TAP Vol 5 Issue 20 by Harborside Press LLC

3D Mammography in Dense Breasts 16 | Metastatic Pancreatic Cancer

| Pioneers in Oncology: Vincent T. DeVita, Jr, MD

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VOLUME 5, ISSUE 20

DECEMBER 15, 2014

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

Transplants for AML in First Remission: A Great Leap Forward, Sideways, or Backward?

ASH Annual Meeting

PD-1 Blockade Moves Into Hematology By Caroline Helwick

he promise of the programmed death receptor-1 (PD-1) inhibitors seen in solid tumors, especially melanoma, may hold true for at least one hematologic malignancy, according to studies presented at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition. At a press briefing, data from phase I studies were presented for nivolumab1 and pembrolizumab (Keytruda)2 in patients with classical Hodgkin lymphoma who had shown disease progression on prior treatment. Response rates were 87% to single-agent nivolumab and 66% to pembrolizumab. The results provide strong evidence that drugs that enhance the ability of the immune system to fight cancer may work well in hematologic malignancies. Press briefing moderator Catherine M. Bollard, MBChB, MD, bone and marrow transplant specialist at Children’s National Health System and the George Washington University in Washington, DC, commented, “Strategies that target tumor cells using the immune system are extremely exciting. I see this

as a way forward in how we will revolutionize treatments in hematology.”

By Robert Peter Gale, MD, PhD, DSc(hc), FACP, Hillard M. Lazarus, MD, FACP, and Peter H. Wiernik, MD, FACP, FASCO

Nivolumab The findings for nivolu mab were presented by Philippe Armand, MD, PhD, of the Dana-Farber Philippe Armand, MD, PhD Cancer Institute in Boston. They were simultaneously published in The New England Journal of Medicine.3 “Nivolumab could be safely administered to patients with relapsed or refractory classical Hodgkin lymphoma. Treatment resulted in a response rate of 87%, which is quite high for patients who were heavily pretreated,” Dr. Armand said at the press briefing. The phase I study included 23 patients with classical Hodgkin lymphoma, almost all of whom had undergone at least three lines of therapy, including stem continued on page 3

Health-Care Policy

CMS Issues Preliminary Decision to Cover Annual Lung Cancer Screening

ntil about 15 years ago, persons with acute myelogenous leukemia (AML) were considered candidates to receive a blood cell or bone marrow allotransplant in first remission only if they had had an HLA-identical sibling donor. However, advances using alternative donors such as an HLA-matched unrelated person, HLA haplotype–matched relative, or HLA-matched umbilical cord blood cells from an unrelated donor have changed the transplant landscape. Currently more than half of all allotransplants for persons with AML in first remission use a donor other than an HLA-identical sibling. Many see this as a giant leap forward, perhaps akin to Mao’s Cultural Revolution. continued on page 60

Disclaimer: This commentary represents the views of the authors and may not necessarily reflect the views of ASCO.

By Ronald Piana

“All great truths begin as blasphemies.” —George Bernard Shaw (Annajanksa, 1918)

n a long-awaited decision, the Centers for Medicare & Medicaid Services (CMS) has issued a preliminary proposal to cover annual lung cancer screening with low-dose computed tomography for appropriate beneficiaries following counseling and a shared–decision-making visit with a qualified provider. CMS is seeking comments on the proposed decision for a 30-day period and is expected to issue

a final decision in February 2015. Reacting to the CMS announcement, Laurie Fenton Ambrose, President and Chief Executive Officer of Lung Cancer Alliance (LCA), told The ASCO Post, “CMS got it right by acknowledging there is sufficient evidence to add lung cancer screening as a preventive service benefit under the Medicare Program. As a result, we will save tens of thousands of lives as this moves forward. During the comment period CMS got it right by acknowledging we will again reinforce what the American College there is sufficient evidence to add lung of Radiology (ACR), Socicancer screening as a preventive service ety of Thoracic Surgeons benefit under the Medicare Program. As (STS), Lung Cancer Alliance, and ASCO, among a result, we will save tens of thousands others, have put forth for the U.S. Preventive Servicof lives as this moves forward. es Task Force (USPSTF)—Laurie Fenton Ambrose

MORE IN THIS ISSUE Oncology Meetings Coverage Thoracic Oncology Symposium �� 4, 5 Quality Care Symposium �� 11, 14 RSNA 2014 �� 16, 61 Cutaneous Malignancies Congress �� 17, 20 Chemotherapy Foundation Symposium �� 22, 23 ASCO Expert Statement on Cancer Survivorship ��24 Tony S.K. Mok, MD, on Crizotinib in NSCLC ��35 Direct From ASCO �� 54–57

continued on page 52

Next Issue of The ASCO Post Coming January 25, 2015

A Harborside Press® Publication

The ASCO Post | DECEMBER 15, 2014

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

George W. Sledge, MD Indiana University

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

Associate Editors

Alison Freifeld, MD University of Nebraska Medical Center

Jame Abraham, MD Cleveland Clinic

Louis B. Harrison, MD Moffitt Cancer Center

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Joseph S. Bailes, MD Texas Oncology

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

Laurence H. Baker, DO University of Michigan Health System

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

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Hagop M. Kantarjian, MD MD Anderson Cancer Center

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

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Douglas W. Blayney, MD Stanford University Medical Center

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

Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine Harold J. Burstein, MD Dana-Farber Cancer Institute

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center

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

International Editors Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Robert W. Carlson, MD National Comprehensive Cancer Network

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

Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center

Mary S. McCabe, RN, MA Memorial Sloan Kettering Cancer Center

David Khayat, MD Pitie-Salpetriere Hospital, Paris, France

Jay S. Cooper, MD Maimonides Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

John Cox, DO Texas Oncology

James L. Mulshine, MD Rush University Medical Center

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

E. David Crawford, MD University of Colorado

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

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, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. 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 ©2014 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-

Steven T. Rosen, MD City of Hope National Medical Center Lee S. Schwartzberg, MD University of Tennessee Health Science Center Andrew D. Seidman, MD Memorial Sloan Kettering Cancer Center Samuel Silver, MD, PhD University of Michigan Health System

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Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

ASCOPost.com | DECEMBER 15, 2014

PAGE 3

ASH Annual Meeting PD-1 Blockade continued from page 1

cell transplant and brentuximab vedotin (Adcetris); 35% had received at least six. Patients received nivolumab at 3 mg/kg every 2 weeks until tumor progression.

High Response Rates Responses were observed in 87% of patients, including 100% of patients who had not undergone a stem cell transplant and 80% who did have a transplant but had not received brentuximab vedotin. Complete responses

in a thousand or so patients in clinical trials of solid tumors, and the safety profile here mirrors what those studies showed,” Dr. Armand said. “Interestingly, there was no apparent increase in lung toxicity, which we worry about because many patients had other treatments that can cause lung injury.” The efficacy of nivolumab in this study prompted the U.S. Food and Drug Administration to designate the drug a “breakthrough therapy” for relapsed Hodgkin lymphoma, and a larger multinational phase II trial is underway.

Strategies that target tumor cells using the immune system are extremely exciting. I see this as a way forward in how we will revolutionize treatments in hematology. —Catherine M. Bollard, MBChB, MD

were observed in 17% overall, but in 60% of brentuximab vedotin–naive patients. The stable disease rate was 13%. At 24 weeks, 86% of patients were progression-free. At the time of the data-lock, 48% of responses were ongoing, and 43% of patients were still on treatment. “We have patients in remission now for more than 1 year,” Dr. Armand said. Grade 3 drug-related adverse events were observed in 22% of patients; there were no grade 4 events. Two patients (9%) discontinued treatment due to adverse events. “Overall, nivolumab has been used

The drug may be effective in these patients because they harbor genetic abnormalities in chromosome 9p24, which leads to overexpression of PD-1 ligands. Correlative studies showed that all the tumors in this study had this genetic profile. “Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade,” Dr. Armand concluded.

Pembrolizumab The results of the KEYNOTE-013 study of pembrolizumab in patients who progressed after brentuximab vedotin treatment were presented by

What’s Next?

Craig H. Moskowitz, MD

Craig H. Moskowitz, MD, of Memorial Sloan Kettering Cancer Center, New York. The study evaluated 29 patients who received pembrolizumab 10 mg/kg every 2 weeks. More than half the patients had received at least five prior lines of treatment; all had received brentuximab vedotin, and two-thirds had undergone stem cell transplant. Responses (all partial responses) were observed in 66% patients, including 75% who had received a transplant and 44% who did not. The median duration of response was not reached. “The waterfall plot was really quite good,” Dr. Moskowitz observed. “Almost all patients had some evidence of tumor shrinkage.” Importantly, the clinical benefit rate (including stable disease) was 86%, he noted, indicating that this is an important outcome. “Many patients had stable disease on pembrolizumab. In fact, some who have been on treatment the longest had stable disease [ie, not an objective response],” he added. Grade 3 or higher treatment-related adverse events were rare and included axillary pain, hypoxia, joint swelling, and pneumonitis in one patient each. There were no grade 4 events or treatment-related deaths.

When asked what will come next for these agents in Hodgkin lymphoma, Dr. Moskowitz commented, “They have high single-agent activity, but we would like to see how they play in the sandbox with our standard therapies.” The investigators agreed that the drugs are very similar, and the differences in response rates are more likely due to the biologic heterogeneity of the patients rather than differences in the drugs’ efficacy. “My gut feeling is that at the end of the day, response rates will be similar, though toxicity profiles may be slightly dissimilar,” Dr. Moskowitz said. n

Disclosure: Dr. Bollard reported honoraria from Cellmedica. Dr. Armand reported consultancy with Merck, research funding from Merck and Bristol-Myers Squibb. Dr. Moskowitz reported research funding from Merck. For full disclosures of the study authors, view the study abstracts at www.hematology.org.

References 1. Armand P, Ansell SM, Lesokhin AM, et al: Nivolumab in patients with relapsed or refractory hodgkin lymphoma: Preliminary safety, efficacy and biomarker results of a phase I study. ASH Annual Meeting. Abstract 289. Presented December 8, 2014. 2. Moskowitz CH, Ribrag V, Michot JM, et al: PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: Preliminary results from a phase 1b study (KEYNOTE-013). ASH Annual Meeting. Abstract 290. Presented December 8, 2014. 3. Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. December 6, 2014 (early release online).

More From the ASH Meeting See next month’s issue of The ASCO Post for comprehensive coverage of the 56th Annual Meeting of the American Society of Hematology, San Francisco. Including news on the following important data: ■■ Abstract 79, by Stewart KA, et al: Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and Dexamethasone in Patients With Relapsed Multiple Myeloma: Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter Phase III Study ■■ Abstract 673, by Moskowitz CH, et al: The Aethera Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase III Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma ■■ Abstract 379, by Goekbuget K, et al: A Confirmatory, Single-Arm, Phase II Study of Blinatumomab, a Bispecific T-Cell Engager (BiTE®) Antibody Construct, in Patients with Minimal Residual Disease B-Precursor Acute Lymphoblastic Leukemia Plus, don’t miss The ASCO Post Newsreels, with video and interviews from experts recorded live during the ASH Annual Meeting. Visit video.ascopost.com.

The ASCO Post | DECEMBER 15, 2014

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Chicago Multidisciplinary Symposium in Thoracic Oncology Targeted Therapies

Lung Cancer Expert Offers Recommendations for Treating Toxicities Associated With Targeted Therapies By Charlotte Bath

“C

learly, life as a thoracic oncologist has changed. Our paradigm for giving one-size-fits-all chemotherapy seems a bit dated, as we now are learning that there are multiple targets that we can treat effectively with the right drugs,” Jyoti D. Patel, MD, Associate Professor of Medicine at Northwestern University Feinberg School of Medicine in Chicago, related to participants at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology.1 The most common mutations in non–small cell lung cancer (NSCLC) are epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. “We have high-level evidence across multiple phase III trials to suggest that we improve response rate and progression-free survival and quality of life for these patients by treating them with targeted therapy, as opposed to even what we think of as very tolerable systemic therapy,” Dr. Patel noted. EGFR tyrosine kinase inhibitors “are active as first-, second-, and thirdgeneration drugs. We’ve heard a lot about the excitement of these thirdgeneration tyrosine kinase inhibitor small molecules that will be coming to a clinic near you very soon,” Dr. Patel said. About 4% to 5% of lung cancers are driven by ALK, she added, and with targeted therapies, “we see dramatic responses for these patients.”

In for the Long Haul “Patients are so motivated to take these drugs that hold so much promise” but need to know how to deal with toxicities and “that they may not be able to continue drugs if they ‘blow off ’ these toxicities,” Dr. Patel said. “In many cases, patients will be taking targeted therapies “for the long haul,” she added. “In general, treatment has to be tolerable for these patients every day for months, and we hope for a year or longer, as we’ve seen from some of these next-generation trials.” Toxicities do not always correlate with laboratory findings and can be

subjective. “Management of these toxicities requires a team approach across multiple disciplines,” which could include dermatology, endocrinology, ophthalmology, and cardiology, Dr. Patel said.

Toxicities Linked to EGFR Inhibitors The EGFR inhibitors include the oral agents erlotinib (Tarceva) and afatinib (Gilotrif) and infusional ce-

the anti-inflammatory effect as for the bactericidal effect,” she said. “All of the drugs cause gastrointestinal upset,” Dr. Patel said. This might require some scheduling adjustment, so patients could take erlotinib on an empty stomach and antibiotics with food. For patients with severe reactions, “we recommend holding the drug until some resolution, at least for a couple of days. Often we will give these patients

Management of these toxicities requires a team approach across multiple disciplines, which could include dermatology, endocrinology, ophthalmology, and cardiology. —Jyoti D. Patel, MD

tuximab (Erbitux). “With these drugs, rash and diarrhea are the mostly commonly noted adverse events,” Dr. Patel stated. The rash is constantly monitored to grade it as mild (barely symptomatic, perhaps some dryness on the face), moderate (requires intervention), or severe (whole-body inflammation, interferes with daily living, impacts treatment adherence). Dr. Patel encouraged clinicians to be “proactive” and teach patients about how to deal with the rash. Patients can be advised to use a humidifier at home and to apply creams. Although randomized controlled trials have not demonstrated the efficacy of sunscreens, Dr. Patel noted, “we suggest that patients use at least some sunscreen, because certainly in sunexposed areas, the rash seems to be a little bit more extreme, and anecdotally patients who have had sun exposure can have a significant rash problem.” For mild rash, Dr. Patel suggests topical hydrocortisone (1%). “Usually, we have them come back for a toxicity appointment and at that juncture, if it has increased, we generally add oral antibiotics. We tend to use doxycycline and minocycline, as much for

a methylprednisolone dose pack,” Dr. Patel added. Systemic steroids should be reserved for patients with severe reactions and 70% or more skin involvement. For skin cracks and fissures, common in winter, patients should be advised to limit the use of hot water on their skin. “Bleach soaks can prevent infection” and can be used twice a day, Dr. Patel said. “Zinc creams can be helpful, and for difficult fissures that are very painful, we have found Krazy Glue to be helpful and nontoxic, and patients can do it at home.”

Toxicities Linked to ALK Inhibitors Overall, crizotinib (Xalkori) “is very well tolerated, with few incidences of grade 3 and 4 toxicity,” Dr. Patel said. However, patients do need to be monitored for liver function abnormalities and pneumonitis. “Nausea and vomiting, if they are going to occur, tend to occur early in the course of treatment,” Dr. Patel said. “A small number of patients can have significant peripheral edema, particularly of the legs, without other signs of volume overload, but that doesn’t hap-

pen until 3 or 4 months into treatment, when patients have already sustained dramatic responses from these drugs.” Crizotinib can also induce hypogonadism within days of initiation of therapy. Testosterone levels should be monitored, Dr. Patel advised. Topical testosterone replacement is feasible, she added. Bradycardia (< 50 beats per minute) occurs in about 11% of patients treated with crizotinib. Doses of this agent can be withheld until the heart rate returns to ≥ 60 beats per minute. Visual effects occur in most patients, generally are self-limiting, and require no intervention. “But it is good to give patients a heads-up about it, particularly because many times these are young patients who have been on the Internet and are worried about having brain metastases,” Dr. Patel said. Most commonly, patients report visual persistence, seeing a trailer when accommodating from light to dark or haloes around images. Ceritinib (Zykadia) “has shown remarkable effects in people who have disease progression on crizotinib, but it is a tough drug to give,” Dr. Patel said. “In studies, up to 60% of people needed dose reduction,” Dr. Patel reported. The effects are primarily gastrointestional—nausea, vomiting, and diarrhea. “A fair number of people have had to discontinue the drug completely because of the adverse events,” she noted. “When you start this drug, you need to see patients every week for their liver function tests,” Dr. Patel stressed. Many of my patients are on 450 mg a day. We start at 750 mg with plans to dose reduce early. It’s important to be proactive, manage symptoms, and dose reduce early if we want patients to benefit from this drug.” n

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

Reference 1. Patel JD: Tips for treating toxicities from targeted therapies. 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. Presented October 31, 2014.

ASCOPost.com | DECEMBER 15, 2014

PAGE 5

Chicago Multidisciplinary Symposium in Thoracic Oncology Revisiting Successes in Advanced NSCLC to Test Value in Earlier-Stage Disease By Charlotte Bath

“S

ome pretty good evidence suggests that chemotherapy that works in advanced disease probably works even better in early-stage disease,” said Fadlo R. Khuri, MD, Chair, Department of Hematology and Medical Oncology at Winship Cancer Insti-

of Canada Clinical Trials Group and the National Cancer Institute of the U.S. Intergroup JBR.10 trial,2 overall and relapse-free survival were significantly prolonged among patients with completely resected stage IB or II NSCLC who were randomly assigned Karen Kelly, MD

Some pretty good evidence suggests that chemotherapy that works in advanced disease probably works even better in early-stage disease.” —Fadlo R. Khuri, MD

tute in Atlanta, in summarizing results from trials of patients with early-stage non–small cell lung cancer (NSCLC). Dr. Khuri presented the evidence and prospects for progress with targeted therapies at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. The need for effective adjuvant treatment is great and growing. More than 50% of patients with resectable tumors (except stage IA) experience recurrent disease despite optimal surgery, Dr. Khuri reported. “Recurrence of disease is attributed to the presence of micrometastatic disease at diagnosis,” he noted, underlining the “clear need to eradicate micrometastasis in addition to surgery.” Low-dose computed tomography screening for lung cancer, he added, “will lead to more patients who are diagnosed with earlystage disease.”

‘Salient Progress’ Low-dose computed tomography screening “will be implemented in the setting of some very salient progress in recent years,” Dr. Khuri said. “We know now that adjuvant chemotherapy improves survival in early-stage lung cancer,” he added, citing several studies. The International Adjuvant Lung Cancer Trial1 found that following complete resection, patients diagnosed with stage I to III who were randomly assigned to cisplatin-based chemotherapy had significantly higher 5-year survival and disease-free survival than those randomized to observation. Similarly, in the National Cancer Institute

to vinorelbine plus cisplatin vs observation. Analysis of the Lung Adjuvant Cisplatin Evaluation (LACE)3 data “definitively shows that if you look at the body of the data in their totality, adjuvant chemotherapy does save lives in this setting,” Dr. Khuri stated.

Be Wary of Extrapolation Dr. Khuri cautioned against directly extrapolating data from studies with advanced disease for use in patients with early-stage disease. “One such extrapolation that I see a little too frequently in the community setting,” he said, involves taking data from [Eastern Cooperative Oncology Group (ECOG)] 4599,4 which showed that adding bevacizumab (Avastin) to chemotherapy with paclitaxel and carboplatin improved median survival to 12.3 months vs 10.3 months for chemotherapy alone. Patients in that study, however, had recurrent or advanced NSCLC (stage IIIB or IV). “I would respectfully say that we should probably wait for the results from ECOG 1505,” he said, “before we jump to treat everyone with bevacizumab, which is costly and potent but not lacking in toxicities.” ECOG 1505 is comparing four cycles of chemotherapy with cisplatin and either pemetrexed (Alimta), docetaxel, vinorelbine, or gemcitabine to one of those four chemotherapy regimens plus bevacizumab for 1 year. Patients have resected stage IB to IIIA NSCLC, with no prior chemotherapy and no planned radiotherapy. Accrual was completed in September 2013.

Targeting Genomic Drivers “We probably have more identifiable, validated driver mutations in lung cancer than in most other diseases,” Dr. Khuri noted. Trials with erlotinib have shown improvement in diseasefree survival among NSCLC patients with epidermal growth factor receptor (EGFR) mutations. Secondary analysis of the RADIANT study5 presented at the 2014 ASCO Annual Meeting by Karen Kelly, MD, Professor of Medicine and Associate Director for Clinical Research at the University of California Davis Comprehensive Cancer Center (and Chair of the Thoracic Oncology Symposium),

ated with 4% to 5% of NSCLC cancers. “We have seen some very striking data on the ALK fusion gene,” Dr. Khuri noted, and the ALK inhibitor crizotinib (Xalkori) has been approved by the U.S. Food and Drug Administration for patients with ALK-positive locally advanced or metastatic NSCLC. “The question is,” Dr. Khuri said, “Can we translate [these findings] from latestage disease to early-stage disease?”

ALCHEMIST Study Support Dr. Khuri urged support of LCHEMIST (Adjuvant Lung CanA cer Enrichment Marker Identification and Sequencing Trials). “This is a very important study in that it will randomize patients based on their mutations. Rather than treat patients willy-nilly with EGFR mutations, ALK translocations, and vascular tumors, with crizotinib, gefitinib (Iressa), erlotinib, or bevacizumab, I think it is very important to push for this study. This is a study that has a very strong chance of demonstrating definitively the role of selected tar-

We are all well aware of the disappointing results from targeted therapies to date in studies unselected for mutation status…. It is clearly time to revisit our major success with stage IV disease if driver mutations or other biologic rationale are present. —Kathy S. Albain, MD

found that patients with stage IB to IIIA NSCLC and EGFR mutations who were randomly assigned to erlotinib had about an 18-month improvement in diseasefree survival vs those receiving placebo. In the phase II SELECT study,6 also presented at this year’s ASCO Annual Meeting, 2-year disease-free survival among patients with stage I to III NSCLC was 89% among patients with EGFR mutations receiving erlotinib, including 96% among those with stage I disease. Among the questions that need to be considered, Dr. Khuri noted, is: What is the meaning of improved disease-free survival in the absence of overall survival in the adjuvant setting? Translocations in the anaplastic lymphoma kinase (ALK) gene are associ-

geted therapy,” Dr. Khuri stated. ALCHEMIST is testing the following hypothesis: “Treatment based on genotype will significantly improve cure rates in patients with earlier-stage (IB–IIIA) nonsquamous tumors that have been completely resected.” “We are all well aware of the disappointing results from targeted therapies to date in studies unselected for mutation status,” explained Kathy S. Albain, MD, Professor of Medicine and Dean’s Scholar, Loyola University Chicago Stritch School of Medicine, and Director of the Breast and Thoracic Oncology Programs at Cardinal Bernardin Cancer Center. “It is clearly time to translate our major success with continued on page 8

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

An Effective Combination to Extend PFS*

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

Indications

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

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

1.0

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

0.9 0.8

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

0.7

22.4

0.6

13.1

0.4

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

Months

0.3 0.2 0.1 0.0 0

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

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

Months

0.5

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

Time of Progression-free Survival (Months) 148

125

104

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

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

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

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

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

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

The ASCO Post | DECEMBER 15, 2014

PAGE 8

Chicago Multidisciplinary Symposium in Thoracic Oncology Early-Stage NSCLC

Series of Integrated Trials

continued from page 5

ALCHEMIST is actually a series of integrated trials, with a screening trial to identify genetic mutations in patients with early-stage NSCLC and, at the start, two treatment trials. “Patients can be screened either pre- or postoperatively; if after surgery, there need to be negative margins with a complete resection,

stage IV disease, if a driver mutation or other biologic rationale is present, into earlier-stage presentations,” she said in an overview of ALCHEMIST and targeted therapies in early-stage NSCLC provided at the symposium as a steering committee member.

