Interstitial Lung Disease (ILD)/Pneumonitis: ILD/pneumonitis, which can be fatal, has been reported in association with VOTRIENT. In clinical trials, ILD/pneumonitis occurred in 0.1% of patients treated with VOTRIENT. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue VOTRIENT in patients developing ILD or pneumonitis. 5.10 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. 5.11 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)]. 5.12 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. 5.13 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. 5.14 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)]. 5.15 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. 5.16 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. 5.17 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)]. 5.18 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, Interstitial Lung Disease (ILD)/Pneumonitis, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.11, 5.15-5.16)]. 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 Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 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%), palmarplantar 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.

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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 Placebo (N = 290) (N = 145) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 Parameters % % % % % % Hematologic Leukopenia 37 0 0 6 0 0 Neutropenia 34 1 <1 6 0 0 Thrombocytopenia 32 <1 <1 5 0 <1 Lymphocytopenia 31 4 <1 24 1 0 Chemistry ALT increased 53 10 2 22 1 0 AST increased 53 7 <1 19 <1 0 Glucose increased 41 <1 0 33 1 0 Total bilirubin increased 36 3 <1 10 1 <1 Phosphorus decreased 34 4 0 11 0 0 Sodium decreased 31 4 1 24 4 0 Magnesium decreased 26 <1 1 14 0 0 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 singlearm 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. Eye Disorders: Retinal detachment/tear. 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 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 (5.18)]. 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 (preweaning), 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 (5.17)]. 8.5 Geriatric Use: In pooled clinical trials with VOTRIENT, 30% (618/2080) of patients were aged >65 years. Patients aged >65 years had an increase in ALT elevations of >3 X ULN compared to patients aged <65 years (23% versus 18%) [see Warnings and Precautions (5.1)]. 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). Postimplantation 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. • ILD has been reported in association with VOTRIENT. Patients should be advised to report pulmonary signs or symptoms indicative of ILD or pneumonitis. • 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.

Important Safety Information for VOTRIENT® (pazopanib) tablets (cont) Wound Healing: VOTRIENT® (pazopanib) tablets may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein at baseline and periodically as clinically indicated. Interrupt treatment for 24-hour urine protein ≥3 grams, and discontinue for repeat episodes despite dose reductions. Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms, and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT.

B:14.25”

T:13”

S:12.5”

Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, GI hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 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. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early postnatal development, and resulted in toxicity to the lungs, liver, heart, and kidney, and in death. VOTRIENT may

potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their health care 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. 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 patients 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. Drug Interactions: Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and 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 P-glycoprotein (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. Adverse Reactions in the Randomized RCC Trial: A dose interruption was required for 42% of patients on VOTRIENT. The VOTRIENT dose was reduced for 36% of patients. The most common adverse reactions (≥20%) for VOTRIENT vs placebo were diarrhea (52% vs 9%), HTN (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 vs 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%).

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

11/15

VRT-1126150

CHOOSE MORE THAN 6 YEARS

FIRST-LINE EFFICACY SIGNIFICANT IMPROVEMENTS IN PFS1,2

OVERALL (N=435)

9.2 vs MONTHS 4.2 Placebo

MONTHS VOTRIENT

HR=0.46 (95% CI, 0.34-0.62) P<0.0011

FIRST LINE (n=233)

11.1vs MONTHS 2.8 Placebo

MONTHS VOTRIENT

Phase 3, randomized, double-blind, placebocontrolled multicenter trial to evaluate the efficacy and safety of VOTRIENT® (pazopanib) tablets in first-line or cytokine-pretreated patients (N=435) with advanced 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.