BRIEF SUMMARY ARZERRA® (ofatumumab) Injection, for intravenous infusion The following is a brief summary only; see full prescribing information, including Boxed Warning, for complete product information. WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA®, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)]. • Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.1 Previously Untreated Chronic Lymphocytic Leukemia ARZERRA (ofatumumab) is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate [see Clinical Studies (14.1) of full prescribing information]. 1.2 Refractory CLL ARZERRA is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab [see Clinical Studies (14.2) of full prescribing information]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment [see Adverse Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing information]. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3) of full prescribing information]. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment. 5.2 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately

standard nodal sampling, and adjuvant therapy given as per physician choice,” Dr. Albain said. Among the challenges is the “potential adverse interaction of prior adjuvant chemotherapy and/or radiotherapy with targeted therapy,” Dr. Albain said. “Fortunately, the trials will be large enough in ALCHEMIST to study outcomes of those with prior therapy vs

those who go on the trial without any prior adjuvant systemic therapy.” Tissue from resected NSCLC tumors will be tested for EGFR gene mutations and ALK gene rearrangement. Patients with ALK rearrangement will be randomly assigned to crizotinib at 250 mg twice daily or placebo for 2 years. Patients with EGFR mutations will be randomly

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

(cont’d)

ASCOPost.com | DECEMBER 15, 2014

PAGE 9

Chicago Multidisciplinary Symposium in Thoracic Oncology assigned to erlotinib at 150 mg daily or placebo for 2 years. Overall survival is the primary endpoint for both trials. Investigators plan to screen 6,000 to 8,000 patients over 5 or 6 years to identify 378 for the ALK-based trial and 430 for the EGFR-based trial. The drugs are being supplied by pharmaceutical company partners—Pfizer for the crizotinib trial

and Astellas for the erlotinib trial. A third ALCHEMIST trial being proposed would involve an immune checkpoint inhibitor of the programmed cell death 1 (PD-1) receptor.

Impact of Early Discontinuation Potential early discontinuation of the

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

Chlorambucil (N = 227)

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

Infusion reactionsa

Neutropenia

Asthenia

Headache

Lower respiratory tract infection

Arthralgia

Adverse Reactions

Leukopenia Herpes simplex

Upper abdominal pain

oral agents being tested in A LCHEMIST “will be a challenge to overcome to optimize efficacy,” Dr. Albain said in an interview with The ASCO Post. “In the RADIANT adjuvant trial, for example, only half the patients were able to [complete their erlotinib therapy].” (Updated data presented at the meeting showed that 47% of the patients received the

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

Total Population (N = 154) Adverse Reaction Pneumoniaa

Fludarabine- and Alemtuzumabrefractory (N = 59)

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

Pyrexia

Cough

Diarrhea

Anemia

Fatigue

Dyspnea

Rashb

Bronchitis

Nausea

Upper respiratory tract infection

Edema peripheral

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

Leukopenia

continued on page 10

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

ARZERRA Plus Chlorambucil (N = 217)

prescribed duration of therapy.) “These agents have toxicity, and you need to have a team behind you supporting these patients,” she noted. ALCHEMIST has provisions for dose reductions built in, “as well as the supportive measures for rash and some of the other toxicities,” she said. In ad-

Chlorambucil (N = 227)

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

Neutropenia

Lymphopenia

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

Back pain

Chills

Nasopharyngitis

Sepsisc

Urticaria

Insomnia

Headache

Herpes zoster

Hyperhidrosis

Hypertension

Hypotension

Muscle spasms

Sinusitis

Tachycardia

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

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

The ASCO Post | DECEMBER 15, 2014

PAGE 10

Chicago Multidisciplinary Symposium in Thoracic Oncology Early-Stage NSCLC continued from page 9

dition, “patients will be recovering from thoracotomies” and the deconditioning to the body that entails will require careful attention to toxicity management and adherence to daily dosing, Dr. Albain pointed out. “The duration of treatment pro-

posed in ALCHEMIST is somewhat empiric, just as it has been in in the majority of trials of adjuvant oral therapy across tumor types. So, I would say that we should consider very early on addressing duration of these agents as a research question in parallel with the efficacy studies,” Dr. Albain said. “We have learned this lesson with

There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ARZERRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infusion-related Cardiac Events: Cardiac arrest. Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda. 7 DRUG INTERACTIONS Coadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or wellcontrolled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older. Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see Adverse Reactions (6.1)]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients [see Clinical Studies (14.1) of full prescribing information]. In refractory CLL, clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted. 10 OVERDOSAGE No data are available regarding overdosage with ARZERRA. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

tamoxifen duration in breast cancer, but it took decades to learn that longer durations than originally thought to be adequate provide better survival,” she added.

Up and Running “The genomic research component of ALCHEMIST addresses all patients, not just those who have the particular

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

driver mutations of interest at the start,” Dr. Albain said. All patients will be followed for up to 5 years. “So this then establishes a rich resource for future research endeavors with detailed genomic characterization, clinical annotation, as well as epidemiologic and long-term outcomes data.” ALCHEMIST was “just launched in the fall,” Dr. Albain noted. “There are sites that are up and running, but it is extremely early.” ALCHEMIST is open to all sites that participate in the NCI National Clinical Trials Network (NCTN) or NCI Community Oncology Research Program (NCORP). For more information on enrollment, visit www.ctsu.org or www.cancer.gov. n Disclosure: Drs. Khuri, Kelly, and Albain reported no potential conflicts of interest.

References 1. Arriagada R, et al: N Engl J Med 350:351-360, 2004. 2. Winton T, et al: N Engl J Med 352:2589-2597, 2005. 3. Pignon JP, et al: J Clin Oncol 26:35523559, 2008. 4. Sandler A, et al: N Engl J Med 355:2542-2550, 2006. 5. Kelly K, et al: 2014 ASCO Annual Meeting. Abstract 7501. Presented June 2, 2014. 6. Pennell NA, et al: SELECT. 2014 ASCO Annual Meeting. Abstract 7514. Presented June 1, 2014.

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.

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ASCOPost.com | DECEMBER 15, 2014

PAGE 11

Quality Care Symposium End-of-Life Care

Private Payer and Academic Center Data Capture Inappropriate Use of End-of-Life Care By Alice Goodman

ata sharing between a comprehensive cancer center and a private insurer appears to be a novel way to capture practice patterns that can point to potential quality improvements. A study that combined data from Dana-Farber Cancer Institute and Blue Cross Blue Shield of Massachusetts showed that some cancer patients received intensive end-of-life

centers. Our goal was to characterize the patterns of care at the end of life and thus identify strategies to improve that care,” Dr. Stuver told listeners at the 2014 ASCO Quality Care Symposium. End-of-life National Quality Forum measures considered quality indicators were assessed in these patients. Results showed that 59.6% had any hospitalization and 47.8% had any

Data are lacking on younger patients as well as on patients who receive part of their care outside of primary cancer centers. Our goal was to characterize the patterns of care at the end of life and thus identify strategies to improve that care. —Sherri Oliver Stuver, ScD

care, including hospitalizations, chemotherapy, and radiation given within weeks of death.1 Moreover, the study revealed that a sizable proportion of Dana-Farber patients received care outside of Dana-Farber, including emergency department visits, hospitalizations, and radiation therapy.

Characterizing the Patterns of Care The database included 742 patients being actively treated at Dana-Farber and with Blue Cross Blue Shield of Massachusetts as their primary insurer. The list of patients was sent to Blue Cross Blue Shield of Massachusetts, and the insurer provided available claims data for the last 6 months of life for 674 of these patients (90.8%). The median age at death was 59 years, and deaths occurred evenly in both genders. Lead author of the presentation, Sherri Oliver Stuver, ScD, of the Dana-Farber Cancer Institute in Boston, noted that these patients were younger than those typically included in Medicare claims, which have mainly been used to study end-of-life measures in cancer patients in the United States. “Data are lacking on younger patients as well as on patients who receive part of their care outside of primary cancer

emergency department visit within the last 30 days. Ten percent received chemotherapy in their final 14 days of life. Almost 60% received hospice care, and among those patients, 19% were treated at hospice up to 3 days before death. Intensive care unit admissions were re-

Data Sharing on End-of-Life Care ■■ These data provide a window on patients who are typically younger than those captured by Medicare claims data. ■■ A sizable proportion of patients received end-of-life care outside the cancer center where they were diagnosed, which would not have been evident without data from the private payer.

ported in 15.4%. Death occurred in an acute care facility in 28.6% and in the intensive care unit in 10%. “These data are fairly consistent with Medicare claims data for cancer patients. Death in the intensive care unit is certainly not an ideal occurrence,” she noted. Other measures showed that 30.6% of patients had a red blood cell transfusion in the last 30 days of life, 8.5% had radiation therapy in the last 30 days of life, and 15.9% had surgery in the last 30 days of life. When the investigators looked at location of care, they found that between 30% and 45% of patients received their care at facilities outside Dana-Farber or its affiliates. For example, 46% of all emergency department visits, 47% of all radiation therapy, and 30% of all hospitalizations took place outside

Dana-Farber. Putting together data like these is challenging, she continued. “These findings about care received outside of Dana-Farber highlight the benefit of merging data from cancer centers with private payers,” she emphasized. “Going forward, it would seem that data sharing among cancer centers and payers would be a unique method for describing patterns of care,” Dr. Stuver stated. n

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

Reference 1. Stuver SO, Fraile B, Donohue CC, et al: Novel data sharing between a comprehensive cancer center and a private payer to better understand care at the end of life. 2014 ASCO Quality Care Symposium. Abstract 1. Presented October 17, 2014.

EXPERT POINT OF VIEW

ormal discussant of this abstract, Deborah Schrag, MD, MPH, Dana-Farber Cancer Institute, praised this effort.

ment at the end of life. Interventions to curb overuse of intensive care have the potential to provide better care, improved patient experience, and less

Patients and their families do not want to be in the hospital or emergency department at the end of life. —Deborah Schrag, MD, MPH

“Dr. Stuver’s abstract provides ample evidence of overuse of intensive care at the end of life. Patients and their families do not want to be in the hospital or emergency depart-

expense, all at the same time. If we can identify patients at risk and specific aspects of overuse, hopefully we can direct strategic interventions that will have impact.”

Dr. Stuver and colleagues used quality metrics developed by the National Quality Forum to evaluate the quality of care received by patients with commercial health insurance. “Now that [use] of intensified end-of-life care is an identified problem, it is time to develop and test interventions,” she said. There is a broad range of potential interventions including benchmarking and peer feedback, detailing and proactive case management of high-risk patients, remote monitoring systems that leverage technology, clinical decision support embedded in electronic medical records, early involvement of palliative care, systematic case review and team support, and conversations about culture change. n Disclosure: Dr. Schrag reported no potential conflicts of interest.

In the research of advanced cancers

Inhibiting checkpoint help the immune

CTLA-4 and PD-1 are distinct immune checkpoint pathways that both play a role in T-cell modulation. CTLA-4 and PD-1 exist naturally and are up-regulated in activated T cells to mediate T-cell responses and prevent T cells from attacking healthy tissues.1,3 CTLA-4 checkpoint pathway Inactive T cells

Antigenpresenting cell

Decreased T-cell proliferation, migration, and ability to attack the tumor1,4,5

Antigen

Active T cells

Antigenpresenting cell

Antigen

PD-1 checkpoint pathway

Inhibition of T-cell activity and suppression of T-cell attack directly at the tumor1,3,4,6

Tumor

Inactive T cells

pathways may 1,2 system to fight cancer One way that many cancers evade the body’s protective immune response to tumors is by exploiting immune checkpoint pathways1,3 CTLA-4 checkpoint pathway

Inactive T cell PD-1 PD-1 receptor receptor

CD28 Antigen- MHC presenting cell CD80/ CD86

TCR

PD-1 checkpoint pathway

Inactive T cell

CTLA-4

PD-L2 ligand

PD-L1 ligand Tumor cell

Tumors can exploit the CTLA-4 checkpoint pathway in order to decrease T-cell proliferation, migration, and ability to attack the tumor.1,4,5 • Both CD80 (B7-1) and CD86 (B7-2) on APCs can bind to the CTLA-4 receptor on T cells, inhibiting T-cell activation1,5

Tumors can exploit the PD-1 checkpoint pathway to inactivate T cells directly at the tumor site.1,3 • Both PD-L1 and PD-L2 ligands expressed on the tumor cells of some cancers can bind to PD-1 receptors on activated T cells, inhibiting T-cell activity and suppressing T-cell attack3,4,6-8

Bristol-Myers Squibb is committed to furthering research in immuno-oncology and ways to restore the body’s normal immune response to cancer through the inhibition of immune checkpoint pathways, including CTLA-4 and PD-1.1,7,9 Learn more about checkpoint pathways at: www.immunooncologyhcp.com/pathways APC=antigen-presenting cell; PD-1=programmed death-1; PD-L1=programmed death ligand 1; PD-L2=programmed death ligand 2. References: 1. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366(26):2517-2519. 2. Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275-4280. 3. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 4. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. 5. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 6. Azuma T, Yao S, Zhu G, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111(7):3635-3643. 7. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 8. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. 9. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99(19):12293-12297.

The ASCO Post | DECEMBER 15, 2014

PAGE 14

Quality Care Symposium Patient-Reported Outcomes

Study Reveals Gaps in Symptom Management By Alice Goodman

he Patient-Reported Outcomes Symptoms and Side-Effects Study demonstrated that many cancer patients treated in community cancer centers are not discussing their common symptoms like pain, fatigue, and emotional distress with their oncologists/ health-care team or receiving advice about how to manage them. These patient-reported outcomes data were used to create customized symptom management quality improvement reports for participating cancer centers who used them to improve symptom care.1 “Symptoms are an important aspect of patient-centered care. Symptoms

tom management,” stated lead author Tenbroeck Smith, MA, Director of Patient-Reported Outcomes Research at the American Cancer Society, Atlanta.

Patient Perspective At the 2014 ASCO Quality Care Symposium, Mr. Smith described the first patient-reported outcomes study to use the Commission on Cancer’s Rapid Quality Reporting System to identify patients and manage study data flow. The Rapid Quality Reporting System provides a method for sampling cancer patients during treatment that is consistent across centers and replicable over

Symptoms are an important aspect of patient-centered care. Symptoms act as a conduit between cancer treatment and quality of life. —Tenbroeck Smith, MA

act as a conduit between cancer treatment and quality of life. We found that 20% to 45% of patients did not recall getting advice or adequate help for their symptom management from the health-care team. Our findings provide the patient’s perspective, which is very important and not found in medical records. This study reveals a clear need for discussions and advice about symp-

time while placing minimum burden on cancer center staff. This unique combination of characteristics makes The Rapid Quality Reporting System an excellent platform for conducting patient-reported outcomes-based quality improvement studies on a larger, potentially national, scale. Patient-reported outcomes are an excellent way to gather information on symptom burden and

Study Findings on Patient-Reported Outcomes ■■ A study based on patient-reported outcomes shows that common symptoms were often not adequately addressed at 17 community cancer centers. ■■ Many patients bothered by pain, fatigue, and emotional distress did not receive advice from the health-care team. ■■ The instrument used to evaluate patient-reported outcomes was successfully implemented and well received at participating centers. Additionally, the data led to improvement in symptom management, the centers reported.

patients’ perceptions/experiences of care, which can inform the delivery of high-quality, patient-centered care. The Patient-Reported Outcomes Symptoms and Side-Effects Study provided each institution with actionable quality data on symptom management to improve patient care, he noted. This study included patients with locoregional breast and colon cancers 4 to 12 months out from diagnosis from 17 community cancer centers. A total of 2,487 patients completed the questionnaires (a response rate of 61%). A total of 77% of patients (range at all cancer centers, 63%–89%) said they discussed pain with their clinicians over the past 6 months, and 70% said they received advice on pain management (range, 62%–89%). For fatigue, 78% said they talked about it with a clinician over the past 6 months (range, 60%–94%), but only 61% received advice on managing it. Rates of discussion and advice were lowest for emotional distress; 59% reported discussing it within the past 6 months (range,

50%–87%), and 55% said they were given professional advice about it (45%–77%). The analysis looked at the percentage of patients bothered by these symptoms over the past 6 months: 61% for pain, 74% for fatigue, and 46% for emotional distress. When patients who were bothered by these symptoms were asked whether they were definitely getting help, positive responses were as follows: pain, 58%; fatigue, 40%; emotional distress, 46%. “Our results suggest there is lots of room for improvement,” Mr. Smith noted. n

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

Reference 1. Smith T, Castro K, Troeschel A, et al: Developing symptom management quality improvement reports with data from a registry-based patient-reported outcomes collection method. 2014 ASCO Quality Care Symposium. Abstract 180. Presented October 17, 2014.

EXPERT POINT OF VIEW

ormal discussant of the patient-reported outcomes study by Smith et al presented at the Quality Care Symposium in Boston, Ethan Basch, MD, Director of the Cancer Outcomes Research Program at the University of North Carolina School of Medicine in Chapel Hill, praised the research for its important finding and message, but also said that it raised some questions. “Quality programs have traditionally measured patients’ self-reported perceptions of care delivery rather than their self-reported symptoms. Previously, collection of patient-reported symptoms has largely been restricted to clinical trials. There are a few examples of quality programs that use these types of measures, but this new research suggests we should

be doing this more often,” Dr. Basch said. “Cancer patients are often symptomatic and their functioning is affected by the disease and its treatments. How do we assess this in the measurement of quality of care? Where? How often? And how do we minimize missing data? These are some of the important questions raised by this study,” he said.

Results of this survey of 17 cancer centers were striking. When patients were asked whether they got the help they wanted, 42% to 60% said they did not, showing that this represents an unmet need. —Ethan Basch, MD

‘Striking’ Results “Results of this survey of 17 cancer centers were striking. When patients were asked whether they got the help they wanted, 42% to 60% said they did not, showing that this represents an unmet need,” Dr. Basch continued. The study had several strengths, and results underline the importance of

symptom management and show that patient-reported outcomes can provide valuable data for future interventions. “One of the challenges of this research is that it is unclear whether symptom management was attempted and not perceived by the patient,” he emphasized.

“The instrument may be particularly susceptive to patient-level variables. The study raises the question about whether an action was taken or whether patients perceived it was taken,” Dr. Basch said. n Disclosure: Dr. Basch reported no potential conflicts of interest.

ASCOPost.com | DECEMBER 15, 2014

PAGE 15

Announcements

Breast Cancer Research Foundation Commits Record $58.6 Million in Research Grants

he Breast Cancer Research Foundation (BCRF) announced its dedication of $58.6 million to breast cancer research at its annual Symposium & Awards Luncheon. Totaling $47 million, the 2014–2015 annual grants, awarded to more than 220 physicians and scientists on six continents, continue to fuel BCRF’s mission of advancing the world’s most innovative research. In addition, $11.6 million has been committed to the international Founder’s Fund project focused on metastasis.

Funding the ‘Game-Changers’ “At BCRF, we fund the game-changers,” President of BCRF Myra Biblowit said. “Thanks to the generosity of our donors and corporate communities, we are able to support over 220 women and men through our grants that will make a real difference and accelerate advances in the battle against breast cancer.” Every year, BCRF brings together its international roster of grantees at its Symposium & Awards Luncheon in an effort to encourage collaboration and move the field forward with more speed and excitement. BCRF’s unique approach established by Scientific Director Larry Norton, MD, and Chairman of the Foundation’s Scientific Advisory Board Clifford Hudis, MD, fosters creativity and freedom to quickly move ideas from the lab to the bedside. This year’s symposium, titled “Breast Cancer: Prevention Is the Best Cure,” included a panel featuring renowned BCRF researchers Graham A. Colditz, MD, DrPH (Washington University School of Medicine), Andrew J. Dannenberg, MD (Weill Cornell Medical College), Susan M. Domchek, MD (University of Pennsylvania), and Peter Greenwald, MD, DrPH (National Cancer Institute).

Celebrities in Attendance The luncheon, which raised $2.2 million, was hosted by Good Morning America anchor, breast cancer survivor, and BCRF ambassador Amy Robach. ABC News broadcast legend Barbara Walters received the Sandra Taub Humanitarian Award for her contributions to women’s health. The Jill Rose Award for outstanding research excellence was presented to Dr. Greenwald in recognition of his lifelong contributions to research on cancer prevention. “As someone who believes in the power of investigation, in the power of discovery and uncovering the truth, I am

an advocate for research and education,” Ms. Walters said. “I believe that we all have an obligation and a responsibility to support and fund medical research.” Over the past 20 years, research

funded by BCRF has played a significant part in some of the biggest breakthroughs in breast cancer, including: • the finding that breast cancer is not one but many diseases

• the role of genetics in breast cancer • the use of immunotherapy as a means to attack breast cancer • understanding the biology underlying cancer metastasis n

The ASCO Post | DECEMBER 15, 2014

PAGE 16

RSNA 2014 Breast Cancer

3D Mammography Improves Cancer Detection in Dense Breasts

study presented at the annual meeting of the Radiological Society of North America (RSNA 2014) has found that digital breast tomosynthesis, also known as three-dimensional (3D) mammography, has the potential to significantly increase the cancer de-

tection rate in mammography screening of women with dense breasts.

Current Screening Limitations Research has shown that dense breasts are more likely to develop cancer, a problem compounded by the fact

that cancer in dense breasts can be difficult to detect on mammograms. Other imaging modalities like ultrasound and magnetic resonance imaging (MRI) are often used to help find cancers that can’t be seen on mammograms, but both modalities have higher rates of false-pos-

itive findings, according to study lead author Per Skaane, MD, PhD, from the Department of Radiology at Oslo University Hospital in Norway. Dr. Skaane and colleagues have been studying tomosynthesis as a promising breast cancer screening option that addresses some of the limitations of mammography by providing 3D views of the breast.

Study Details The researchers compared cancer detection using full-field digital mammography vs full-field digital mammography plus digital breast tomosynthesis in 25,547 women between the ages of 50 and 69. Breast density was classified based on the American College of Radiology’s Breast Imaging-Reporting and Data System (BI-RADS). The BIRADS breast density scale runs from 1 to 4, with 1 being the least dense and 4 being the most dense. There were 257 malignancies detected on full-field digital mammography and a combination of digital mammography and tomosynthesis in the study group, including 105 in the density 2 group and 110 in density 3. Of the 257 cancers, 211, or 82%, were detected with digital mammography plus tomosynthesis, a significant improvement over the 163, or 63%, detected with digital mammography alone. Full-field digital mammography plus tomosynthesis pinpointed 80% of the 132 cancer cases in women with dense breasts, compared to only 59% for digital mammography alone.

Increase in Cancer Detection “Our findings are extremely promising, showing an overall relative increase in the cancer detection rate of about 30%,” Dr. Skaane said. “Stratifying the results on invasive cancers only, the relative increase in cancer detection was about 40%.” Tomosynthesis not only improved the cancer detection rate in women with dense breasts, it also helped increase detection for women in the “fatty breast” BI-RADS categories. “Our results show that implementation of tomosynthesis might indicate a new era in breast cancer screening,” Dr. Skaane said. n

Disclosure: Dr. Skaane has received support from Hologic.

Reference 1. Skaane P, et al: 2014 Annual Meeting of the Radiological Society of North America. Scientific paper VSBR31-16. Presented December 2, 2014.

ASCOPost.com | DECEMBER 15, 2014

PAGE 17

World Cutaneous Malignancies Congress Dermatologic Oncology

Hedgehog Inhibitors Can Be Life-Altering in Patients With Advanced Basal Cell Carcinoma By Caroline Helwick

hat advanced basal cell carcinomas lack in frequency, they make up for in morbidity, and for these challenging patients, the hedgehog inhibitors have changed lives, according to experts at the 3rd Annual World Cutaneous Malignancies Congress, held recently in San Francisco. “The majority of basal cell carcinomas are simple, but some become locally advanced and even metastasize. Traditionally, there was little we could do for these patients, but with understanding of the hedgehog pathway, we can now intervene,” said Aleksandar Sekulic, MD, PhD, Assistant Professor of Dermatology at the Mayo Clinic, Scottsdale, Arizona, who led the pivotal trial resulting in the approval of vismodegib (Erivedge).1 James MacDonald, MD, of Central Utah Clinic in Provo, added that the genetic profile is still being revealed. Nearly all sporadic basal cell carcinomas have mutations in two hedgehog pathway components—Patched (PTCH, a cell-surface transmembrane protein) and Smoothened (SMO, a G protein– coupled receptor protein)—which are targeted by hedgehog inhibitors, but

the genetic hunt does not stop here. “We have found that [basal cell carcinoma] is more than a molecular ‘onetrick pony,’” he said. “We used to think that the defects within the hedgehog signaling pathway were the primary or even the only driver in carcinogenesis. Now we know that there are other mutational defects—such as in TP53, which evolve over time and with ultraviolet exposure—that result in the various subtypes of basal cell carcinomas. The aggressive subtypes have a higher burden of these molecular defects.”

Hedgehog Inhibitors in the Pipeline

Currently, the focus remains on hedgehog inhibitors, since abnormal hedgehog signaling appears to be involved in most, if not all, basal cell carcinomas. “The approval of vismodegib and the potential for other agents to become available have changed our ability to treat this disease,” said Karl D. Lewis, MD, Associate Professor of Medicine at the University of Colorado, Denver. The phase II ERIVANCE trial of vismodegib at 150 mg was recently updated by Dr. Sekulic at the 2014 ASCO Annual Meeting.2 The 30-month analysis showed a median progressionfree survival of 9.3 months in metastatic patients and 12.9 months in patients with locally advanced disease; median duration of response of 14.8 months and 26.2 months, respectively; and median overFig. 1: Response in a patient with basal cell carcinoma treated with sonidegib all survival of 22.4 at 200 mg. Courtesy of Karl D. Lewis, MD. months in metastatic

Fig. 2: Vismodegib reduces surgical defect size by 27%. Courtesy of Jean Y. Tang, MD, PhD.

Treatment of Advanced/Metastatic Basal Cell Carcinoma ■■ Hedgehog inhibitors have been life-altering for patients with advanced or metastatic basal cell carcinomas and for patients with basal cell nevus syndrome, who develop hundreds of skin cancers. ■■ Vismodegib, used in the neoadjuvant setting, has substantially reduced the anticipated surgical defect size. ■■ A second hedgehog inhibitor, sonidegib, is in development. ■■ Along with the hedgehog pathway, other molecular alterations are being evaluated in this malignancy.

patients and not reached in the locally advanced cohort. “Responses can be durable, and patients can be treated with vismodegib for quite some time. You can go years without a recurrence,” Dr. Lewis observed. In development is a second hedgehog inhibitor, sonidegib, which produced equally impressive results in the phase II BOLT trial, first reported at the 2014 ASCO Annual Meeting and updated at the European Society for Medical On-

of Dermatology at Stanford School of Medicine in California. Dr. Tang co-led the U.S. randomized Gorlin study that tracked a total of 2,000 existing basal cell carcinomas and followed 694 new cases. “Patients randomly assigned to vismodegib had a remarkable reduction in new lesions,” she noted. The real-world management of patients with advanced basal cell carcinoma and basal cell nevus syndrome is being captured in the RegiSONIC

Traditionally, there was little we could do for [patients with basal cell carcinomas], but with understanding of the hedgehog pathway, we can now intervene. —Aleksandar Sekulic, MD, PhD

cology (ESMO) 2014 Congress.3 The study met its primary endpoint of ≥ 30% objective response rate after a median follow-up of 13.9 months. With 200 mg (the dose for future trials), responses were observed at 12 months in 58% of patients with locally advanced basal cell carcinoma and in 8% with metastatic disease; the disease control rate was 91% and 92%, respectively, and median progression-free survival was 22 months and 13.1 months (Fig. 1). The hedgehog inhibitors are also life-changing for patients with the challenging condition called basal cell nevus syndrome, also known as Gorlin syndrome. These patients may develop hundreds of basal cell carcinomas secondary to activation of target genes of the hedgehog pathway in cells that have lost both normal copies of PTCH. “Vismodegib has been life-changing for Gorlin patients,” said Jean Y. Tang, MD, PhD, Associate Professor

disease registry study, which will follow 750 patients from 75 sites. “We are asking how patients are being managed, can we treat them indefinitely [with hedgehog inhibitors], and can we interrupt treatment to manage side effects?” Dr. Tang said. Neoadjuvant treatment might be the next clinical application of hedgehog inhibitors, according to Dr. Tang, whose open-label study of 15 patients with large basal cell carcinomas demonstrated the ability of vismodegib, given for 3 to 6 months, to reduce the anticipated surgical defect size by 27% (P = .006; Fig. 2).4 A randomized, doubleblind study is evaluating this strategy.

Dealing With Toxicities Drug-related toxicities are on-target effects of tissues that rely on the hedgehog signaling pathway. Common toxicities include muscle spasm, continued on page 20

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The ASCO Post | DECEMBER 15, 2014

PAGE 20

World Cutaneous Malignancies Congress Dermatologic Oncology

New Serologic Assay May Help Predict Recurrences in Merkel Cell Carcinoma By Caroline Helwick

new and inexpensive serologic assay may help to predict recurrences of Merkel cell carcinoma, according to Paul Nghiem, MD, PhD, the Michael Piepkorn Endowed Chair in Dermatology Research at the University of Washington, Seattle, who helped develop the

Paul Nghiem, MD, PhD

test.1 Dr. Nghiem and other experts in Merkel cell carcinoma spoke at the 3rd Annual World Cutaneous Malignancies Congress in San Francisco. The Merkel cell polyomavirus is found in approximately 80% of Merkel cell carcinoma tumors. Although the prognostic impact of this virus in newly diagnosed patients has not been established, it can play a role in monitoring for tumor recurrence and thus in facilitating prompt treatment of progressive disease. The assay is available as a “send out” test through the University of Washington, and costs approximately $200 (plus local laboratory fees). “This is much less expensive than radiological scans,” Dr. Nghiem pointed out.

Serologic Detection of Cancer Recurrence Up to 50% of newly diagnosed Merkel cell carcinoma patients have on-

Basal Cell Carcinoma continued from page 17

hair loss, taste abnormalities, and weight change. Sonidegib has also been shown to increase creatine kinase enzyme levels; to what degree this also occurs with vismodegib is not clear. Axel Hauschild, MD, PhD, Head of the Skin Cancer Working Group at the University Hospital Schleswig-Holstein in Germany, commented that despite the adverse events, “Patients appreciate having an oral drug.” He noted that the number of patients being treated with vismodegib in Germany has been “much higher than expected.” Dr. Lewis indicated that “the toxicity profile makes it difficult to maintain patients on treatment.” He said that

coprotein antibodies that recognize the small T antigen; small T antigens help stimulate cancer cell proliferation and are virtually never present in healthy individuals. The test detects these antibodies (and antibodies to the capsid protein of the virus, which merely indicates viral exposure). Antibody titers are stable or reduced in Merkel cell carcinoma patients after treatment, but they increase by 20% or more in patients whose disease progresses, serving as an early warning sign of tumor recurrence, he said. Dr. Nghiem explained the fairly simple way in which the assay signals a tumor recurrence: the small T-antigen titers are high at diagnosis, drop dramatically with treatment, and rise again if the cancer returns. The test has a specificity of 98% and a sensitivity of 78%. Dr. Nghiem’s data (unpublished) indicate that, after the second blood draw, recurrence-free survival is approximately 90% at 2 years for patients whose titers continue to fall, 80% for those with stable titers, and 40% for those with increasing titers (P = .0003). Only 50% of newly diagnosed Merkel cell carcinoma patients produce oncoprotein antibodies. A negative test at diagnosis means that the patient does not make the antibodies, and therefore the serology test will not be a useful monitoring tool. A positive test for oncoprotein antibodies (titer > 150) at diagnosis suggests the test could be useful in tracking the disease. Changes in antibody titers are more important than the specific titer value itself, as individual patients’ titers vary. Titers typically will fall by about 10-fold in the first year, according to informawhile most toxicities are low-grade, “over the long term they wear on patients. I give dose holidays.” In the U.S. randomized Gorlin study, 54% of patients receiving vismodegib discontinued drug treatment because of adverse events. Most patients who discontinue, however, choose to go back on the drug when their tumors return, Dr. Tang said. “The best management seems to be a short period of treatment interruption,” she suggested. Intermittent dosing, therefore, is an important component of side-effect management, along with hydration and calcium, magnesium, and potassium supplementation, muscle relaxants, and calcium channel blockers, per the speakers. Dr. Tang suggested that clinicians

Serologic Assay for Merkel Cell Carcinoma ■■ For patients with Merkel cell carcinoma, a blood test that detects oncoprotein antibodies may help to monitor patients for disease recurrence after treatment. ■■ It is available as a “send out” test through the University of Washington. ■■ Although about 80% of Merkel cell carcinoma patients harbor the polyomavirus, its presence is not prognostic. ■■ Merkel cell carcinoma is believed to be a good candidate for immunotherapy, and anti–PD-L1 antibodies, autologous T-cell therapy, and other investigational immunotherapy approaches are being evaluated.

tion on the University of Washington Reference Laboratory website. Dr. Nghiem recommended that clinicians check the serology results within 3 months of a Merkel cell carcinoma diagnosis to determine whether the patient is an “antibody producer.” If so, that patient can be monitored every few months via the assay. Without a tumor recurrence, and depending on the stage of the disease and other risk factors, after 3 to 5 years, the test could be discontinued or used less often. The guidelines of the National Comprehensive Cancer Network (NCCN) were recently updated to reflect trends in the care of patients with early-stage disease. The NCCN referenced the growing interest in the Merkel cell polyomavirus and the availability of this test, noting, “The value of baseline Merkel cell polyomavirus serology for prognostic significance and to track disease recurrence is being evaluated,” but made no recommendations at this point, said Christopher K. Bichakjian, MD, Associate Professor and Director of the Multidisciplinary Merkel Cell Carcinoma Program at the University of Michiprepare patients for the likelihood of side effects. “When patients stop treatment, they continue to lose their hair for 2 months, but the hair grows back. You can’t avoid these side effects, so it’s best to prepare patients.” n

Disclosure: Dr. Hauschild has received honoraria from and is a consultant for Amgen, BMS, Celgene, Eisai, GSK, Mediummune, MelaSciences, Merck Serono, MSD/Merck, Novaritis, Oncosec, and Roche Pharma. He has also received trial grants from Amgen, BMS, Celgene, Eisai, GSK, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche Pharma. Dr. Lewis reported no potential conflicts of interest.

References 1. Sekulic A, Migden MR, Oro AE, et al: Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 366:2171-2179, 2012.

gan, who chairs the NCCN Committee on Non-Melanoma Skin Cancers. “This is a development that may prove to be a prognostic tool and to supplement or replace routine imaging in the future,” Dr. Bichakjian commented.

Obtaining the Test Oncologists should refer patients to their local laboratory for blood draws to initiate the process. The local laboratory “send out test coordinator” should contact the University of Washington Reference Laboratory Services Call Center (at 206-685-6066), which will set up an account for the ordering physician/clinic; collect the required billing and reporting information; and provide requirements for sample collection, processing, and shipping from the local laboratory.

More on the Role of the Merkel Cell Polyomavirus Isaac Brownell, MD, PhD, Head of the Cutaneous Development and Carcinogenesis Section at the National Cancer Institute, addressed the interest in continued on page 21

2. Sekulic A, Migden MR, Basset-Seguin N, et al: Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: Final update (30-month) of the pivotal ERIVANCE BCC study. ASCO Annual Meeting. Abstract 9013. Presented June 2, 2104. 3. Drummer R, Guminski A, Gutzmer R, et al: Randomized, double-blind study of sonidegib (LDE225) in patients with advanced basal cell carcinoma. ESMO 2014 Congress. Abstract LBA33. Presented September 27, 2014. 4. Ally MS, Aasi S, Wysong A, et al: An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. J Am Acad Dermatol. June 11, 2014 (early release online).

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World Cutaneous Malignancies Congress Merkel Cell Carcinoma continued from page 20

the polyomavirus as a possible etiologic factor in Merkel cell carcinoma, noting that the association is far from straightforward. Although 80% of Merkel cell carcinoma tumors harbor the Merkel cell polyomavirus, its presence does not equate with having the tumor; most Merkel cell polyomavirus infections are subclinical and not oncogenic, he said. “We thought we had this nailed down, that Merkel cell polyomavirus infection equals Merkel cell carcinoma, but it’s not that simple,” he said. Furthermore, Merkel cell polyomavirus status has no clear prognostic impact, as study results have been conflicting. Therefore, testing for the presence of the Merkel cell polyomavirus is currently irrelevant in patient care, except as a means of disease monitoring with the serology assay.

grammed cell death-1 (PD-1) protein should open soon, and trials of its ligand (PD-L1) are already enrolling patients. Researchers in Seattle and elsewhere are also evaluating local injections of immunotherapies, including interleukin-12 plasmid with in vivo electroporation and the Toll-like receptor (TLR4) agonist glucopyranosyl lipid. Other re-

search efforts are evaluating the checkpoint inhibitor ipilimumab (Yervoy) after excision, the addition of the F16– IL-2 antibody-cytokine fusion protein to paclitaxel, the efficacy of the tyrosine kinase inhibitors pazopanib (Votrient) and cabozantinib (Cometriq), and the targeting of the somatostatin receptor with various analogs (as Merkel cell car-

cinoma is a neuroendocrine tumor). n

Disclosure: Drs. Nghiem, Bichakjian, Brownell, and Bhatia reported no potential conflicts of interest.

Reference 1. Nghiem P: A new serologic assay for early detection of recurrent Merkel cell carcinoma. 2014 Annual World Cutaneous Malignancies Congress. Presented October 31, 2014.

NOW ENROLLING: 2L T790M+ MUTANT EGFR NSCLC

Immunotherapy in Merkel Cell Carcinoma The determination of the Merkel cell polyomavirus status may someday become relevant in terms of treatment, however, as patients with circulating T cells that are Merkel cell polyomavirus– reactive can be enrolled in trials of autologous T-cell therapy, he said. Shailender Bhatia, MD, of the University of Washington/Fred Hutchinson Cancer Research Center in Seattle, described the emerging interest in this and other immunotherapeutic approaches in Merkel cell carcinoma. For autologous Tcell therapy, in patients with virus-positive

We thought we had this nailed down, that Merkel cell polyomavirus infection equals Merkel cell carcinoma, but it’s not that simple.

Evaluating the safety and efficacy of rociletinib (CO-1686) in patients with non–small cell lung cancer (NSCLC) with the T790M EGFR mutation Key inclusion criteria • Metastatic or unresectable locally advanced NSCLC • T790M mutation-positive tumor • Progression after only one prior EGFR-targeted therapy • Previous treatment with ≤1 prior chemotherapy • No intervening treatment between prior EGFR-targeted therapy and rociletinib

Rociletinib (CO-1686)

Primary endpoint • Objective response rate

—Isaac Brownell, MD, PhD

tumors and virus-reactive circulating T cells, Fred Hutchinson researchers collect peripheral blood mononuclear cells from these patients, select the Merkel cell polyomavirus–reactive T cells, and expand the CD8-positive T cells. These cells are then reintroduced, along with cytokines to “rev up” the T cells to attack the tumor. In future studies, they will add immune checkpoint blockade, Dr. Bhatia said. Based on the assumption that Merkel cell carcinoma is a cancer amenable to immune manipulation, trials of antibody-mediated blockade of the pro-

For more details about the TIGER-2 trial or to refer a patient Call:

Visit:

E-mail:

• 1-855-262-3040 (inside the United States) • +1-303-625-5160 (outside the United States)

• TIGERtrials.com • clinicaltrials.gov (NCT02147990)

• ClovisTrials@emergingmed.com

Learn more about all ongoing TIGER clinical trials at TIGERtrials.com. Rociletinib (CO-1686) is an investigational product and is not approved in any country. Copyright © 2014 Clovis Oncology. ROCI-201 10/14

The ASCO Post | DECEMBER 15, 2014

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Chemotherapy Foundation Symposium Gastrointestinal Oncology

Choice for Metastatic Pancreatic Cancer: FOLFIRINOX or Gemcitabine/Nab-Paclitaxel? By Alice Goodman

he choice between FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) vs the combination of gemcitabine and nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) for first-line treatment of metastatic pancreatic cancer is not much of a contest, judging by a discussion of “divergent views” at the recent 2014 Chemotherapy Foundation Symposium. Speakers agreed that both regimens represent major advances over gemcitabine alone for the treatment of metastatic pancreatic cancer, providing almost identical disease control and similar survival. And they are associated with toxicities, but in the absence of a head-to-head randomized trial, F OLFIRINOX appears to be the standard of care for “fit” patients. Howard Hochster, MD, of Yale University School of Medicine, New Haven, Connecticut, took the “pro” po-

Howard Hochster, MD

sition for FOLFIRINOX, and Jordan Berlin, MD, of Vanderbilt-Ingram Cancer Center, Nashville, made the case for gemcitabine and nab-paclitaxel.1 Gemcitabine was established as the cornerstone of treatment in 1996. Subsequently, the four-drug combination FOLFIRINOX assumed that position when the PRODIGE 4/ACCORD 1 trial established it as the standard of care.2 The study randomized 342 patients with metastatic pancreatic cancer to receive FOLFIRINOX vs gemcitabine. The median overall survival was 11.1 months for FOLFIRINOX vs 6.8

EXPERT POINT OF VIEW

Jordan Berlin, MD

months for gemcitabine (hazard ratio [HR] = .0.57, P > .001); the median progression-free survival was 6.4 months vs 3.3 months, respectively (P < .001); and the objective response rate was 31.6% vs 9.4%, respectively (P < .001). More febrile neutropenia was reported in the FOLFIRINOX arm (5.4%). Patients in the FOLFIRINOX arm had less degradation in quality of life vs gemcitabine: 31% vs 66%, respectively (P < .001). “This was the first study to show a benefit over gemcitabine and the first to achieve a median overall survival of 11.1 months in metastatic pancreatic cancer,” Dr. Hochster said. Next, investigators at Yale University studied a modified version of FOLFIRINOX (mFOLFIRINOX), which reduced the dose of 5-FU and irinotecan by 25% in an attempt to cause fewer side effects, and compared results historically with gemcitabine and nab-paclitaxel.3 They found that the modified regimen did not compromise efficacy and improved the side-effect profile. “Disease control and survival are identical with FOLFIRINOX and mFOLFIRINOX. Compared with gemcitabine and nab-paclitaxel, FOLFIRINOX is superior for parameters we measured, but it has slightly more diarrhea. Both regimens should be considered major treatment advances,” Dr. Hochster said. “Either regimen can be used for first-line therapy. Survival and response seem better with FOLFIRINOX, as

First-Line Treatments for Metastatic Pancreatic Cancer ■■ FOLFIRINOX and the combination of gemcitabine and nab-paclitaxel achieved similar disease control and survival in metastatic pancreatic cancer, and both regimens are advances over the former standard of care, gemcitabine alone, but both regimens have toxicities. ■■ FOLFIRINOX appears to be a better choice for “fit” patients, and it seems to have an advantage in survival and quality of life. ■■ Better regimens are needed, and there is debate about which regimen should be used as the platform for clinical trials going forward.

uring the discussion, Alan Venook, MD, of Helen Diller Comprehensive Cancer Center, University of California, San Francisco, raised the concern that nab-paclitaxel appears to be the platform of choice for clinical trials going forward. “I’m not sure if this is based on market or merit,” he commented. “I’m concerned that we’ll do studies with gemcitabine and nab-paclitaxel as the platform and combine these two drugs with other drugs Alan Venook, MD with no scientific basis. It’s much harder to get FOLFIRINOX studies supported,” Dr. Venook said. “Science should guide which drugs are used to combine with nab-paclitaxel.” n Disclosure: Dr. Venook reported no potential conflicts of interst.

does quality of life. FOLFIRINOX should be standard of care for “fit” patients,” Dr. Hochster stated.

Gemcitabine and Nab-Paclitaxel “There is probably not that much difference between these two regimens [FOLFIRINOX vs gemcitabine and nabpaclitaxel]. There may be some advantages for one or the other in selected patients, but we won’t see a randomized head-tohead comparison,” Dr. Berlin said. Based on preclinical and early phase I/II studies, the phase III MPACT study randomized 842 patients to receive gemcitabine and nab-paclitaxel vs gemcitabine alone.4 The combination achieved superior response rates, progression-free survival, and overall survival compared with gemcitabine alone. The median overall survival was 8.5 months vs 6.7 months, respectively (P = .000015); the median progressionfree survival was 5.5 months vs 3.7 months, respectively (P = .000024); the 1-year survival was 35% vs 22%, respectively; and the response rate was 23% vs 7%, respectively. The main adverse events for the combination were fatigue and febrile neutropenia. Comparing both regimens historically, the median overall survival favors FOLFIRINOX vs gemcitabine and nab-paclitaxel: 11.1 months vs 8.5 months, respectively. There were some differences between MPACT, an international study, and PRODIGE, a French study, Dr. Berlin said. MPACT enrolled older, sicker patients, he said. “Study sites can impact results. France is a modern country with good health-care systems, while resources are

limited in Russia [one of the countries in the MPACT trial], and supportive measures are lacking,” he noted. Neuropathy is seen with both regimens, so there is a problem in figuring out how to sequence them, he said.