HR=0.40 (95% CI, 0.27-0.60) P<0.0011,2

• A median PFS of 7.4 months vs 4.2 months with placebo in cytokine-pretreated patients (HR=0.54 [95% CI, 0.35-0.84], P<0.001)1,2 NATIONAL COMPREHENSIVE CANCER NETWORK® (NCCN®) CATEGORY 1 RECOMMENDATION

ST-LINE CATEGORY 1

NCCN

Pazopanib (VOTRIENT®) has a Category 1 recommendation as a first-line therapy in the NCCN Clinical Practice Guidelines In Oncology (NCCN® Guidelines) for relapsed or stage IV unresectable RCC of predominant clear cell histology. NCCN Guidelines® also include other therapies as first-line treatment options. Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.3

VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma.

Important Safety Information for VOTRIENT® (pazopanib) tablets (cont) Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Patients older than 65 years are at an increased risk. 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 preexisting 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 preexisting cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (eg, calcium, magnesium, potassium) within the normal range should be performed. Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF), has 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. In a randomized RCC trial of VOTRIENT compared with sunitinib, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 13% (47/362) of patients on VOTRIENT compared with 11% (42/369) of patients on sunitinib. CHF occurred in 0.5% of patients on each arm. Monitor blood pressure (BP), and manage promptly using a combination of antihypertensive therapy and dose modification of VOTRIENT

(interruption and reinitiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of CHF. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. Hemorrhagic Events: 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 (GI) hemorrhage in the past 6 months. Arterial 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

SAFETY AND DOSING

SAFETY AND TOLERABILITY PROFILE

• Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, interstitial lung disease/ pneumonitis, 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 • Adverse reactions occurring in ≥10% of patients who received VOTRIENT were diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting, fatigue, asthenia, abdominal pain, and headache

A LOW INCIDENCE OF GRADE 3/4 ADVERSE REACTIONS WITH VOTRIENT1,4: Grade 3/4 (%)

All Grades (%)

Fatigue

Asthenia

Hand-foot syndrome

Stomatitis

Mucositis

ONCE-DAILY ORAL DOSING1 • Available in 200-mg tablets

4 x 200 mg

• Recommended starting dose is 800 mg • Must be taken without food at least 1 hour before or 2 hours after a meal

Not actual size.

• Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability

For additional information on dosing modiﬁcation based on drug interactions, please see next page.

Important Safety Information for VOTRIENT® (pazopanib) tablets (cont) 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 or have a history of these events. Do not use VOTRIENT in patients who have had an arterial thromboembolic event in the past 6 months. Venous Thromboembolic Events (VTEs): 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. Thrombotic Microangiopathy (TMA): 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. GI Perforation and Fistula: In RCC trials, GI perforation or fistula was 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. Interstitial Lung Disease (ILD)/Pneumonitis: ILD/ pneumonitis, which can be fatal, has been reported in 0.1% of patients in the clinical trials treated with VOTRIENT. Monitor patients for ILD/pneumonitis and discontinue VOTRIENT if symptoms of ILD or pneumonitis develop.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. Hypertension (HTN): HTN, including hypertensive crisis, has occurred in clinical trials. HTN 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). BP should be well controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased BP promptly with standard antihypertensive therapy and dose reduction or interruption of VOTRIENT, as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if HTN is severe and persistent despite antihypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of HTN.

Please see additional Important Safety Information on next page. Please see Brief Summary of Prescribing Information, including Boxed WARNING, on adjacent pages.

MAKE VOTRIENT YOUR CHOICE FOR FIRST-LINE ADVANCED RCC Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of VOTRIENT® (pazopanib) tablets in first-line or cytokine-pretreated patients (N=435) with advanced renal cell carcinoma (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.

• Median overall 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 • Median ﬁrst-line PFS of 11.1 months vs 2.8 months with placebo (HR=0.40 [95% CI, 0.27-0.60], P<0.001)1,2 CI, conﬁdence interval; HR, hazard ratio.

Indication

VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Important Safety Information for VOTRIENT® (pazopanib) tablets 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. Please see additional Important Safety Information on subsequent pages. Please see Brief Summary of Prescribing Information, including Boxed WARNING, on adjacent pages.

For more information, visit VOTRIENT.com.