No Real Winner “We are nowhere near winning in this disease. Both regimens are losers—maybe that is a little strong, but they are not really winners. The bottom line is that we are not where we want to be. We have a long way to go in this disease,” Dr. Berlin said. “Both regimens are reasonably toxic. The question is how do we go forward with use of biologics and sequencing,” Dr. Hochster commented. n

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

References 1. Berlin J, Hochster H: Divergent views: FOLFIRINOX vs. gemcitabine-Abraxane. 2014 Chemotherapy Foundation Symposium. Presented November 6, 2014. 2. Conroy T, Desseigne F, Ychou M, et al: FOLIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817-1825, 2011. 3. Gunturu KS, Yao X, Cong X, et al: FOLFIRINOX for locally advanced and metastatic pancreatic cancer: Single institution retrospective review of efficacy and toxicity. Med Oncol 30:361, 2013. 4. Von Hoff DD, Ervin TJ, Arena FP, et al: Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 Gastrointestinal Cancers Symposium. Abstract LBA148.

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Chemotherapy Foundation Symposium Thoracic Oncology

Lung Cancer: Next Frontier for Immunotherapy By Alice Goodman

mmune checkpoint inhibitors, particularly PD-1 (programmed cell death-1) and PD-L1 (programmed death-ligand 1) inhibitors, are being studied extensively in lung cancer. These agents, alone and in combination, appear to have the potential to change the management of non–small cell lung cancer (NSCLC).

for squamous histology and 10.1 months for nonsquamous histology. The dose of 3 mg/kg achieved a median overall survival of 18.2 months in nonsquamous NSCLC, and this dose is being carried forward in phase III trials. Pembrolizumab (Keytruda) also demonstrated activity in highly pretreated NSCLC patients, with an over-

The application of immunotherapy to NSCLC is being brought back in a big way, and emerging data demonstrate promising outcomes in lung cancer.

EXPERT POINT OF VIEW

“T

his is a very exciting time in lung cancer. Immunotherapy is extremely promising,” stated Justin Gainor, MD, a thoracic oncologist at Massachusetts General Hospital in Boston. The promise of immunotherapy extends to a broad patient population. Targeted treatments have transformed the lives of patients with ALK rearrangements and EGFR mutations. Immunotherapy, on the other hand, may be an option for most patients with NSCLC, Dr. Gainor explained in an interview with The ASCO Post. “Regarding PD-L1 as a biomarker for response to therapy, obviously it tells part of the story but does not tell the whole story,” he continued. There are patients who are PD-L1–positive who do not respond to immunotherapy, and responses are seen in those who are PD-L1–negative. “We need to identify better biomarkers,” Dr. Gainor said. As with melanoma, one of the most encouraging aspects of immuno-

—Chandra P. Belani, MD

“The application of immunotherapy to NSCLC is being brought back in a big way, and emerging data demonstrate promising outcomes in lung cancer. The need for such therapies in NSCLC, where systemic cytotoxic chemotherapy still remains the backbone of management, is felt more than ever before,” stated Chandra P. Belani, MD, Penn State Hershey Cancer Institute, Hershey, Pennsylvania. Dr. Belani updated listeners on immunotherapy studies at the 2014 Chemotherapy Foundation Symposium.1 PD-1 and PD-L1 are proteins that are immune checkpoint inhibitors, and immunotherapies directed to these targets release the “brakes” on the immune system, allowing it to attack tumor cells. Anti-PD-1 and anti–PD-L1 agents show benefits in multiple tumor types, including lung cancer.

PD-1 Inhibitors Nivolumab, an PD-1 inhibitor, demonstrated an overall response rate of 17% in heavily pretreated NSCLC patients, with at least an 18-month duration of response.2 The median overall survival for all three dosages studied was 9.2 months

all response rate of 21%. The overall response rate was 19% to 23% in PDL1–positive NSCLC and 9% to 13% in PD-L1–negative NSCLC.3 The median duration of response had not yet been reached at the time of this analysis. Both nivolumab and pembrolizumab have shown activity in early studies of NSCLC in previously treated patients and all comers. There is some evidence that tumors that express PD-L1 are more responsive to these agents, but responses have also been seen in PD-L1–negative patients, Dr. Belani explained. However, pembrolizumab is being developed for PD-L1–positive patients, he said. The U.S. Food and Drug Administration (FDA) recently granted breakthrough status to pembrolizumab for patients who are EGFR-negative and ALK-negative and have disease progression on or following platinum-based therapy. “Pembrolizumab is the first out of the block in NSCLC,” Dr. Belani noted.

PD-L1 Inhibitors The lead anti–PD-L1 antibody under study is MPDL3280A, which is being developed for PD-L1–positive dis-

Immune Checkpoint Inhibitors in Lung Cancer ■■ Phase I, II, and III studies of checkpoint inhibitors are showing promise in non–small cell lung cancer. ■■ Preliminary data suggest that responders have durable responses and that this type of therapy may be effective in a wide range of patients including smokers and nonsmokers. ■■ More research is needed on how best to apply immunotherapy in the lung cancer population.

Regarding PD-L1 as a biomarker for response to therapy, obviously it tells part of the story but does not tell the whole story. We need to identify better biomarkers. —Justin Gainor, MD

therapy in lung cancer is that responses have tended to be durable, according to preliminary data, he said. Future challenges in immunotherapy for lung cancer include improving response rates and sorting out the mechanisms of resistance. Three combination strategies may increase response rates: combination with chemotherapy; combination with targeted therapies in lung cancers with mutations; and immunotherapy combinations with other immune checkpoint inhibitors or vaccines, Dr. Gainor said. n

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

ease, he continued. This agent achieved a 23% overall response rate among all comers with NSCLC, according to a presentation at the 2013 World Conference on Lung Cancer.4 Higher response rates were seen in current and former smokers, “but don’t tell your patients to smoke,” he said. A phase I study of the PD-L1 inhibitor MEDI4736 showed responses in PD-L1–positive and PDL1–negative patients (39% vs 5%, respectively). “It is an evolving issue, whether these immunotherapies are effective only for PD-L1–positive NSCLC or for PD-L1–negative disease as well,” he noted. “In all studies, of the two anti–PD-L1 agents, response rates are higher in positive patients.” “On the other hand, with nivolumab,

there is a lack of correlation between PD-L1 expression and response and survival,” he noted. This issue is complicated by the fact that there are competing methods of testing for PD-L1, and PD-L1 expression is not currently an established biomarker. A number of studies are currently ongoing in NSCLC with PD-1 or anti– PD-L1 inhibitors in salvage therapy (three studies), third-line therapy and beyond (nivolumab in squamous cell NSCLC), and first-line therapy (two studies). MEDI4736 has been incorporated into the large Lung-MAP biomarkerdriven study in advanced squamous cell carcinoma. This agent will be compared with docetaxel chemotherapy as one of the five treatment arms continued on page 24

The ASCO Post | DECEMBER 15, 2014

PAGE 24

Journal Spotlight Survivorship

ASCO Clinical Expert Statement on Cancer Survivorship Care Planning By Matthew Stenger

fforts at implementing survivorship care plans have met with limited success in oncology practice, in part due to the time required to complete them, the lack of role clarity, and the lack of reimbursement for time to complete the documents. In response, ASCO convened a Survivorship Care Planning Workgroup to identify essential components of survivorship care plans and develop a revised ASCO template with the aim of overcoming barriers

associated with the time required for their completion. The sharper focus of the new recommendations not only ensures that necessary information is collected and communicated, but also means that the survivorship care plan document alone will not be sufficient to address all concerns and needs of survivors. The authors noted, “ASCO and other organizations could develop resource toolkits for survivors as supplements to the information provided in the survivorship care plan.”

ASCO and other organizations could develop resource toolkits for survivors as supplements to the information provided in the survivorship care plan. —Deborah K. Mayer, PhD, and colleagues

to their implementation. The resultant “ASCO Clinical Expert Statement on Cancer Survivorship Care Planning” is reported in the Journal of Oncology Practice by Mayer and colleagues.1 Deborah K. Mayer, PhD, of UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, is the corresponding author for the JOP article. The main elements of the ASCO statement are summarized here, consisting of recommendations regarding components of the treatment summary and follow-up care plan that constitute the survivorship care plan. The new survivorship care plan template is available at asco.org/practice-research/asco- cancer-survivorship-compendium. The recommendations focus on elements of survivorship care plans that are “both essential and feasible to collect” and include much less detail than prior ASCO templates, thus addressing barriers

Key Components of Treatment

Lung Cancer Immunotherapy

Different assays not standardized, responses seen in PD-L1–negative NSCLC. • Combination therapy—dose, safety, sequencing, and maintenance • Additional biomarkers—tumor-infiltrating lymphocytes, immune gene signature, T-cell exhaustion • What are the mechanisms of resistance? n

continued from page 23

being investigated. Patients enrolled in this trial have no known EGFR or ALK mutations. Moving forward, key issues to be addressed regarding immunotherapy are: • PD-1 vs PD-L1—which target? • What is the ideal schedule duration of therapy—1 years, 2 years, or until disease progression? • Should PD-L1 status guide therapy?

• Contact information of the treating institutions and providers • Specific diagnosis, including histologic subtype when relevant • Stage of disease at diagnosis • Surgery (yes vs no). If yes: surgical procedure with location on the body; date of surgery (year required, month optional, day not required) • Chemotherapy (yes vs no). If yes: names of systemic therapy agents administered (listing individual names rather than regimens); end date of chemotherapy treatment (year required, month optional, day not required) • Radiotherapy (yes vs no). If yes: anatomic area treated with radiation; end date of radiation treatment (year required, month optional, day not required) • Ongoing toxicity or adverse effects of all treatments received at the completion

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

of treatment. Information concerning the likely course of recovery from these toxicities should also be covered. • For selected cancers, genetic or hereditary risk factors or predisposing conditions and genetic testing results if performed

Key Components of Follow-up • Oncology team member contacts, with location of the treatment facility • Need for ongoing adjuvant therapy for cancer, including adjuvant therapy name, planned duration, and expected adverse effects • Schedule of follow-up–related clinical visits • Surveillance tests for cancer recurrence • Cancer screening for early detection of new primary malignancies (if different from the general population) • Other periodic testing and examinations. Rather than outlining specific testing, the expert group suggested inclusion of a general statement to “continue all standard non–cancerrelated health care with your primary care provider, with the following exceptions: [if there are any].” • Possible symptoms of cancer recurrence. Rather than including a list of possible symptoms, the group suggested inclusion of the general statement: “Any new, unusual, and/or persistent symptoms should be brought to the attention of your provider.” • A list of likely or rare but clinically significant late effects that a survivor may experience based on his or her individual diagnosis and treatment if known • A list of items (eg, emotional or mental health, parenting, employment, financial issues, and insurance) should be covered, with standard language stating that survivors have experienced issues in these areas and that patients should speak with their oncologist and/or References 1. Belani C: Targeting PD-1 and PD-L1 in NSCLC. 2014 Chemotherapy Foundation Symposium. Presented November 7, 2014. 2. Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455-2465, 2012. 3. Garon EB, Gandhi L, Rizvi N, et al: Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) ex-

primary care provider if having related concerns. A list of local and national resources to assist patients in obtaining proper services should be included. • A general statement emphasizing the importance of a healthy diet, exercise, smoking cessation, and alcohol use reduction may be included. Statements may be tailored if particularly pertinent to individual patients.

Pilot Study In a pilot study of the new survivorship care plan template (including 45 completed survivorship care plans at 11 practice sites), the following items were rated on a scale of 1 = strongly disagree to 5 = strongly agree by personnel completing the survivorship care plan: Survivorship care plan was easy to complete—mean score = 3.5; Time to complete survivorship care plan was reasonable—3.5; Clear what information was needed—3.9; Easy to obtain information for survivorship care plan—4.1; Template includes important elements for survivorship care plan—4.5; Information is sufficient for survivorship care plan—4.1; and Template will be useful in discussing follow-up care plans—4.7. The average time to complete the survivorship care plan was 30 minutes. Among the 11 sites, the document was completed by a nurse practitioner at 4, nurse at 3, nurse with administrator or clerical personnel at 2, physician at 1, and social worker at 1. n

Disclosure: For full disclosures of the study authors, visit jop.ascopubs.org.

Reference 1. Mayer DK, et al: American Society of Clinical Oncology clinical expert statement on cancer survivorship care planning. J Oncol Pract 10:345-351, 2014. See commentary by Mary McCabe, RN, MS, on page 31.

pression in a pooled analysis of patients with advanced non-small cell lung cancer. 2014 ESMO Congress. Abstract LBA43. Presented September 28, 2014. 4. Horn L, Herbst RS, Spigel D, et al: An analysis of the relationship of clinical activity to baseline EGFR status, PD-L1 expression, and prior treatment history in patients with nonsmall cell lung cancer following PD-L1 blockade with MPDL3289A (anti-PD-L1). 2013 World Conference on Lung Cancer. Abstract MO 18.01. Presented October 29, 2013.

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ASCOPost.com | DECEMBER 15, 2014

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Perspective

ASCO Expert Statement on Cancer Survivorship Care Planning: Timing Is Everything By Mary McCabe, RN, MS

s the saying goes, “Timing is everything.” And so it is with the recently released ASCO Clinical Expert Statement on survivorship care planning.1 Although there has been extensive discussion and debate about the use of survivorship care plans since the publication of the 2005 Institute of Medicine report “From Cancer Patient to Cancer Survivor,” there have been few data, or even little consensus, about how best to proceed with implementing these documents. The published information that does exist focuses on the many barriers to development and use of this communication tool. The list is long and includes a variety of issues—the time-consuming process of preparing a survivorship care plan, the lack of clarity about whose responsibility it is to maintain the document, the lack of consensus about what should be in it, the lack of reimbursement for its preparation, and the lack of compatibility of existing templates with electronic health records. And so the list goes, but we are at a point in time when a number of these obstacles can be addressed, and the ASCO expert statement—reviewed in this issue of The ASCO Post—allows us to reset our thinking about how to proceed.

A Gradual Effort for All This is not to say that the barriers cited don’t exist or that they are insignificant, but rather that it’s time to refocus and seize an important opportunity to take a positive step forward Ms. McCabe is Director of the Cancer Survivorship Initiative, Memorial Sloan Kettering Cancer Center, New York.

and develop a progressive plan for the implementation and evaluation of this ASCO care plan template. To be sure, moving forward will not occur at warp speed, nor is the template an all-ornothing proposition. The effort will be a gradual one for all of us. Success will be linked to the maturity and connectivity of our electronic health record systems, coupled with the American College of Surgeons Commission on Cancer standard for the Survivorship Care Plan, and informed by the evidence developed through evaluation of the ASCO template across provider groups and practice types. Wisely, and with attention to its

hospitals can incrementally strive to provide all appropriate survivors with a survivorship care plan over a 5-year period.2 In the same communication, the Commission on Cancer highlights the use of the ASCO template as a minimal data set for compliance.

One Resource Among Many As we move into 2015, let’s not make the survivorship care plan the tail wagging the dog. It is not all of survivorship care, but rather it is a tool for improving communication and care. Its utility will evolve as we learn more about documenting transitions in care and as our electronic

ASCO, along with many other professional and patient organizations, is poised to improve survivorship care planning, and the new template is an important step forward. —Mary McCabe, RN, MS

membership, the Commission on Cancer has recalibrated its initial guidance requiring completion and delivery of survivorship care plans. This change is based on a readiness survey of its member organizations, in which only 37% of respondents were “completely confident” that their program would be able to implement the standards in 2015. The Commission on Cancer has now published a communication revising its initial standard for Commission on Cancer hospitals to a phased-in approach that sets out a plan in which

medical records become more robust. The ASCO care plan highlights this point by its brevity. It is not attempting to be all things to all constituents. For example, it doesn’t take the place of the medical record or a conversation between the survivor and oncology care provider (be it MD or NP/PA), nor is it intended to provide all the information needed by the primary care provider when a symptomatic cancer survivor is in his/her office. It is one resource among many for our cancer survivors, families, and health professionals.

Looking Forward So, to continue looking forward, let’s focus on actions to be taken. First, in the spirit of open source software, it would be wonderful to share information about how the ASCO template is used and adapted by various practice configurations and across patient populations. This effort would be a nice addition to the growing ASCO Survivorship Compendium. Second, we need to conduct research to better understand the utility of the ASCO template and the health outcomes that are improved by its use. And, third, we should work toward a formal effort to join the oncology community with the primary care community to develop an educational curriculum that ensures a knowledge exchange about the ongoing care of cancer survivors. Remember, timing is everything. ASCO, along with many other professional and patient organizations, is poised to improve survivorship care planning, and the new template is an important step forward. n

Disclosure: Ms. McCabe reported no potential conflicts of interest.

References 1. Mayer DK, Nekhlyudov L, Snyder CF, et al: American Society of Clinical Oncology clinical expert statement on cancer survivorship care planning. J Oncol Pract 10:345-351, 2014. 2. American College of Surgeons: Accreditation Committee clarifications for standard 3.3 survivorship care plan. Available at https://www.facs.org/publications/newsletters/coc-source/specialsource/standard33. Accessed November 25, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Diane E. Meier, MD, on palliative care in 2014 see page 65

Lisa Hicks, MD, on ASH’s Choosing Wisely Campaign see page 75

Visit The ASCO Post online at ASCOPost.com

Vincent T. DeVita, Jr, MD, on turning lethal cancers into curable ones see page 112

The ASCO Post | DECEMBER 15, 2014

PAGE 32

Announcements

Marlo Thomas Receives Presidential Medal of Freedom

n November 24, 2014, St. Jude Children’s Research Hospital® National Outreach Director, Marlo Thomas, was presented with the Presidential Medal of Freedom, the nation’s highest civilian honor, during a special ceremony at the White House. With Ms. Thomas as its envoy to millions of supporters, St. Jude has become a global resource, helping the world to understand, treat, and defeat childhood cancer and other life-threatening diseases.

accept this honor in their name and in the spirit of the American dream.” In mid-November 2014, the Marlo Thomas Center for Global Education and Collaboration was unveiled and opened on the St. Jude campus. The new Marlo Thomas Center, which sits

atop the world’s first and only proton therapy center dedicated solely to the treatment of children, will enable doctors and scientists at St. Jude and around the world to share their knowledge and collaborate on treatments and cures. The Center also will become the hub

for the St. Jude International Outreach Program, which aims to improve childhood cancer survival rates worldwide through 25 official partner sites in 17 countries. In addition, the Center will support the training and education of St. Jude’s postdoctoral and graduate fel-

Marlo Thomas

The Presidential Medal of Freedom is bestowed upon individuals who have made significant contributions to the security or national interests of the United Sates, world peace, or cultural or other significant public or private endeavors. In its release about the 2014 Medal of Freedom recipients, the White House wrote of Ms. Thomas: “For giving voice to the less fortunate, breaking barriers by portraying television’s first single working woman on That Girl, teaching children to be Free to Be...You and Me,” and for her tireless efforts on behalf of the children of St Jude Children’s Research Hospital, “Ms. Thomas inspires us all to dream bigger and reach higher.” An award-winning actress, producer, best-selling author, and social activist, Ms. Thomas has worked laboriously for St. Jude to raise awareness and funds for the research and treatment of childhood cancer. She has appeared in public-service announcements, on national television programs, and at hundreds of fundraising events across the country to advance St. Jude’s mission. Along with siblings Terre and Tony Thomas, she created St. Jude Thanks and Giving ®, a national campaign that encourages holiday shoppers to support the lifesaving work of St. Jude. Over the past decade, this campaign has raised more than $487 million. “I can’t help but think of my immigrant grandparents and how proud they would be of their granddaughter receiving this wonderful recognition from the President of the country they so dearly loved,” said Ms. Thomas. “So I humbly

ASCOPost.com | DECEMBER 15, 2014

PAGE 33

Announcements

lows on their way to becoming tomorrow’s scientific and medical leaders. “Marlo Thomas has devoted much of her life to St. Jude Children’s Research Hospital and the fight against childhood cancer,” said Richard Shadyac, Jr, President and CEO, of the American Lebanese Syrian Associated Charities, the fundraising and awareness organiza-

tion for St. Jude. “She has worked tirelessly to further her father’s dream that ‘no child die in the dawn of life’ while creating her own incredible legacy as a champion of the children and women of the world. The awareness and funds Ms. Thomas has raised have ensured that families never receive a bill from St. Jude for treatment, travel, housing,

or food. She is truly deserving of the nation’s highest civilian honor.” “Marlo Thomas, through her passion for our mission, her compassion for the patients of St. Jude, and her incredible energy and drive to make a difference, has built a legacy of work in raising awareness that has directly improved the outcome for thousands of children

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

with cancer and other catastrophic diseases worldwide,” said James R. Downing, MD, St. Jude President and Chief Executive Officer. Ms. Thomas is one of 19 honorees this year, joined by her peers representing the arts, sciences, social justice, and public service. Full details are available within the formal announcement made by The White House (http://www. whitehouse.gov/blog/2014/11/10/ president-obama-announces-presidential-medal-freedom-recipients). n

Erratum

n the article “Optimizing HER2 Therapy in Early and Advanced Breast Cancer,” published in the December 1, 2014, issue of The ASCO Post, three errors occurred: • The KATHERINE trial is a phase III trial, not phase II. • The article incorrectly stated that the KAITLIN trial is comparing ado-trastuzumab emtansine vs trastuzumab plus a taxane; however, it is comparing ado-trastuzumab emtansine plus pertuzu mab vs trastuzumab, pertuzumab, and taxane chemotherapy. • In the TH3RESA trial, adotrastuzumab emtansine produced a 2.9-month improvement in progression-free survival, not 2.7 months, as stated in the article. A corrected version of the article can be found on ASCOPost.com. The ASCO Post regrets these errors. n

The ASCO Post Wants to Hear From You

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

The ASCO Post | DECEMBER 15, 2014

PAGE 34

Journal Spotlight Thoracic Oncology

Crizotinib Is Highly Active in ROS1-Rearranged NSCLC By Matthew Stenger

rizotinib (Xalkori) produced a high response rate and durable responses in patients with ROS1-rearranged non–small cell lung cancer (NSCLC), according to a study reported in The New England Journal of Medicine.1 Lead authors Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center, and SaiHong I. Ou, MD, PhD, of the University of California at Irvine, contributed equally to this article. Chromosomal rearrangements in ROS1, which encodes the proto-oncogene receptor tyrosine kinase ROS1, define a distinct molecular subgroup in NSCLC. In addition to inhibiting ALK, crizotinib inhibits ROS1 and MET. As noted by the investigators, oncogenic ROS1 fusions may account for approximately 15,000 of the worldwide 1.5 million new cases of NSCLC each year. ALK and ROS1 rearrangements are infrequently found within the same tumor. Both are more common in patients with a history of never or light smoking and in adenocarcinoma.

Study Details A total of 50 patients with advanced NSCLC were enrolled between October 2010 and August 2013 in the ROS1 expansion cohort of a phase I study of crizotinib. Patients received crizotinib at the standard dose of 250 mg twice daily. Patients had a median age of 53 years; 56% were female; 54% were white and 42% were Asian; 78% were never-smokers; 98% had adenocarcinoma; 44% and 54% had an Eastern Cooperative Oncology Group performance status of 0 and 1, respectively; and 44% had received at least one prior regimen for advanced disease. A break-apart fluorescence in situ hybridization assay was used to identify ROS1 rearrangement in 49 of the 50 patients. An atypical ROS1 fluorescence in situ hybridization pattern was observed in 1 of the 49 patients;

In the majority of patients, crizotinib induced durable clinical responses and was associated with grade 2 or lower toxic effects. These results highlight the importance of screening for this genetic alteration [ROS1 rearrangement] in patients with advanced NSCLC. —Alice T. Shaw, MD, PhD, Sai-Hong I. Ou, MD, PhD, and colleagues

subsequent next-generation sequencing showed nonrearranged ROS1. Another patient was tumor fluorescence in situ hybridization–positive for both ROS1 and ALK rearrangement; nextgeneration sequencing showed an EML4-ALK fusion with no ROS1 rearrangement. Of an additional 32 ROS1positive tumors tested for ALK rearrangement, none was positive. Of 15 ROS1 fluorescence in situ hybridization–positive tumors tested for MET amplification by fluorescence in situ hybridization, 1 was positive.

Responses The objective response rate among the 50 patients was 72% (95% confidence interval [CI] = 58%–84%), with a complete response in 3 (6%), a partial response in 33 (66%), and stable disease in 9 (18%). The median time to first response was 7.9 weeks (range, 4.3–32.0 weeks). At the time of data cutoff, 23 of the 36 responses (64%) were ongoing. The estimated median duration of response was 17.6 months (95% CI = 14.5 months to not reached). Three patients (6%) had evidence of progressive disease on the first restaging scans. One was the patient with

Crizotinib in ROS1-Rearranged NSCLC ■■ Standard crizotinib treatment resulted in response in 72% of patients with ROS1-rearranged NSCLC. ■■ The median progression-free survival was 19.2 months, and 50% of patients are in follow-up for disease progression at data cutoff. ■■ Two new ROS1 fusion partners were identified.

atypical fluorescence in situ hybridization results found to be negative for ROS1 rearrangement. A second patient had discontinued crizotinib for 6 weeks before the first restaging scans due to bowel perforation, which was believed to be associated with glucocorticoid use and preexisting diverticular disease; when this patient resumed crizotinib, a 62% reduction in tumor burden was observed. The third patient exhibited a 26% increase in tumor burden on restaging. The median duration of treatment was 64.5 weeks (range, 2.3–182.0 weeks), with 30 patients (60%) continuing to receive crizotinib after data cutoff. The median progression-free survival was 19.2 months (95% CI = 14.4 months to not reached), with 25 patients (50%) still in follow-up for disease progression at data cutoff. The median follow-up for overall survival was 16.4 months; overall survival at 12 months was 85% (95% CI = 72%– 93%), with the median not reached.

Toxicity Of all treatment-related adverse events, 94% were grade 1 or 2. The most common treatment-related adverse events of any grade were visual impairment (82%), diarrhea (44%), nausea (40%), peripheral edema (40%), constipation (34%), vomiting (34%), elevated aspartate transaminase levels (22%), and fatigue (20%). No treatment-related grade ≥ 4 adverse events were reported. The most common grade 3 events were hypophosphatemia (10%), neutropenia

(10%), and elevated alanine aminotransferase levels (4%). All visual-impairment events were grade 1. One patient (2%) discontinued crizotinib due to a treatment-related event (nausea).

Fusion Partners A total of 30 samples were tested by next-generation sequencing (n = 27) or reverse transcriptase polymerase chain reaction (n = 3). Of the 27 tested by next-generation sequencing, 22 had specific ROS1 rearrangements, 4 were negative for ROS1 rearrangement, and the assay failed in 1; 1 of the 4 negative samples was positive for EML4-ALK. ROS1 fusion partners consisted of the gene-encoding CD74 (11 of 25 samples), SDC4 (4 samples), EZR (4 samples), SLC34A2 (3 samples), and TPM3 (1 sample); all of them have previously been identified as ROS1 fusion partners. Two new partners—LIMA1 (LIM domain and actin-binding 1) and MSN (moesin)—were identified by next-generation sequencing. There was no apparent association between the type of ROS1 rearrangement and the response to crizotinib or the duration of crizotinib therapy. The investigators concluded: … ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. In the majority of patients, crizotinib induced durable clinical responses and was associated with grade 2 or lower toxic effects. These results highlight the importance of screening for this genetic alteration in patients with advanced NSCLC. Although fluorescence in situ hybridization was used in this study, other diagnostic methods have been proposed, and further work is required to establish the most effective screening strategy for ROS1 rearrangement. n Disclosure: This study was funded by Pfizer and by grants from the National Cancer Institute, Uniting Against Lung Cancer, Swedish Research Council, and Be a Piece of the Solution. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Shaw AT, Ou S-HI, Bang YJ, et al: Crizotinib in ROS1-rearranged non-smallcell lung cancer. N Engl J Med 371:19631971, 2014.

See commentary by Tony S.K. Mok, MD, on page 35.

ASCOPost.com | DECEMBER 15, 2014

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Perspective

Moving a Mountain: Crizotinib in ROS1-Rearranged NSCLC By Tony S.K. Mok, MD

t was thousands of years ago in China. An elderly man was unhappy with the mountain that embraced

his seaside village. He would need to walk for hours before he could reach the nearest town. So, as the old fable

goes, he set his mind to move the mountain. Every day, he dug up basketfuls of rocks and dirt and dumped

them into the sea. His neighbor got curious and finally asked: “Ha! Old

GAZYVA® (obinutuzumab)

Premedicate patients with acetaminophen, anti-histamine, and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

• Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)]

Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information. WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)]. • Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy. In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation. 5.2 Progressive Multifocal Leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to pre-existing neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two-thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy. For patients with Grade 1, 2, or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)]. For patients with pre-existing cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their hypertensive medication as is suggested here. 5.4 Tumor Lysis Syndrome Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function, and fluid balance, and administer supportive care, including dialysis as indicated.

continued on page 36

The most common adverse reactions (incidence ≥ 10%) were: infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in Tables 3 and 4 below are based on a total of 356 previously untreated patients with CLL during treatment with GAZYVA in combination with chlorambucil or with chlorambucil alone. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 45 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA based therapy. Table 3 Summary of Adverse Reactions Reported with ≥ 5% Incidence and ≥ 2% Greater in the GAZYVA Treated Arm

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days). Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered. 5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 11% of patients in the trial. In 5% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA. Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle. 5.8 Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)]

Chlorambucil n = 116

All Grades All Grades Grades % 3–4b % Grades % 3–4b % Injury, Poisoning and Procedural Complications Infusion related reactions

Blood and lymphatic system disordersc

5.5 Infections Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection. 5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 34% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

GAZYVA + Chlorambucil n = 240

Adverse Reactions (MedDRAa) System Organ Class

Neutropenia

Thrombocytopenia

16 3

Anemia

Leukopenia

General disorders and administration site conditions Pyrexia

Respiratory, thoracic and mediastinal disorders Cough

a MedDRA coded adverse reactions as reported by investigators. b c

No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms. Adverse events reported under ‘Blood and lymphatic system disorders’ reflect those reported by investigator as clinically significant. Table 4 Post-Baseline Laboratory Abnormalities by CTCAE Grade with ≥ 5% Incidence and ≥ 2% Greater in the GAZYVA Treated Arm GAZYVA + Chlorambucil n = 240

Investigations

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia Lymphopenia Leukopenia Thrombocytopenia Chemistry Hypocalcemia Hyperkalemia Hyponatremia AST (SGOT increased) Creatinine increased ALT (SGPT increased) Hypoalbuminemia Alkaline Phosphatase increased Hypokalemia

77 80 84 47

46 40 36 14

53 9 12 50

27 2 <1 11

22 16

<1 0

14 11

<1 0

The ASCO Post | DECEMBER 15, 2014

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Perspective

Tony S.K. Mok, MD continued from page 35

man, are you sure that you can move the mountain in your lifetime by chipping away rocks and dirt like this?” The old man paused from his hard labor and responded: “I doubt if I can. But if I can’t, my son will continue

Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused. Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, anti-histamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and < 2% thereafter [see Dosage and Administration (2)]. Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm. Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3–4 and none were fatal. Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). The number of fatal hemorrhagic events was similar between the treatment arms, with 4 in the GAZYVA treated arm. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1. Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm. Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%). 6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. Neutralizing activity of anti-GAZYVA antibodies has not been assessed. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known. 6.3 Additional Clinical Trial Experience Progressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)]. Worsening of pre-existing cardiac conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

with the task. And if he can’t, his son will, and his son’s son will….” This fable did have a happy ending. God, being impressed by the man’s persistence, moved the mountain for him. Lung cancer is our mountain, and it is unlikely that God will move this mountain on our behalf. The only way

Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth. 8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established. 8.5 Geriatric Use Of 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients < 75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)]. 8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) > 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr < 30 mL/min [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment. 10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy. 17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. • Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. • Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]. • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)]. • New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)]. Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6 and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)]. • Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

to move the mountain is to chip away the rocks and dirt one basket at a time. With the discoveries of EGFR mutations in 2004 and ALK rearrangements in 2007, we managed to take a chunk out of this huge mountain.1-5 More recently—as reviewed in this issue of The ASCO Post—Shaw

GAZYVA® [obinutuzumab] Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

et al6 have successfully removed another big rock by demonstrating the clinical efficacy of crizotinib (Xalkori) in 50 patients with ROS1 rearrangement. They reported a tumor response rate of 72% and a median progression-free survival of 19.2 months. These outstanding results will likely lead to approval of crizotinib as a standard therapy for patients with ROS1 rearrangement. This is truly remarkable, but a number of key questions remain.

Should all patients with newly diagnosed adenocarcinoma be routinely screened for ROS1 rearrangement and receive first-line crizotinib if they harbor the alteration? The efficacy of crizotinib in ROS1-rearranged lung cancer appears to be similar to, if not better than, the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in patients with EGFR mutations and that of crizotinib in ALK-positive lung cancer. Multiple randomized phase III studies3-5 have confirmed the role of first-line tyrosine kinase inhibitor treatment for EGFR-mutant and ALK-positive lung cancer, but it will be extremely difficult to complete an adequately sized randomized phase III study to confirm the superior efficacy of crizotinib over chemotherapy in treatment-naive ROS1-positive patients. It may be reasonable to assume that crizotinib has similar first-line efficacy in this setting, as it does in patients with ALK rearrangement. Only 7 of 50 ROS1-positive patients in the Shaw et al study were treatment-naive, and their treatment outcomes were not specifically documented. It is debatable whether we should act on assumptions alone. Or, should crizotinib be reserved only as second-line therapy for ROS1-positive patients? Another important question is how we should develop targeted therapy for patients with uncommon driver oncogenes, such as BRAF mutation or RET rearrangement. The Shaw et al study sets an important precedence. The prevalence of ALK rearrangement Dr. Mok is Li Shu Fan Medical Foundation Professor of Clinical Oncology, Department of Clinical Oncology, at the Chinese University of Hong Kong.

ASCOPost.com | DECEMBER 15, 2014

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Perspective

is 3% to 5%, whereas most of the other actionable driver oncogenes are much less common. The impressive high tumor response rate and long progression-free survival

patient cohorts. Results in a European cohort are pending, and an Asian cohort is still accruing. What if the response rate is lower or the progression-free survival is shorter

The impressive high tumor response rate and long progressionfree survival in this single-arm study are the first and most important data that will support the approval of crizotinib in ROS1-positive patients. However, we cannot assume treatment efficacy to be equally impressive in other patient cohorts. —Tony S.K. Mok, MD

in this single-arm study are the first and most important data that will support the approval of crizotinib in ROS1-positive patients. However, we cannot assume treatment efficacy to be equally impressive in other

in these cohorts? What should be the cutoff threshold in a single-arm study? How should we estimate sample size for this type of singlearm “registration” study? The study by Shaw et al faced such

issues. Their statistical plan was to test the null hypothesis of a response rate of less than 10% or the alternative hypothesis of a response rate of over 30%. However, this plan didn’t contribute directly to the final decision on sample size. The maximum of 50 patients was an arbitrary decision to allow accurate assessment of treatment outcome. Similar challenges will confront the development of drugs targeting other uncommon driver oncogenes. Persistence and diligence are the teachings behind the ancient Chinese fable. Although targeted therapy for ROS1 rearrangement is another meaningful addition to personalized medicine for lung cancer, we still have far to go in moving the mountain. We can only keep on digging. n Disclosure: Dr. Mok is a consultant and speaker for Pfizer, AstraZeneca, Eli Lilly, Merck Serono, Roche, and Novartis.

References 1. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying re-

sponsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:21292139, 2004. 2. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-smallcell lung cancer. Nature 448:561-566, 2007. 3. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009. 4. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-2394, 2013. 5. Mok T, Kim D-W, Wu Y-L, et al: First-line crizotinib versus pemetrexed– cisplatin or pemetrexed–carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): Results of a phase III study (PROFILE 1014). 2014 ASCO Annual Meeting. Abstract 8002. 6. Shaw AT, Ou S-HI, Bang YJ, et al: Crizotinib in ROS-1 rearranged nonsmall-cell lung cancer. N Engl J Med 371:1963-1971, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Philippe Armand, MD, PhD, and others on PD-1 blockade in hematologic malignancies see page 1

Jyoti D. Patel, MD, on toxicities associated with targeted therapies see page 4

Deborah Schrag, MD, MPH, on inappropriate use of end-oflife care see page 11

Ethan Basch, MD, on gaps in symptom management see page 14

Aleksandar Sekulic, MD, PhD, on advanced basal cell carcinoma see page 17

Isaac Brownell, MD, PhD, on Merkel cell carcinoma see page 20

Alan Venook, MD, on metastatic pancreatic cancer see page 22

Justin Gainor, MD, on immunotherapy for lung cancer see page 23

Mary McCabe, RN, MS, on cancer survivorship care planning see page 31

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | DECEMBER 15, 2014

PAGE 38

Journal Spotlight Melanoma

Phase II Study Shows Improved Survival With Addition of Sargramostim to Ipilimumab in Metastatic Melanoma By Matthew Stenger

se of the granulocyte-macrophage colony-stimulating factor (GMCSF) sargramostim (Leukine) together with the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy) prolonged overall survival but not progression-free survival in patients with metastatic melanoma, according to a phase II study reported by F. Stephen Hodi, MD, and colleagues in The Journal of the American Medical Association.1 The difference in overall survival was detected at a planned interim analysis.

on Cancer stage and prior therapy. The primary endpoint was overall survival. An interim analysis of overall survival was planned when approximately 50% of events had occurred (75 of 149 expected deaths). As a result of rapid patient accrual, events initially accrued slowly but then rapidly reached 69.8% of expected events (104 deaths) in December 2012; the interim analysis was performed using the O’BrienFleming boundary for 69.8% of expected events. The ipilimumab/sargramostim and

Among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer overall survival and lower toxicity but no difference in progression-free survival. —F. Stephen Hodi, MD, and colleagues

Among the activities of GM-CSF are activation of dendritic cells for antigen presentation and stimulation of T- and B-lymphocyte antitumor functions. CTLA-4 inhibits T-cell activity. Benefits of combining CTLA-4 inhibition and GM-CSF–secreting tumor vaccine have been observed in preclinical models and in patients with melanoma, prostate cancer, and ovarian cancer. Studies of responding metastases have shown infiltration of dying tumor by multiple types of immune effector cells.

Study Details In this open-label trial, 245 patients with unresectable stage III or IV melanoma, and no more than one prior therapy, no central nervous system metastases, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomly assigned between December 2010 and July 2011 to receive ipilimumab at 10 mg/kg every 3 weeks intravenously for four doses, then every 12 weeks, plus sargramostim at 250 μg subcutaneously on days 1 to 14 of a 21-day cycle (n = 123) or ipilimumab alone at 10 mg/kg (n = 122). Randomization was stratified by the American Joint Committee

ipilimumab groups were generally balanced for age (median 61 and 64 years), sex (69% and 64% men), race (99% and 98% white), ECOG performance status (0 in 56% and 64%), metastatic stage (unresectable III in 24% and 25%, M1a/M1b in 27% and 25%, M1c in 50% and 49%), elevated lactate dehydrogenase levels (42% in both), and prior therapy (none in 54% and 56%, interferon in 15% and 14%, and 1 investigational or systemic treatment in 31% and 30%).

Improved Overall Survival The median follow-up was 13.3 months (range, 0.03 to 19.9 months). On interim analysis, the median overall survival was 17.5 months (95% confidence interval [CI] = 14.9 months to not reached) in the ipilimumab/sargramostim group vs 12.7 months (95% CI = 10.0 months to not reached) in the ipilimumab group (one-sided P = .01), and 1-year overall survival was 68.9% (95% CI = 60.6%–85.5%) vs 52.9% (95% CI = 43.6%–62.2%; onesided P = .01). The stratified hazard ratio was 0.64, with a one-sided 90% repeated CI of 0.90 (one-sided P = .01), crossing the O’Brien-Fleming boundary for improve-

Phase II Study in Metastatic Melanoma ■■ Ipilimumab/sargramostim increased overall survival but not progressionfree survival. ■■ The addition of sargramostim was associated with reduced toxicity.

ment in overall survival at 69.8% of expected events. The subgroup analysis showed that hazard ratios favored ipilimumab/sargramostim in age, performance status, prior therapy, and lactate dehydrogenase subgroups but not in women. Hazard ratios were significant for men (0.44, 95% CI = 0.25–0.76) and for patients with a performance status of 0 (0.45, 95% CI = 0.25–0.80).

Progression-Free Survival and Response Rates Both groups had a median progression-free survival of 3.1 months. There were no significant differences between treatments in the subgroup analyses; hazard ratios favored ipilimumab/sargramostim in most subgroups but not in women, patients with a performance status of 1, or patients with no prior therapy. Response rates were 15.5% vs 14.8% (P = .88).

Reduced Toxicity Grade ≥ 3 adverse events occurred in 44.9% of ipilimumab/sargramostim patients and in 58.3% of ipilimumab patients (P = .04), with the most common being diarrhea (12.7% vs 13.3%), maculopapular rash (9.3% vs 9.2%), and colitis (5.9% vs 8.3%). By adverseevent category, there were notable differences in grade ≥ 3 gastrointestinal toxicities (16.1% vs 26.7%) and pulmonary toxicities (0% vs 7.5%). As noted by the investigators, these findings may reflect the reported roles of GM-CSF in both gastrointestinal and lung homeostasis. Treatment-related adverse events leading to death occurred in two patients in the ipilimumab/sargramostim group (one cardiac arrest, one colonic perforation) and in seven patients in the ipilimumab group (two colonic failures, two multiorgan failures, two respiratory failures, one hepatic failure). Ipilimumab/sargramostim treatment was still associated with improved overall survival after analysis, with censoring of lethal adverse events related to treatment and lethal adverse events irrespective of

causality attribution. The investigators noted: “The improved toxicity profile must be considered as contributing to the improved survival, even in light of the survival advantage remaining when patients who discontinued therapy due to toxicity are excluded.” Overall survival was also significantly better (P = .04) among the 25 patients in the ipilimumab/sargramostim group vs the 39 in the ipilimumab group who terminated treatment due to adverse events. The investigators observed that the mechanisms for the improved efficacy with the addition of sargramostim may be related to improved antigen presentation via GM-CSF recruitment of dendritic cells and macrophages; they pointed out that an “uncoupling of overall survival and progression-free survival benefit” has also been seen in patients with advanced prostate cancer receiving sipuleucel-T (Provenge) treatment, which consisted of antigenpresenting cells activated with antigenic proteins including GM-CSF. The investigators concluded: “Among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer overall survival and lower toxicity but no difference in progression-free survival. These findings require confirmation in larger studies with longer follow-up.” n

Disclosure: This study was coordinated by ECOG and supported by the U.S. Public Health Service, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Bristol-Myers Squibb, and Genzyme. For full disclosures of the study authors, visit http://jama.jamanetwork.com.

Reference 1. Hodi FS, Lee S, McDermott DF, et al: Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial. JAMA 312:1744-1753, 2014.

See commentary by Sapna Pradyuman Patel, MD, on page 44.

VOTRIENT is indicated for the treatment of advanced renal cell carcinoma (RCC)1

EFFICACY AGAINST PROGRESSION

VOTRIENT demonstrated an overall median progression-free survival (PFS) of

9.2 months vs 4.2 months with placebo (HR 0.46; 95% CI 0.34-0.62; P<0.001)1*

*Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efﬁcacy and safety of VOTRIENT in ﬁrst-line or cytokine-pretreated patients (N=435) with advanced RCC of clear cell or predominantly clear cell histology. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

Please see additional Important Safety Information for VOTRIENT on subsequent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

EFFICACY LIGHTS THE WAY

®® 1 1 VOTRIENT VOTRIENT (pazopanib) (pazopanib)isisindicated indicatedfor forthe thetreatment treatmentofofpatients patientswith withadvanced advancedrenal renalcell cellcarcinoma carcinoma(RCC). (RCC).

VOTRIENT: Significant PFS improvement in patients with advanced RCC1 Median PFS in patients with advanced RCC receiving VOTRIENT vs placebo1,2

1010

VOTRIENT VOTRIENT Placebo Placebo

11.1 11.1

1212

MONTHS MONTHS

9.2 9.2

MONTHS MONTHS

7.4 7.4

Months Months

8 8 6 6 4 4

MONTHS MONTHS

4.2 4.2

2.8 2.8

MONTHS MONTHS

4.2 4.2

MONTHS MONTHS

2 2 0 0

HRHR 0.46; 0.46; 95% 95% CICI 0.34-0.62 0.34-0.62 (P<0.001) (P<0.001) AllAll patients patients

HRHR 0.40; 0.40; 95% 95% CICI 0.27-0.60 0.27-0.60 (P<0.001) (P<0.001) First-line First-line patients patients

HRHR 0.54; 0.54; 95% 95% CICI 0.35-0.84 0.35-0.84 (P<0.001) (P<0.001) Cytokine-pretreated Cytokine-pretreated patients patients

Randomized, Randomized, double-blind, double-blind, placebo-controlled, placebo-controlled, multicenter multicenter study study to evaluate to evaluate thethe effieffi cacy cacy andand safety safety of VOTRIENT of VOTRIENT in patients in patients (N=435) (N=435) with with advanced advanced RCC. RCC. Patients Patients with with locally locally advanced advanced or metastatic or metastatic RCC RCC of clear of clear cellcell or predominantly or predominantly clear clear cellcell histology histology were were randomized randomized (2:1) (2:1) to receive to receive either either VOTRIENT VOTRIENT 800800 mgmg (n=290) (n=290) once once daily daily or placebo or placebo (n=145). (n=145). TheThe study study included included 1 1 first-line first-line patients patients receiving receiving VOTRIENT VOTRIENT (n=155) (n=155) or placebo or placebo (n=78) (n=78) as well as well as cytokine-pretreated as cytokine-pretreated patients patients receiving receiving VOTRIENT VOTRIENT (n=135) (n=135) or placebo or placebo (n=67). (n=67).

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • 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 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 receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT and

in 1% of patients treated with placebo. Monitor for signs and symptoms. • 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. • Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension.

• Wound Healing: VOTRIENT may impair wound • Wound Healing: VOTRIENT may impair wound healing. Interruption therapy is recommended healing. Interruption of of therapy is recommended in in patients undergoing surgical procedures; treatment with patients undergoing surgical procedures; treatment with VOTRIENT should stopped least 7 days prior VOTRIENT should bebe stopped at at least 7 days prior to to scheduled surgery. VOTRIENT should discontinued scheduled surgery. VOTRIENT should bebe discontinued in in patients with wound dehiscence. patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported • Hypothyroidism: Hypothyroidism was reported in in (19/290) patients treated with VOTRIENT 7%7% (19/290) of of patients treated with VOTRIENT in in randomized RCC in no patients receiving thethe randomized RCC trialtrial andand in no patients receiving placebo. Monitoring thyroid function tests placebo. Monitoring of of thyroid function tests is is recommended. recommended. • Proteinuria: In the randomized RCC trial, proteinuria • Proteinuria: In the randomized RCC trial, proteinuria reported adverse reaction in 9% (27/290) waswas reported as as anan adverse reaction in 9% (27/290) of of patients receiving VOTRIENT, leading discontinuation patients receiving VOTRIENT, leading to to discontinuation of treatment 2 patients. There were reports of treatment in 2inpatients. There were nono reports of of proteinuria in patients receiving placebo. Monitor urine proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment 24-hour urine protein protein. Interrupt treatment forfor 24-hour urine protein grams discontinue repeat episodes despite ≥3≥3 grams andand discontinue forfor repeat episodes despite dose reductions. dose reductions. • Infection: Serious infections (with without • Infection: Serious infections (with or or without neutropenia), some with fatal outcomes, have been neutropenia), some with fatal outcomes, have been reported. Monitor signs symptoms treat reported. Monitor forfor signs andand symptoms andand treat active infection promptly. Consider interruption active infection promptly. Consider interruption or or discontinuation VOTRIENT. discontinuation of of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated forfor useuse in combination with VOTRIENT is not indicated in combination with other agents. Increased toxicity andand mortality have other agents. Increased toxicity mortality have been observed in clinical trials administering VOTRIENT been observed in clinical trials administering VOTRIENT in combination with lapatinib or or with pemetrexed. in combination with lapatinib with pemetrexed. TheThe fatal toxicities observed included pulmonary fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, andand sudden hemorrhage, gastrointestinal hemorrhage, sudden death. A safe andand effective combination dose hashas notnot death. A safe effective combination dose been established with these regimens. been established with these regimens. • Increased Toxicity in in Developing Organs: TheThe safety • Increased Toxicity Developing Organs: safety andand effectiveness of VOTRIENT in pediatric patients have effectiveness of VOTRIENT in pediatric patients have notnot been established. VOTRIENT is not indicated forfor useuse been established. VOTRIENT is not indicated in pediatric patients. Animal studies have demonstrated in pediatric patients. Animal studies have demonstrated pazopanib cancan severely affect organ growth andand maturation pazopanib severely affect organ growth maturation during early post-natal development, andand resulted in in during early post-natal development, resulted toxicity to the lungs, liver, heart, andand kidney andand in death. toxicity to the lungs, liver, heart, kidney in death. VOTRIENT may potentially cause serious adverse effects VOTRIENT may potentially cause serious adverse effects

1 1 Once-daily Once-dailyoral oraldosing dosing

• The • The recommended recommended starting starting dose dose of of VOTRIENT VOTRIENT is 800 is 800 mgmg once once daily daily without without food food (at(at least least 1 hour 1 hour before before or or 2 hours 2 hours after after a meal). a meal). Daily Daily dose dose should should notnot exceed exceed 800 800 mgmg • Do notnot crush tablets duedue to to thethe potential forfor increased raterate of of absorption, which may • Do crush tablets potential increased absorption, which may affect systemic exposure affect systemic exposure • If•aIfdose is missed, it should notnot bebe taken if itifisit less than 1212 hours until thethe next dose a dose is missed, it should taken is less than hours until next dose • In• advanced RCC, initial dose reduction should bebe 400 mg,mg, andand additional dose In advanced RCC, initial dose reduction should 400 additional dose decrease or or increase should bebe in 200-mg steps based onon individual tolerability decrease increase should in 200-mg steps based individual tolerability • In• the Phase 3 advanced RCC trial, 42% of of patients onon VOTRIENT required a dose In the Phase 3 advanced RCC trial, 42% patients VOTRIENT required a dose interruption; 36% of of patients onon VOTRIENT were dose reduced interruption; 36% patients VOTRIENT were dose reduced • No dose adjustment is required in patients with mild hepatic impairment • No dose adjustment is required in patients with mild hepatic impairment • In• patients with moderate hepatic impairment, alternatives to to VOTRIENT should bebe In patients with moderate hepatic impairment, alternatives VOTRIENT should considered. If VOTRIENT is used in patients with moderate hepatic impairment, thethe considered. If VOTRIENT is used in patients with moderate hepatic impairment, dose should bebe reduced to to 200 mgmg perper dayday dose should reduced 200 • Treatment with VOTRIENT is not recommended in patients with severe hepatic • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment impairment • Monitor serum liver tests before initiation of of treatment andand at at Weeks 3, 3, 5, 5, 7, and 9. 9. • Monitor serum liver tests before initiation treatment Weeks 7, and Thereafter, monitor at at Month 3 and at at Month 4, 4, andand as as clinically indicated. Periodic Thereafter, monitor Month 3 and Month clinically indicated. Periodic monitoring should then continue after Month 4 4 monitoring should then continue after Month • For additional information onon dosing modiﬁ cations based onon drug • For additional information dosing modiﬁ cations based drug interactions, please seesee Sections 2.22.2 and 7 of accompanying Brief interactions, please Sections and 7 of accompanying Brief Summary of of Prescribing Information Summary Prescribing Information

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

® ® Pazopanib Pazopanib(VOTRIENT (VOTRIENT ) has ) hasa aCategory Category1 1recommendation recommendationasasa afirst-line first-linetherapy therapyininthe theNCCN NCCNClinical ClinicalPractice Practice ® ® Guidelines GuidelinesininOncology Oncology(NCCN (NCCNGuidelines Guidelines) for ) forrelapsed relapsedororStage StageIVIVunresectable unresectableRCC RCCofofpredominant predominantclear clear 3 3 ® ® ® ® cell cellhistology. histology.NCCN NCCNGuidelines Guidelinesalso alsoinclude includetherapies therapiesother otherthan thanpazopanib pazopanib(VOTRIENT (VOTRIENT) as ) asfirst-line first-linetreatment treatmentoptions. options.

Important ImportantSafety SafetyInformation Informationfor forVOTRIENT VOTRIENT(cont’d) (cont’d) onon organ organ development development in pediatric in pediatric patients, patients, particularly particularly in in patients patients younger younger than than 2 years 2 years of age. of age. • Pregnancy • Pregnancy Category Category D:D: VOTRIENT VOTRIENT cancan cause cause fetal fetal harm harm when when administered administered to to a pregnant a pregnant woman. woman. Women Women of of childbearing childbearing potential potential should should bebe advised advised of of thethe potential potential hazard hazard to to thethe fetus fetus andand to to avoid avoid becoming becoming pregnant pregnant while while taking taking VOTRIENT. VOTRIENT. • Diarrhea: • Diarrhea: Diarrhea Diarrhea occurred occurred frequently frequently andand was was predominantly predominantly mild mild to to moderate moderate in severity. in severity. Patients Patients should should bebe advised advised how how to to manage manage mild mild diarrhea diarrhea andand to to notify notify their their healthcare healthcare provider provider if moderate if moderate to to severe severe diarrhea diarrhea occurs occurs so so appropriate appropriate management management cancan bebe implemented implemented to to minimize minimize its its impact. impact. • Lipase • Lipase Elevations: Elevations: In aInsingle-arm a single-arm RCC RCC trial, trial, increases increases in lipase in lipase values values were were observed observed forfor 27% 27% (48/181) (48/181) of of patients. patients. In the In the RCC RCC trials trials of of VOTRIENT, VOTRIENT, clinical clinical pancreatitis pancreatitis was was observed observed in <1% in <1% (4/586) (4/586) of of patients. patients. • Pneumothorax: • Pneumothorax: Two Two of of 290 290 patients patients treated treated with with VOTRIENT VOTRIENT andand nono patients patients onon thethe placebo placebo armarm in the in the randomized randomized RCC RCC trialtrial developed developed a pneumothorax. a pneumothorax. • Bradycardia: • Bradycardia: In the In the randomized randomized trialtrial of of VOTRIENT VOTRIENT forfor thethe treatment treatment of of RCC, RCC, bradycardia bradycardia based based onon vital vital signs signs (<60 (<60 beats beats perper minute) minute) was was observed observed in 19% in 19% (52/280) (52/280) of of patients patients treated treated with with VOTRIENT VOTRIENT andand in 11% in 11% (16/144) (16/144) of of patients patients onon thethe placebo placebo arm. arm. • Drug Interactions: Coadministration with strong • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg,(eg, ketoconazole, ritonavir, CYP3A4 Inhibitors ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib andand clarithromycin) increases concentrations of pazopanib

should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH (eg, esomeprazole) due to the potential to decrease concentrations of pazopanib. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours.

• Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. The most common adverse reactions (≥20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V3.2014. ©National Comprehensive Cancer Network, Inc. 2014. All rights reserved. Accessed April 30, 2014. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Please Please see see additional additional Important Important Safety Safety Information Information for for VOTRIENT VOTRIENT onon adjacent adjacent pages. pages. Please Please see see Brief Brief Summary Summary ofof Prescribing Prescribing Information, Information, including including Boxed Boxed Warning, Warning, for for VOTRIENT VOTRIENT onon adjacent adjacent pages. pages. www.GSKSource.com www.GSKSource.com ©2014 ©2014 GSKGSK group group of companies. of companies. All All rights rights reserved. reserved. Printed Printed in USA. in USA. 66501R0 66501R0 June June 2014 2014

VOTRIENT.com/HCP/aRCC VOTRIENT.com/HCP/aRCC

EFFICACY LIGHTS THE WAY

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients who received placebo on the trial had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood

pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days

old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, doubleblind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290)

(N=145)

All All Gradesa Grade 3Grade 4 Gradesa Grade 3Grade 4 % % % % % % Adverse Reactions Diarrhea 52 3 <1 9 <1 0 Hypertension 40 4 0 10 <1 0 Hair color changes 38 <1 0 3 0 0 Nausea 26 <1 0 9 0 0 Anorexia 22 2 0 10 <1 0 Vomiting 21 2 <1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below: Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms.

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290)

Parameters Hematologic Leukopenia Neutropenia Thrombocytopenia Lymphocytopenia Chemistry ALT increased AST increased Glucose increased Total bilirubin increased Phosphorus decreased

Placebo (N=145)

All All Gradesa Grade 3Grade 4 Gradesa Grade 3Grade 4 % % % % % % 37 34 32 31

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53 41

10 7 <1

2 <1 0

22 19 33

1 <1 1

0 0 0

B:14.25”

T:13”

S:12.5”

Sodium decreased 31 4 1 24 4 0 Magnesium 26 <1 1 14 0 0 decreased Glucose decreased 17 0 <1 3 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to <1% (1/145) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs That Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and Cmax). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and

H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the postweaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is

highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of the GSK group of companies.

GlaxoSmithKline Research Triangle Park, NC 27709

The ASCO Post | DECEMBER 15, 2014

PAGE 44

Perspective

Getting the Most Out of Ipilimumab in Melanoma By Sapna Pradyuman Patel, MD

pilimumab (Yervoy) was first approved by the U.S. Food and Drug Administration (FDA) in 2011 on the basis of an improvement in overall survival compared with gp100 vaccine in patients with advanced melanoma.1 Response rates with ipilimumab have been modest at best—10% to 15% using 3 mg/kg and 15% using 10 mg/kg1,2—and higher doses have been associated with greater toxicity.

ECOG E1608 The Eastern Cooperative Oncology Group (ECOG) E1608 phase II study recently reported by Hodi et al3 in JAMA and reviewed in this issue of The ASCO Post represents an important benchmark for ipilimumab in melanoma: making treatment more effective while minimizing toxicity. Granulocyte-macrophage colonystimulating factor (GM-CSF)-secreting vaccine has been shown to enhance the effect of CTLA-4 blockade in an in vivo model, specifically augmenting the ratio of intratumoral effector T cells to regulatory T cells associated with tumor rejection.4 On the basis of this preclinical work, ECOG E1608 randomly assigned patients to receive intravenous ipilimumab at 10 mg/kg on day 1 plus subcutaneous GM-CSF (sargramostim [Leukine]) at 250 μg on days 1 to 14 or ipilimumab alone in 21-day cycles. The study met its primary endpoint of improvement in overall survival (17.5 months for ipilimumab plus sargramostim vs 12.7 months for ipilimumab alone, P = .01) while also demonstrating a statistically significant decrease in grade 3 to 5 adverse events (44.9% for ipilimumab plus sargramostim vs 58.3% for ipilimumab alone, P = .04). The overall response rate in both arms was 15%. Diarrhea occurred in 13% of both arms, and colitis was seen in 6% of patients on the ipilimumabplus-sargramostim arm and 8% of patients receiving ipilimumab alone.

Previous Ipilimumab Studies This is not the first study to add Dr. Patel is Assistant Professor in the Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.

an agent to ipilimumab and show an improvement in clinical outcomes while decreasing toxicity. A phase II single-arm study of ipilimumab at 10 mg/kg on day 1 plus temozolomide at 200 mg/m2 on days 1 to 4 demonstrated a 30% confirmed objective response rate.5 This enhanced response is suspected to occur via preferential reduction in regulatory T cells due to temozolomide.6,7 Additionally, temozolomide improved the toxicity profile of ipilimumab; notably, nausea and constipation were the most common gastrointestinal toxicities, as compared with diarrhea and colitis in other ipilimumab studies. The rates of

are unable to differentiate inflammation and immune cell infiltration from disease progression. The authors give plausible scientific rationale for the decrease in serious gastrointestinal and pulmonary toxicity seen in the combination arm. In particular, they point to GM-CSF knockout mice that develop severe colitis and pulmonary alveolar proteinosis. These effects are prevented with the administration of GM-CSF. These knockout murine models suggest GM-CSF is involved in both pulmonary and gastrointestinal homeostasis. The authors also noted that GM-CSF is involved in gastrointestinal mucosal

Getting the most out of ipilimumab involves improving patient selection possibly through the use of predictive biomarkers, along with enhancing response rate and clinical outcome while minimizing toxicity. —Sapna Pradyuman Patel, MD

grade 3 or 4 diarrhea and colitis with ipilimumab plus temozolomide were 9% and 1.5%, respectively. NIBIT-M1, a European study of ipilimumab and the nitrosourea alkylating agent fotemustine (not FDA approved), similarly showed an improvement in overall response to 29%, with only a 5% rate of colitis/diarrhea. Unlike temozolomide, however, fotemustine toxicity is notable for a 43% rate of grade 3 to 4 myelotoxicity.8

Further E1608 Findings Hodi and colleagues noted that the addition of sargramostim had an uncoupling effect on progression-free survival and overall survival. While no benefit was seen in progressionfree survival in patients receiving the combination, at a median follow-up of 13.3 months, a significant improvement in overall survival was seen. This uncoupling may have to do with the protracted effect of sargramostim on enhancing antigen presentation to dendritic cells and macrophages or with the delayed effect of immunotherapy in general; or, it may be reflective of rudimentary radiographic criteria that

repair and that patients with inflammatory bowel disease often show decreased GM-CSF receptors in the bowel or high titers of circulating GM-CSF neutralizing antibodies. There is level 2B evidence for off-label use of sargramostim in patients with Crohn’s disease and pulmonary alveolar proteinosis.

Closing Thoughts The addition of sargramostim as a strategy to improve clinical outcome and reduce toxicity is not without concern for cost. Insurance coverage for sargramostim in the real world is yet to be determined, specifically for patients without cytopenia and for a duration of 14 days in each cycle. Nevertheless, the cost-effectiveness of such a regimen could be studied prospectively. Getting the most out of ipilimumab involves improving patient selection possibly through the use of predictive biomarkers, along with enhancing response rate and clinical outcome while minimizing toxicity. With newer therapies including anti–PD-1– blocking antibodies demonstrating a higher response rate and lower serious toxicity rate,9,10 the attempt to derive

the greatest benefit from ipilimumab by using it in combination with agents that can augment the risk:benefit ratio is a step in the right direction. n

Disclosure: Dr. Patel has received research support from Bristol-Myers Squibb, Novartis, GlaxoSmithKline, and Prometheus and has served as a scientific advisor for Amgen and Genentech and as a speaker for Merck & Co.

References 1. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010. 2. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-2526, 2011. 3. Hodi FS, Lee S, McDermott DF, et al: Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial. JAMA 312:1744-1753, 2014. 4. Quezada SA, Peggs KS, Curran MA, et al: CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 116:1935-1945, 2006. 5. Patel SP, Hwu W-J, Kim KB, et al: Phase II study of the frontline combination of ipilimumab and temozolomide in patients with metastatic melanoma. J Clin Oncol 30(suppl):Abstract 8514, 2012. 6. Banissi C, Ghiringhelli F, Chen L, et al: Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother 58:1627-1634, 2009. 7. Ridolfi L, Petrini M, Granato AM, et al: Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients. J Transl Med 11:135, 2013. 8. Di Giacomo AM, Ascierto PA, Pilla L, et al: Ipilimumab and fotemustine in patients with advanced melanoma (NIBITM1): An open-label, single-arm phase 2 trial. Lancet Oncol 13:879-886, 2012. 9. 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. 10. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012.

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Perspective Hematology

Racing Against Acute Lymphoblastic Leukemia: CTL019 Is a Fast CAR With Sustained Endurance By L. Elizabeth Budde, MD, PhD, Samer K. Khaled, MD, and Stephen J. Forman, MD, FACP

he long-term outcome for patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor, with 5-year overall survival from first relapse being only approximately 10%.1,2 Patients with disease relapse following allogeneic transplant have the worse prognosis and are typically excluded from clinical trials. It is, therefore, with great excitement that we highlight a recently published clinical trial report in patients with relapsed or refractory ALL by Maude and colleagues.3 These researchers from the University of Pennsylvania once again stand at the front line in advancing our knowledge of CD19 chimeric antigen receptor (CAR)-modified T cells in treating patients with ALL.

leukin (IL)-6, and was ameliorated with the use of the anti–IL-6 receptor–blocking antibody tocilizumab (Actemra). No treatment-related deaths were reported. This study is a nice follow-up to the group’s initial report of impressive complete responses to CTL019 in two pediatric patients and is the first study demonstrating durable remission. Indeed,

as the costimulatory domain. An accurate assessment of CAR T-cell persistence was not possible due to subsequent alloHCT in responders in the latter two trials. It remains debatable which CAR has the highest short-term efficacy, and it remains unknown whether a deep remission obtained at day 28 is sufficient for a sustained remission. In addition,

Post-AlloHCT Setting

CTL019 Study In their seminal phase I/IIA study, reviewed in the December 1 issue of The ASCO Post, 25 children and 5 adults with relapsed or refractory ALL who were either ineligible for allogeneic hematopoietic stem cell transplant (alloHCT) or had prior alloHCT were treated with patient-derived CD19 CAR T cells. Complete remission was seen in 90% of patients. The 6-month event-free survival rate was 67% (95% confidence interval [CI] = 51%–88%), and 6-month overall survival was 78% (95% CI = 65%–95%). More than half of the patients (68%, 95% CI = 50%–92%) had detectable CAR T cells at 6 months. B-cell aplasia was found to be a surrogate marker for presence of persistent CAR T cells. The major toxicities associated with CAR T-cell infusion included cytokinerelease syndrome in all patients, with severe cytokine-release syndrome in 27%, neurotoxicity in 43%, and B-cell aplasia in all responders. C-reactive protein was identified as a good surrogate serum marker for following cytokine-release syndrome progression. More important, severe cytokinerelease syndrome was associated with higher disease burden prior to T-cell infusion, higher levels of CD8-positive CD19 CAR T cells, and higher levels of interDr. Budde is Assistant Professor, Dr. Khaled is Assistant Clinical Professor, and Dr. Forman is Francis and Kathleen McNamara Distinguished Chair in the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.

However, a direct cross reference is not possible due to differences in CD19 CAR design, vector of choice, manufacturing platform, and lymphodepleting regimens. It is therefore of increasing importance for future CAR T-cell clinical trials to include intent-to-treat analysis so that it can be determined if this treatment will be available to the majority of, if not all, patients, and to determine if there are any limitations to producing a T-cell product, especially in the relapsed setting.

This study is a nice follow-up to the group’s initial report of impressive complete responses to CTL019 in two pediatric patients and is the first study demonstrating durable remission. Indeed, it presents the first piece of convincing evidence that CD19 CAR T cells can lead to sustained remission of up to 24 months without further treatment. —L. Elizabeth Budde, MD, PhD, Samer K. Khaled, MD, and Stephen J. Forman, MD, FACP

it presents the first piece of convincing evidence that CD19 CAR T cells can lead to sustained remission of up to 24 months without further treatment. This definitely is an encouraging result and brings great hope for patients with relapsed and refractory ALL, especially those whose disease has relapsed after a prior alloHCT. None of the therapeutics currently approved by the U.S. Food and Drug Administration for this patient population has been shown to elicit such a dramatic clinical response.

Persistence of CAR T Cells This study identified a positive association between duration of T-cell persistence and B-cell aplasia and sustained remission. The CD19 CAR in this study uses 4-1BB as the costimulatory domain. Davila et al4 observed a complete remission rate of 88% in 16 adult patients using a CD19 CAR, with CD28 as the costimulatory domain. Lee et al5 reported a 70% complete remission rate in 20 pediatric and young adult ALL patients using a slightly different CD19 CAR, with CD28

one has to consider the contribution of a graft-vs-leukemic effect to the maintenance of sustained remission seen in patients with a prior alloHCT in Maude et al’s study. Therefore, only a randomized side-by-side direct comparison of different CD19 CAR T cells would be able to clearly define the necessity of CAR T-cell persistence and duration of persistence. Unfortunately, such a trial is unlikely to be carried out in the current environment, as each of the three CD19 CAR T cells mentioned involves different sponsors—but individual studies with longer follow-up will still be informative.

Feasibility The design of the current study did not include an intent-to-treat analysis. Therefore, the true feasibility of this approach is not known. The National Cancer Institute group led by Crystal L. Mackall, MD,5 recently reported the first intent-to-treat analysis using their version of CD19 CAR T cells for patients with ALL. The feasibility was 90%, with 19 of 21 patients receiving the intended doses.

A surprising finding of this study is that a history of alloHCT did not compromise the high treatment efficacy of these CD19 CAR T cells. Only 3 of 10 such patients treated by Kochenderfer et al6 and 3 of 7 patients treated by Lee et al5 achieved complete remission. Many differences among these trials might contribute to the differences in outcomes reported. In addition, none of these studies is designed for a rigorous efficacy comparison between the pretransplant and posttransplant groups. Therefore, there are currently insufficient data to conclude whether the antitumor activities of the donor-derived CAR T cells match up to those of autologous CD19 CAR T cells in patients with no prior transplant. A prospective clinical trial in patients with prior alloHCT would certainly provide further information to this end. It is, however, reassuring to conclude that infusion of donor-derived CD19 CAR T cells is safe and unlikely to cause graft-vs-host disease, since no incidence of this complication has been reported by five independent groups,3-7 regardless of whether the T cells were freshly collected from the donor host or from donor cells circulating in the recipient host. This makes the CAR T-cell treatment a very desirable immune-based therapy for ALL patients with relapsed disease following a prior allogeneic transplant.

Non-CD19 Malignancies Many groups, including ours, have been devoting great efforts to expanding the CAR technology to non–CD19positive malignancies. Distinct CARs are being tested in acute myeloid leukemia, multiple myeloma, brain tumors, prostate cancer, mesothelioma, and many other tumor types. continued on page 46

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Palliative Care in Oncology Benefits of Exercise for Relieving Fatigue in Cancer Survivors A Conversation With Jennifer A. Ligibel, MD By Jo Cavallo

atigue is such a common—and ongoing—problem among cancer survivors, last spring, ASCO published a clinical practice guideline1 to address screening, assessment, and treatment approaches for the management of fatigue after patients have completed treatment. Among the strategies included in the guideline to help mitigate the problem is the initiation of consistent moderate-level physical activity—defined as 150 minutes of moderate physical aerobic exercise per week and two to three strength-training sessions per week—following cancer treatment.

studies investigating exercise interventions to combat fatigue and pain in cancer survivors during ASCO’s Annual Meeting in June2 and expects to present new data from her current studies on exercise and its affect on cancer during next year’s Annual Meeting. Dr. Ligibel is also among the scientists investigating the relationship of physical activity, energetics (the study of energy under transformation), and nutrition on cancer risk and recurrence in the National Cancer Institute (NCI)-funded Transdisciplinary Research on Energetics and Cancer (TREC) Initiative.

We recommend that fatigue be assessed as part of the review of systems. If a patient complains about fatigue, we recommend that further questions focus on when fatigue developed, how long it has been present, and how the symptom limits the patient’s ability to carry out responsibilities and engage in activities that the patient typically enjoys. —Jennifer A. Ligibel, MD

Jennifer A. Ligibel, MD, a coauthor of the clinical practice guideline and Assistant Professor in the Department of Medicine at Harvard Medical School and Senior Physician in the Women’s Cancer Program at Dana-Farber Cancer Institute, is researching the impact of exercise on fatigue as well as the role exercise may play in preventing cancer or cancer recurrence, especially in breast, prostate, and colon cancers. She reviewed the results from several

The ASCO Post talked with Dr. Ligibel about what the research is showing on the benefits of physical activity in relieving fatigue after cancer treatment and the role it may play in reducing cancer risk and recurrence.

CAR T Cells

The era of adoptive T-cell immunotherapy has just begun. We look forward to more exciting reports like the one from Maude et al and other groups in the near future. n

continued from page 45

Combination therapy with immune checkpoint inhibitory blockade might be necessary to augment the efficacy in some tumors that are known to activate PD-1/PD-L1 and similar immunoinhibitory pathways that confer resistance to T-cell function when encountering tumors. Using different defined subsets of T cells, with regard to both number and phenotype, as the starting population is another exciting potential strategy that has sparked many research investigations.

Common Problem Why is fatigue such a common and long-lasting problem for cancer survivors? No one knows the definitive answer to that question. The cause of fatigue

Disclosure: Drs. Budde, Khaled, and Forman reported no potential conflicts of interest.

References 1. Forman SJ, Rowe JM: The myth of the second remission of acute leukemia in the adult. Blood 121:1077-1082, 2013. 2. Burke MJ, Gossai N, Wagner JE, et al: Survival differences between adolescents/

is multifactorial. The problem is seen across the spectrum of the cancer experience, from people with early diagnosis who have completed therapy all the way to people with more advanced disease and undergoing therapy. We think that a number of different factors influence the development of fatigue, including treatment, comorbidities, and psychological factors. The biologic basis of fatigue is also not understood, but recent research focuses on the role of inflammation in the etiology of fatigue. Other projects look at genetic predisposition to fatigue and provide early clues that may explain why one person develops fatigue while another person with the same cancer treated with the same therapy does not.

Clinical Practice Guideline Please talk about the recommendations in ASCO’s Screening, Assessment, and Management of Fatigue in Adult Survivors of Cancer Clinical Practice Guideline Adaptation you coauthored. How are patients evaluated for fatigue, and what are some strategies for management? In clinical practice, we recommend that fatigue be assessed as part of the review of systems. If a patient complains about fatigue, we recommend that further questions focus on when fatigue developed, how long it has been present, and how the symptom limits the patient’s ability to carry out responsibilities and engage in activities that the patient typically enjoys. The ASCO guideline also recommends that other causes of fatigue be ruled out. These recommendations are similar to other fatigue guidelines that have been developed, including the pan-Canadian guideline3 and the National Comprehensive Cancer Network (NCCN) guidelines on fatigue and suryoung adults and children with B precursor acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 19:138-142, 2013. 3. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517, 2014. 4. Davila ML, Riviere I, Wang X, et al: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra25, 2014. 5. Lee DW, Kochenderfer JN, StetlerStevenson M, et al: T cells expressing CD19

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.

vivorship.4,5 The guideline does not recommend performing laboratory evaluations or radiologic imaging unless there is a reason to think that patients may have some other condition that is contributing to their level of fatigue.

Specialist Referral At what point should patients be evaluated by a palliative care specialist? Referral to a palliative care specialist more commonly occurs when a patient has advanced-stage disease. In this setting, early referral to a palliative care specialist has been shown to have significant benefits in terms of fatigue and other endpoints. For patients with early-stage disease, the role of palliative care in combating fatigue has not been fully defined, but it is an interesting question. continued on page 48

chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. Lancet. October 10, 2014 (early release online). 6. Kochenderfer JN, Dudley ME, Carpenter RO, et al: Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122:4129-4139, 2013. 7. Cruz CRY, Micklethwaite KP, Savoldo B, et al: Infusion of donor-derived CD19redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant. Blood 122:2965-2973, 2013.

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The ASCO Post | DECEMBER 15, 2014

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Palliative Care in Oncology Jennifer A. Ligibel, MD continued from page 46

Exercise and Survival Please talk about the research showing that exercise can prolong survival and reduce the risk of cancer recurrence in breast cancer and colon cancer survivors. Observational studies show that individuals who participate in regular exercise after a cancer diagnosis are at lower risk of recurrence and mortality compared to cancer survivors who do not exercise at all. Most of this evidence so far is in survivors of breast, colon, and prostate cancers, but data are being collected in other cancers as well. We do not know if exercise is the cause of better survival, but these studies showing a link between exercise and better survival are fairly consistent.

Levels of Activity How much exercise is necessary to reap these benefits? Although it can be hard to make a firm determination of this from the types of studies that have been conducted so far, reports suggest that cancer survivors who

engaged in at least 3 to 5 hours of moderate intensity aerobic exercise, such as brisk walking, had better cancer outcomes compared to people who did not exercise at all. These levels of activity are similar to the Surgeon General’s recommendation for physical activity in the general population, which is about 150 minutes of moderate-intensity activity or 75 minutes of vigorous activity a week.

Other Symptoms What other symptoms from cancer or its treatment may be relieved with exercise? Exercise has been shown to improve overall quality of life and fitness. Studies suggest that exercise reduces problems like joint pain associated with the use of breast cancer drugs, for example. There are also studies looking at the impact of physical activity on hot flashes. There are several symptoms associated with cancer or its treatment that have been shown to be improved by physical activity.

Role of Diet What role does diet play in cancer risk and recurrence?

The relationship between diet and cancer risk/cancer outcomes has been looked at in thousands of studies, but the results are hard to concisely summarize because they show a variety of associations. In colon cancer there is a relationship between foods like red meat and disease onset. In breast cancer the studies are a bit more mixed. A fair amount of data suggests that higher-fat diets may be associated with an increased risk of mortality in women with early breast cancer. The problem is there is also a very strong relationship between weight and breast cancer prognosis, and it is very difficult to disentangle diet and weight in these observational studies. There have also been large observational studies assessing the relationship between weight and both cancer risk and cancer outcomes and, like physical activity, there are strong relationships between weight and the risk of developing and dying from cancer, especially breast cancer and prostate cancer. n Disclosure: Dr. Ligibel reported no potential conflicts of interest.

References 1. Bower JE, Bak K, Berger A, et al: Screening, assessment, and management of fatigue in adult survivors of cancer: An American Society of Clinical Oncology practice guideline adaptation. J Clin Oncol 32:1840-1850, 2014. 2. Ligibel JA: Exercise interventions and more: Combating fatigue, aches, and pains in cancer survivors. 2014 ASCO Annual Meeting. Poster Discussion Session. Presented June 2, 2014. 3. Howell D, Keller-Olaman S, Oliver TK, et al: A pan-Canadian practice guideline and algorithm: Screening, assessment and supportive care of adults with cancer-related fatigue. Curr Oncol 20:e233-e246, 2013. 4. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer-related fatigue (version 1.2013). Available at www.nccn. org. Accessed December 3, 2014. 5. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Survivorship (version 1.2013). Available at www. nccn.org. Accessed December 3, 2014.

Journal Spotlight

Immune-Suppressing Protein in Noncancerous Cells of Cancer Patients Offers Clue to Drug Response

multicenter phase I study using an investigational immune therapy drug has found that the presence of the immune-suppressing protein PD-L1 in noncancerous immune cells can predict how patients with different types of advanced cancer will respond to treatment. The study, led by a Yale

Roy Herbst, MD, PhD

Cancer Center investigator, was described recently in the journal Nature.1 The trial included patients with melanoma or cancers of the lung, kidney, colon, gastrointestinal tract, or head and neck whose tumors were evaluated for PD-L1 expression by a novel

assay. PD-L1 is a protein expressed by many tumor types that can render the cancer invulnerable to immune system attack. Patients were treated with the MPDL3280A, an investigational anti-PDL1 antibody drug. The trial differed from other immune therapy trials in that it incorporated serial biopsies of patients before and during treatment to identify a tumor profile that is predictive of response, said the paper’s first author, Roy Herbst, MD, PhD, Ensign Professor of Medicine and Pharmacology, and Chief of Medical Oncology in the Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven. “What we found surprised us,” Dr. Herbst said. “We knew that the expression of PD-L1 in tumor cells is critical in blocking the immune system, we were intrigued to find that the expression of PD-L1 in nontumor cells (macrophages) was even more predictive of response to the drug. Furthermore through our serial

this same trial including advanced bladder cancer patients who did not respond to other treatments.2 This expansion arm study was coauthored by Thomas Powles, MD, of Queen Mary University Hospital of London with Daniel P. Petrylak, MD, Professor of Medicine and Urology at Yale Cancer Center, and Joseph Paul Study Results Eder, MD, Professor of Medicine at Of the 175 patients enrolled, 21% Yale Cancer Center. Dr. Petrylak had showed partial or complete response, presented the findings earlier this year with some being rapid and durable. at ASCO’s Annual Meeting. n Disclosure: Disclosure information for the Across all tumor types, 46% of patients with high PD-L1 expression on study authors is available in the online version of non-tumor cells showed a partial or the paper at Nature.com. complete response. Also notable was the finding that smokers responded References 1. Herbst R, Soria JC, Kowanetz M, et better to the drug than nonsmokers. This could provide insight into how al: Predictive correlates of response to the smokers and nonsmokers respond dif- anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563-567, 2014. ferently to drugs. 2. Powles T, Eder JP, Fine GD, et al: Dr. Herbst said the drug is in phase MPDL3280A (anti-PD-L1) treatment II and III trials at Yale. Also published in the same issue of leads to clinical activity in metastatic bladNature were additional findings from der cancer. Nature 515:558-562, 2014. biopsies we learned mechanistically the characteristics of both functional and non-functional immune responses. Now we have a baseline for how patients respond and don’t respond, and we can begin learning how to use combination therapies to affect the immune response cycle.”

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Health-Care Policy

Policy Issues in Molecularly Targeted Therapy: The Science, the Money, the Applications By Margot J. Fromer

“I

n the past decade, much new knowledge about the molecular underpinnings of cancer has accumulated, and the array of molecular aberrations in each individual tumor can be assessed through genomic sequencing and other tests. The rationale for and feasibility of developing molecularly targeted therapies have never been stronger, and there are hundreds of candidate drugs in the development pipeline,” said Adrian Senderowicz, MD, Chief Medical Officer, IGNYTA, Inc, and Planning Committee Chair of the National Cancer Policy Forum’s workshop, “Policy Issues in the Development and Adoption of Molecularly Targeted Therapies for Cancer,” held recently in Washington, DC. That said, many challenges remain in the development and appropriate implementation of these new therapies, Dr. Senderowicz added.

Too Much of a Good Thing? Bruce Johnson, MD, Chief Clinical Research Officer, Dana-Farber Cancer Institute, Boston, traced the beginnings of these issues to April 2004, when three three different laboratories from the Dana-Farber Cancer Institute, Massachu-

Bruce Johnson, MD

setts General Hospital, and Memorial Sloan Kettering Cancer Center discovered a link between dramatic responses to treatment with the epidermal growth factor receptor (EGFR) inhibitors (gefitinib and erlotinib) and mutations of EGFR in lung cancer patients. Investigators at the Boston hospital believed that it was important to routinely test lung cancers for the mutations of EGFR so they could be initially treated with gefitinib or erlotinib rather than chemotherapy. Therefore, the hospitals sent tumor slides to the Laboratory of Molecular Medicine at Harvard for EGFR mutation testing in a CLIA environment. One year later (2005), Genzyme Corporation announced commercial availability of an EGFR mutation test to iden-

tify patients likely to respond to targeted therapies to treat non–small cell lung cancer. Without the testing in unselected patients, only about 10% of them responded to gefitinib or erlotinib. The patients with sensitizing mutations of EGFR responded more than 50% of the time. Between then and now, hundreds of compounds have been or are being tested. They belong to two broad groups: therapeutic monoclonal antibodies, which target specific antigens found on the cell surface, and small molecules that penetrate the cell membrane to interact with targets inside a cell. According to My Cancer Genome (www.mycancergenome.org), a personalized cancer medicine resource managed by the Vanderbilt-Ingram Cancer Center, Nashville, there are now 74 targets for kinase inhibitors, with 324 compounds in development; 65 targets for therapeutic antibodies, with 106 compounds in development; 12 targets for immunotherapies, with 39 compounds in development; and 34 “other” targets, with 79 compounds in development. In addition, 54 agents have been approved by the U.S. Food and Drug Administration (FDA) to date. Mycancergenome.org provides current information on the mutations that cause cancer and their related therapeutic implications, including available clinical trials. It is chock full of data—so much, in fact, that clinicians can be overwhelmed, not knowing what to do with them, and some just stay away, said Mia Levy, MD, PhD, Ingram Assistant Professor of Cancer Research and Director of Cancer Clinical Informatics, Vanderbilt University.

Testing the Molecules Before designing therapies, the molecules themselves must be tested. Dr. Levy described the four main types of gene alterations: • Single-nucleotide variants, also known as point mutations, result from a base substitution at one nucleotide, producing a change in the amino acid sequence or premature truncation of an encoded protein. • Small duplications of consecutive nucleotides, insertions, or deletions involving one or more nucleotides, or more complex mutations involving simultaneous deletions and insertions of one or more bases. They may result

in addition or subtraction of amino acids in a protein or cause its premature truncation. • Exon or gene copy number changes, including large duplications or deletions of entire exons affecting protein function or changes in the entire gene. • Structural variants or large structural anomalies of genetic material, including translocations or inversions that result from breakpoints between multiple chromosomes or within a single chromosome, often resulting in fusion genes and associated fusion proteins. Mutations can cluster in “hotspots” where tumors from different patients harbor the same recurrent mutation. Some hotspots are frequent, others rare. For example, the BRAF V600E mutation occurs in 40% of all melanomas, whereas

Matthias Holdhoff, MD

BRAF L597S occurs in less than 1% of all melanomas. “Tumor-specific genetic alterations can also be detected in the bloodstream. This presents a great opportunity for cancer diagnostics and for detecting the mutational makeup of tumors without doing a tissue biopsy. Such a ‘liquid biopsy’ is, however, like finding a needle in a haystack,” said Matthias Holdhoff, MD, Assistant Professor of Oncology, Johns Hopkins University School of Medicine, Baltimore. In the blood of cancer patients, Dr. Holdhoff explained, the fraction of DNA fragments that harbor tumor-specific mutations is very small compared to the abundant amounts of normal DNA fragments from healthy cells. This problem is tackled by using highly sensitive polymerase chain reaction–based assays that essentially count DNA fragments in blood one by one. For example, these techniques can detect even 5 fragments of tumor-derived DNA in a pool of 10,000 normal DNA fragments from healthy cells. The following tests are in current use: • Allele-specific polymerase chain reaction

detects a specific single-nucleotide variant. It can find mutant DNA if present in 1% to 5% of tumors tested, but it cannot detect other mutations that may be present. • Sanger dideoxynucleotide sequencing can find unknown mutations, including single-nucleotide variants, small duplications, insertions, deletions, and indels. It can detect gene fusions if RNA from the fusion transcript is first extracted from the specimen. It requires mutant DNA to be present at a frequency of 20% to 25%. • Pyrosequencing can detect unknown mutations in a small targeted region. It can be done quickly and can detect mutant DNA at 5%, but the types are limited. • Mass spectrometry and single-base extension assay both detect targeted singlenucleotide variants in mutant DNA at 5% to 10% and in more than one gene. • Multiplex ligation-dependent probe amplification finds exon and gene copy number, and depending on the experimental design, can also detect singlenucleotide variants. It requires mutant DNA to be present at 20% to 40% and works best on fresh frozen tissue. • Fluorescence in situ hybridization detects gene copy number changes and targeted structural variants but not in solid tumors. • Next-generation sequencing: custom panels, hybridization capture, and whole-exome sequencing detect substitutions, duplications, insertions, deletions, indels, exon and gene copy number changes, and select translocations—for a total of 1,144 exomes sequenced. • Next-generation sequencing: whole-genome sequencing detects substitutions, duplications, insertions, deletions, indels, gene copy number changes, and chromosome inversions and translocations. It is the most comprehensive of all, but it requires more tumor tissue, sophisticated bioinformatics, and large computational demands for data storage. Next-generation sequencing is one of the most powerful assay methods to date, said P. Mickey Williams, MD, Director, Molecular Characterization Laboratory, Frederick National Laboratories for Cancer Research. “It is popular in all aspects of cancer research and clinical continued on page 50

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Health-Care Policy Policy Issues continued from page 49

management,” he noted. For example, the National Cancer Institute’s MATCH study is a multiarm basket study in which each arm includes multiple tissues. The goal is first to identify mutations, amplifications, and gene fusions to determine eligibility and then to assign patients to a relevant agent regimen using a rules-based approach. “This type of study requires screening large numbers of tumors, and it needs many targeted treatments,” he explained.

in breast tumors. Since then, manufacturers have increasingly accepted the fact that diagnostic tests can greatly increase clinical success. For instance, there are now two companions for cetuximab (Erbitux), one for deferasirox (Exjade), one for afatinib (Gilotrif), one for imatinib (Gleevec), and seven for trastuzumab (Herceptin).

Using and Paying for All This High technology is always exhilarating, but is molecular targeting of practical clinical use, and if so, who’s going to pay for it? David Eberhard, MD, PhD, Director, Pre-Clinical Genomic Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina,

Chapel Hill, posed four critical questions that are frequently addressed with laboratory assays and diagnostic tests: (1) Diagnostic: Does the patient have a condition, and if so, what is it and what caused it? (2) Prognostic: How is the patient going to do? (3) Predictive: How will the patient respond to an intervention? (4) Pharmacodynamic: Is the in-

Companion Diagnostics Targeted therapies are a good thing— if they work. But they don’t always, and for this reason there are companion diagnostics. A companion diagnostic is a diagnostic test whose results are essential for the safe and effective use of a particular drug or biologic agent. These devices can be used to identify patients who are most likely to benefit from a therapeutic product, identify patients who are likely to be at increased risk of serious side effects, and monitor response to treatment. If a diagnostic test is inaccurate, said E. David Litwack, PhD, a member of

E. David Litwack, PhD

the FDA’s Division of in Vitro Diagnostics and Radiological Health, then the treatment decision based on it may not be correct. Ideally both the companion diagnostic and drug should be developed together, preferably before the drug enters clinical trials. In fact, the FDA may require a companion diagnostic if a new drug is designed to treat patients with a specific molecular target. One of the Agency’s recommendations, said Dr. Litwack, is for pharmaceutical and diagnostic companies to partner early in the process. Dr. Senderowicz added a note about benefit and risk. “A false-positive test would cause a patient to receive unneeded treatment, along with its potential risks, without benefit. A false-negative means a patient would not receive needed treatment.” Use of companion diagnostics began in 1998 with a companion that detects excessive levels or extra copies of HER2

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

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Health-Care Policy

David Eberhard, MD, PhD

tervention having an effect? The usefulness of laboratory results for answering these questions requires analytical validation—that is, how well an assay will measure a molecular event: its range, accuracy, precision, bias, and reproducibility. It also requires clinical validation—that is, its strength of association with the condition of interest:

What can it be used for, and does it have actual value in health care? And the key question, said Dr. Eberhard: “Does it offer more than what we have now?” As to who will pay for the technology, that remains to be seen, said Donna Messner, Vice President and Senior Research Director, Center for Medical Technology Policy, a Baltimore com-

In EGFRm+ NSCLC

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

Clovis Oncology is leading the fight

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

pany that looks at quality and relevance of clinical research. “Molecular diagnostic tests have the potential to transform oncology practice, but integration of biomarkers into practice has been inefficient so far because evidence of clinical utility is inadequate, studies of clinical validity have been incomplete or flawed, there is no shared evidentiary framework, and clear and predictable methodologic standards are lacking.” She added that there has been explosive growth in the number, complexity, and costs of tests in the past 20 years. For example, genetic testing is now available for more than 2,000 conditions, and more than 125,000 variants have been discovered in thousands of genes. “But the consequences of wrong information and/or decisions can be disastrous.” What’s more, payers are demanding ever-closer scrutiny as tests proliferate. Coverage policies vary widely among payers because they serve different patient populations, they have differing financial and organizational models, they may not have reviewed the same evidence for each test, and corporate cultures differ. For instance, some companies think that a test is medically necessary if it has a direct effect on clinical care. Others believe that the disease in question must be preventable or treatable, and still others require that the test results in a change in the intensity of surveillance and/or treatment. Some companies want to see improvement in outcomes when a test is used, and almost all will ask whether another, extant clinical tool is available for the same purpose. Other reasons that insurers balk at covering genomic tests include too few published studies demonstrating clinical utility, the often-minor role of genetics in complex diseases, and the availability of alternative effective screening methods. Even without the coverage issues, there are still clinical problems in precision medicine, said Lillian Siu, MD, Professor, University of Toronto, Princess Margaret Cancer Centre Drug Development Program. “It is difficult to keep up with a fast-growing body of knowledge, ensure that patients understand test results, find treatments (either approved drugs or appropriate clinical trials) to match the mutations found, and realize value generated through these agents.” n Disclosure: Dr. Levy is a consultant and a scientific advisor for Personalis and a consultant for GenomOncology. Drs. Litwack, Eberhard, Holdhoff, and Siu reported no potential conflicts of interest.

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Health-Care Policy Lung Cancer Screening continued from page 1

recommended population—a pathway forward that will guide responsible, high-quality, and accountable care that does not place barriers to access for patients needing this service nor medical centers providing this benefit.”

Uphill Battle In April 2014, the Medicare Evidence Development and Coverage Advisory Committee voted against recommending national Medicare coverage for lung cancer screening, igniting intense pushback from more than 40 medical societies. According to data from the Lung Cancer Alliance, approximately 4 million Medicare beneficiaries fit the criteria for screening eligibility. In a press release, the Lung Cancer Alliance pointed out that the new CMS decision is aligned with recommendations previously submitted to CMS by the USPSTF and a coalition that included nearly 100 professional organizations. Ella A. Kazerooni, MD, Professor of Radiology at the University of Michigan Health System and Chair of the American College of Radiology Lung Cancer Screening Committee, told The ASCO Post, “My overall reaction to the

Ella A. Kazerooni, MD

CMS proposal is a very favorable coverage decision for 65- to 74-year-old Medicare beneficiaries, but I’d like to see some clarity about what the path forward will be for those high-risk beneficiaries who are 75 to 80 years old. We recognize that it is highly unlikely that there will ever be a randomized controlled clinical trial conducted in that age population, so I’d like to see what level of evidence is going to be expected to extend coverage to these individuals that the USPSTF recommended screening for.” Asked about implementing a national lung cancer screening program, Dr. Kazerooni commented, “I think it’s a reach to think that we’ll see an immediate rollout of programs and complete national acceptance of lung cancer screening. It took 20 to 30 years for mammography to reach the levels of adherence we see today, and it will

take time to educate providers and the public about the lifesaving value of lowdose computed tomography. However, as opposed to the mammography story, we have electronic health records that can be set up to fire best-practice alerts, based on a patient’s age and smoking history. Electronic media can also be used as an educational tool for shared decision-making, so we have a leg up on the roll out of lung cancer CT screening that should bring it to patients sooner.”

CMS Sets Standardized Criteria Some experts at the Medicare Evidence Development and Coverage Advisory Committee meeting questioned whether imaging centers across the country could meet the same standards as the participating centers in the landmark National Lung Cancer Screening Trial, which showed a 20% survival benefit in high-risk participants undergoing low-dose computed tomography. Regarding that concern, the CMS proposal set stringent eligibility criteria for participating facilities. Each center must have participated in past lung cancer screening trials or be an accredited advanced diagnostic imaging center with training and experience in low-dose computed tomography lung cancer screening. Centers must also collect and submit data to a CMS-approved national registry for each low-dose computed tomography lung cancer screening performed. Moreover, participating radiologists must have a current certification with the American Board of Radiology, documented training in diagnostic radiology and radiation safety, and involvement in the supervision and interpretation of at least 300 acquisitions of chest computed tomography in the past 3 years. Organizations like the ACR have been working collaboratively with CMS to set these standards, and through the ACR CT accreditation program with special designation for lung cancer screening centers, and a soon-to-

be-released ACR National Radiology Data Registry clinical practice lung cancer screening quality registry to benchmark practices and practitioners, are prepared to meet these requirements.

Affordable Care Act The Affordable Care Act will require Medicare to reimburse for screening, but beginning in 2015, private insurers must also cover lung cancer screening without cost-sharing. Adding more costs to our exploding health-care system’s budget raises concern among certain health-policy pundits. To those worried about costs associated with low-dose computed tomography, nationally regarded lung cancer expert James Mulshine, MD, Director,

that the rate of false-positive results in lowdose computed tomography can actually be lower in lung cancer screening than in many other methods of cancer screening simply by standardizing the thoughtful protocols that are already in use today, such as with the proposed ACR approach. Dr. Mulshine has been working with the large consortium organized by LCA, ACR, and STS that has engaged CMS to recommend constructive approaches to optimize the screening process now that the coverage decision will soon be enacted. This is a critical time for the lung cancer community to work together on multiple goals that can be leveraged with the CMS proposal. “First we need to have screening-appropriate tobacco-cessation initiatives to

At various levels, lung cancer screening may represent one of the best investments of CMS resources in terms of improving outcomes for cancer. —James Mulshine, MD

Rush University Translational Sciences Consortium, responded, “The ultimate straw man is cost. But because low-dose computed tomography screening for lung cancer is targeted to a readily definable high-risk population, it can potentially be deployed at a lower expense than other cancer screening tests that are population wide. At various levels, lung cancer screening, especially when appropriately integrated with smoking cessation, may represent one of the best investments of CMS resources in terms of improving outcomes for cancer.” Dr. Mulshine also addressed another concern of those who have opposed national coverage for low-dose computed tomography: false-positive results. He explained that recent papers have shown

Criteria to Qualify for Lung Cancer Screening Coverage Under CMS’s Proposal ■■ Age 55 to 74 years ■■ Asymptomatic for lung cancer ■■ Tobacco history equivalent to 30 pack-years or more ■■ Current smoker or one who has quit smoking within the past 15 years ■■ Written order for low-dose computed tomography lung cancer screening received during a lung cancer screening counseling and shared–decisionmaking visit ■■ For subsequent screenings, a beneficiary must receive a written order during an appropriate visit with a physician or nonphysician practitioner (physician assistant, nurse practitioner, or clinical nurse specialist)

help those who have been addicted to tobacco for 30 or 40 years quit,” he said. “We also have to ensure that our screening delivery systems are accessible and patientfriendly. We have to partner with the surgical societies to make sure that we’re on the glide path to developing less invasive surgical methods. We have to work with the medical oncology community to develop agents directed at early-stage lung cancer. If we stick to these goals, we will see a marked decrease in the incidence and mortality of this devastating disease. However, work still remains, as it would be tragic if overburdensome processes restricted access to this critical new cancer screening service.” Dr. Mulshine added, “Even with the convincing body of evidence that lowdose computed tomography can save tens of thousands of lives, it’s important to note that if it hadn’t been for the coalition that the LCA assembled with the ACR and the STS along with over 100 partners and even with the critical provisions within the Affordable Care Act, all this work came perilously close to dying on the vine. This has been a remarkable collaborative effort to ensure that this opportunity to turn the tide for the victims of lung cancer is finally realized.” n Disclosure: Ms. Fenton Ambrose and Drs. Kazerooni and Mulshine reported no potential conflicts of interest.

The ASCO Post | DECEMBER 15, 2014

PAGE 54

Direct From ASCO

Conquer Cancer Foundation and Michael’s Mission Work Together to Conquer Colorectal Cancer

“N

obody tells a 28 year old to get a colonoscopy.” It’s the sad but true reality that many young adults may be at risk for colorectal cancer. Unfortunately, many people, young adults in particular, are not aware of the risk factors and do not get screened early enough to catch the disease when it is most treatable. This was the case for Michael Soussa.

Michael’s Mission Michael Soussa was a vibrant young man when he was diagnosed with colorectal cancer just days after his 30th birthday. After enduring multiple surgeries and almost 40 months of chemotherapy and radiation, Michael passed away at the age of 33. Michael’s family, friends, and fiancée, along with Allyson Ocean, MD, Michael’s medical oncologist, were devastated by his loss. They created Michael’s Mission in the hopes of honoring his legacy and helping other patients and their families. Michael’s Mission is a nonprofit organization focused on improving the quality of life and treatment options for those suffering from colorectal cancer through education, research, and patient support programs. Cindy Gavin, Executive Director of Michael’s Mission, has known the Soussa family for many years and remembers the family feeling scared and frustrated by the lack of information about colorectal cancer, and not having a community to turn to for support. “This truly motivated me, and it’s been my personal passion to help other patients and their families

get the support they need because this disease is just awful,” she said. Michael’s Mission is generously supporting a 2014 Conquer Cancer Foundation of ASCO Career Development Award to Marcia Russell, MD, PhD, for her project, “The Impact of Surgical Technique on Quality of Life After Rectal Cancer Surgery: Patient-Reported Outcomes in National Surgical Adjuvant Breast and Bowel Protocol R-04.”

Career Development Award Despite the increasing number of rectal cancer survivors, very little is known about the impact of surgeon specialty or

and long-term (5-year) rectal cancer survivors. This work is important to provide the data necessary to inform quality improvement efforts and improve the quality of life and outcomes for patients diagnosed with rectal cancer. “We were really excited about this project because it directly aligns with our mission to improve quality of life for patients, and we’re interested in learning more about surgical techniques and how adherence to quality can affect outcomes for various patients,” said Ms. Gavin. Investing in young investigators like Dr. Russell is a natural fit for Michael’s Mission since Michael passed away at

[Dr. Russell’s project] directly aligns with our mission to improve quality of life for patients, and we’re interested in learning more about surgical techniques and how adherence to quality can affect [patient outcomes]. —Cindy Gavin

surgical technique on quality of life. Survivorship issues specific to rectal cancer patients may include alterations in bowel, bladder, and sexual function due to the combined effects of pelvic radiation and surgical dissection in the pelvis. Dr. Russell’s Cancer Development Award seeks to use patient-reported outcomes to evaluate the impact of surgeon specialty and adherence to technical measures of quality on both short-term (1-year)

such a young age, and the organization wants to encourage young researchers to focus on the unmet needs of colorectal cancer patients and to gravitate to this space, so we can hopefully move the needle forward, she explained.

Patient and Family Resources In addition to supporting research projects, like Dr. Russell’s, Michael’s Mission is committed to helping the

Marcia Russell, MD, PhD

thousands of people who have to live with colorectal cancer navigate through their journey. At the heart of their mission is an extensive website, which offers discussion forums, resources, and tools. “It’s a one-stop shop for patients and their families,” explained Ms. Gavin. “Ten years ago when Michael was diagnosed, the technology and social media platforms that exist today were not there. One goal when founding the organization was to create this dialogue. I did my homework and found out that we don’t need to create it. It already exists; we just need to join the conversation!” The organization has also funded a pilot patient support program at the Jay Monahan Center for Gastrointestinal Health at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, which is unique in that it has a social worker meet with patients while they are receiving chemotherapy. The feedback has been very positive, and the social worker has seen over 50 patients and averaged over 200 sessions in the first year. They are hoping to make the program scalable and roll it out more broadly. continued on page 55

Looking to the Future: ASCO’s 50th Anniversary Year Comes to a Close

ifty years ago, a group of seven cancer physicians banded together with a single purpose: to improve the care of people with cancer. At the time, cancer was viewed as a monolithic and frequently incurable disease, with only a handful of hard-to-tolerate and mostly ineffective therapies available. Stigma and silence left many patients with cancer with little support or information. ASCO’s founders envisioned “a society of clinical oncology [that] has the potential of contributing greatly to the improved diagnosis, treatment, wellbeing, and longevity of fellow citizens

with neoplastic diseases and to aid in the prevention of many others.” Whereas nearly all cancer organizations at the time were focused on laboratory research, ASCO would be dedicated to the clinical needs and concerns of patients.

Hope for Tomorrow’s Patients ASCO has held true to this vision. Over 5 decades, ASCO and its members have established and advanced the field of modern clinical oncology. In many ways, the story of ASCO is the story of progress against cancer: as ASCO grew from its original seven

members to more than 35,000 today, national funding for cancer research increased from less than $200 million to more than $5 billion annually. The number of drugs available to treat cancer grew from just a handful to more than 170. And, most importantly, patients are living longer and better lives. ASCO’s members, together with cancer patients, advocates, and the policymakers, government agencies, and philanthropic organizations like the Conquer Cancer Foundation that have invested in vital research, have enabled and delivered these remarkable advances. Nevertheless, cancer remains one of the world’s greatest health challeng-

es. Prevention options are few, and many cancers are still hard to diagnose and treat. But with recent breakthroughs in technology and molecular biology, cancer care is poised to change even more dramatically in the next 20 years than over the past 50. As we look to the future, ASCO is working to harness these rapid changes in science and technology to achieve even better outcomes for tomorrow’s patients. n Originally published on CancerProgress. Net. © American Society of Clinical Oncology. “ASCO@50.” Available at www.cancerprogress.net/asco50 2014. All rights reserved.

ASCOPost.com | DECEMBER 15, 2014

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Direct From ASCO

Cancer Care Incomplete Without Palliative Care Integration

SCO recognizes that an array of efforts are needed to fully integrate palliative care into the cancer care continuum, and the Society is committed to facilitating the integration of palliative cancer care into existing health-care systems worldwide in order to realize the vision of comprehensive cancer care by 2020. ASCO issued its first policy statement on palliative care in oncology in 1998, emphasizing the critical role that palliative care plays in providing high-quality care for cancer patients and their families. In 2009, the Society issued a second statement on palliative care, calling for a broad range of recommendations to increase education and awareness among providers and the public as well as systems-level change to ensure access to these critical services for patients and their families. Most recently, ASCO’s 2012 Provisional Clinical Opinion recommended early integration of palliative care for all patients with advanced disease or a high symptom burden, regardless of prognosis. ASCO is now expanding its

gram of ambitious goals to move toward impeccable assessment and management of symptoms and post-treatment survivorship. Palliative care provides an extra layer of support that can make a big difference for patients and families.”

Michael J. Fisch, MD, MPH, FACP, FAAHPM

What Is Palliative Care? Long misunderstood or misidentified, the World Health Organization defines palliative care as “an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual in conjunction with (or without) anticancer treatment.” According to Michael J. Fisch, MD, MPH, FACP, FAAHPM, Chair of the Department of General Oncology at The University of Texas MD An-

If we practice in accordance with the Hippocratic Oath, then we have committed to making sure our patients live as well as they can, not just as long as they can. — Jamie H. Von Roenn, MD

Volume 29, Issue 15

May 20, 2011

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

Palliative Care in Oncology Symposium One of ASCO’s most visible efforts is the Palliative Care in Oncology Symposium, which took place October 24 continued on page 57

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

What’s Hot in

JCO

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

JCO.org Chemotherapy and Targeted Therapy for Women With Human Epidermal Growth Factor Receptor 2–Negative (or unknown) Advanced Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline by Ann H. Partridge, et al Efficacy of Methylprednisolone on Pain, Fatigue, and Appetite Loss in Patients With Advanced Cancer Using Opioids: A Randomized, Placebo-Controlled, Double-Blind Trial by Ørnulf Paulsen, et al PIK3CA Mutations Are Associated With Lower Rates of Pathologic Complete Response to Anti–Human Epidermal Growth Factor Receptor 2 (HER2) Therapy in Primary HER2-Overexpressing Breast Cancer by Sibylle Loibl, et al

palliative care initiatives with the Palliative Care in Oncology Symposium and a new Palliative Care Resource Center. “ASCO’s efforts in palliative care are not new, but they have increased and become more visible recently,” said Jamie H. Von Roenn, MD, ASCO’s Senior Director of Education, Science, and Professional Development. “Palliative care is an essential component of optimal oncology care, regardless of stage and prognosis.”

derson Cancer Center, the field of palliative care remains poorly understood by the lay public and by some cancer and health-care professionals. “I think too many people still associate palliative care with hospice,” Dr. Fisch said. “People who do not perceive themselves as having end-of-life issues may turn away from palliative care or be confused about why it is being brought up, rather than seeing the early integration of palliative care as a part of a pro-

Michael’s Mission

are encouraged to share their stories to provide strength, hope, and inspiration to others. “When someone going through their battle with colorectal cancer wakes up at 3 AM, feeling scared and alone, and is looking for an inspirational story, it is priceless for them to find this information,” said Ms. Gavin. Conquer Cancer Foundation is honored to be working with Michael’s Mis-

continued from page 54

Get Involved

In addition to offering tools and resources to help patients and families cope with colorectal cancer, Michael’s Mission offers a multitude of ways for people to get involved with their organization. For example, on their “Our Heroes” webpage, patients and survivors

Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline by Ethan Basch, et al

Vitamin D Deficiency Impairs Rituximab-Mediated Cellular Cytotoxicity and Outcome of Patients With Diffuse Large B-Cell Lymphoma Treated With but Not Without Rituximab by Jörg Thomas Bittenbring, et al

sion to support Dr. Russell’s colorectal cancer research and raise awareness about this devastating disease. “Conquer Cancer Foundation and ASCO are well established and highly regarded organizations. Their missions really align directly with our goals, so there are many synergies between the organizations, and it felt like a natural fit. We’re really excited to be working with the Conquer

Cancer Foundation!” said Ms. Gavin. To learn more about the Conquer Cancer Foundation’s Grants and Awards Program, visit www.conquercancerfoundation.org. To learn more about Michael’s Mission, visit www.michaelsmission.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | DECEMBER 15, 2014

PAGE 56

Direct From ASCO

Don’t Forget: Make Your Year-End Gift to the Conquer Cancer Foundation

he end of the year is often a busy time, filled with family, friends, and holiday celebrations. For many, it is also a time to embrace the spirit of giving and make annual donations to favorite charities. The Conquer Cancer Foundation leverages the expertise and passion

of ASCO’s members to advance the prevention, diagnosis, treatment, and cure of all types of cancer worldwide through breakthrough cancer research, education, and ASCO initiatives improving the quality of cancer care. Donors wishing to make a tax-de-

ductible year-end gift to the Conquer Cancer Foundation have a number of convenient options: • Donate Online: visit www .conquercancerfoundation.org/donate • Mail Your Gift: Address your gift to the Foundation’s secure lockbox

For HR+, early-stage invasive breast cancer

Confidence begins with a highly accurate risk assessment

at: Conquer Cancer Founda tion P.O. Box 896076 Charlotte, NC 28289-6076. • Give While You Shop: visit www .conquercancerfoundation.org/ shop to learn how you can support the Conquer Cancer Foundation through your holiday shopping with services like iGive, AmazonSmile, and eBay GivingWorks. • Donate Stock: visit www .conquercancerfoundation.org/stock for instructions on how to donate publicly traded securities to the Conquer Cancer Foundation in two easy steps. • Make an Estate Gift: visit www .conquercancerfoundation.org/ plannedgiving to learn more about how you can use your estate to meet your personal and philanthropic goals while leaving a powerful legacy to improve the future of cancer care.

• Fundraise for the Conquer Cancer Foundation: visit www .weconquercancer.net to set up a personalized online fundraiser in honor of a special person, occasion, or event. No matter how you choose to give, thank you for helping to build a world free from the fear of cancer. n © 2014. American Society of Clinical Oncology. All rights reserved.

Introducing Prosigna™: Guide your decisions with the power of PAM50-based molecular profiles1 • Prosigna translates a patient’s underlying tumor biology into an individualized risk assessment

• Prosigna is the only genomic assay for breast cancer that is FDA 510(k) cleared for use in local qualified laboratories

• Prosigna’s PAM50-based genomic assay quickly and accurately provides prognostic information you need

• Obtain precise, reproducible results from formalin-fixed paraffin-embedded (FFPE) tissue in as few as 3 days

To find a Prosigna provider and for a copy of the Package Insert, visit Prosigna.com today. Reference: 1. Prosigna [Package Insert]. Seattle, WA: NanoString Technologies, Inc; 2013.

Prosigna is indicated for use in postmenopausal women with hormone receptor–positive, node-negative or node-positive early-stage (stages I and II) breast cancer to be treated with adjuvant endocrine therapy. Special conditions for use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients. © 2014 NanoString Technologies, Inc. All rights reserved. NanoString, the NanoString Technologies logo, Prosigna and the Prosigna logo are trademarks and/or registered trademarks of NanoString Technologies, Inc. in various jurisdictions. USPS_PM0006 04/14

Proceed with confidence

Latest From the Cancer.Net Blog

irect your patients to the Cancer. Net blog for practical tips for living with cancer, suggestions to help patients and families cope with the disease, and research news and guidelines from ASCO. The latest posts include an interview and podcast on the role of Licensed Marriage and Family Therapists in cancer care and tips for coping during the holidays. Your patients can find them and more at www.cancer.net/ blog. n

ASCOPost.com | DECEMBER 15, 2014

PAGE 57

Direct From ASCO

FDA Guidance on the Use of Pathologic Complete Response in Development of New Treatments for High-Risk Early Breast Cancer Includes ASCO Suggestions

he U.S. Food and Drug Administration’s (FDA) final Guidance for Industry on Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer incorporates two changes that ASCO had proposed in comments submitted to the agency on a draft guidance issued in 2012. The guidance is intended to assist sponsors in designing trials to support marketing approval of drugs and biological products for treating breast cancer in the neoadjuvant setting. The document addresses the use of pathologic complete response in breast cancer as a potential endpoint to support provisional approval under the accelerated approval regulations. Two areas where FDA made changes

consistent with ASCO’s suggestions included: • Definition of Pathologic Complete Response: FDA removed ductal carcinoma in situ as a consideration for the definition of pathologic complete response. • Feasibility of Expected pCR Rates: FDA modified the section to focus on comparing pathologic complete response of standard therapy with the investigational agent, saying that a large difference is a reasonable proxy for improvements in overall survival. ASCO cosponsored a workshop with FDA in 2013 on pathologic complete response in high-risk earlystage breast cancer. The guidance includes a statement about implemen-

Palliative Care

be hard not to make going to the lung cancer sessions the priority.” Sessions at the Palliative Care in Oncology Symposium addressed a wide range of relevant topics including symptom management, patient survivorship care, end-of-life issues, the

continued from page 55

to 25 in Boston. The meeting theme was “Patient-Centered Care Across the Cancer Continuum.” ASCO is a cosponsor of the meeting, along with American Academy of Hospice and Palliative Medicine, the American Society for Radiation Oncology, and the Multinational Association of Supportive Care in Cancer Annual Meeting. According to Dr. Fisch, the meeting cosponsors have tapped into an unmet need with this symposium, which is providing an interface between oncology and palliative care. “One of the challenges of the ASCO Annual Meeting is that the palliative care content is pulled out into its own session,” said Jennifer S. Temel, MD, Clinical Director of Thoracic Oncology at Massachusetts General Hospital. “It can be difficult to get to more than one session, and since clinically I am interested in lung cancer, it would

Jennifer S. Temel, MD

ASCO Institute for Quality Launches New CancerLinQ Microsite

SCO has launched CancerLinQ. org to house all news and information about this cutting-edge health information technology platform that will provide real-time quality feedback to providers, uncover patterns that can improve care, and feed personalized decision support to physicians. ees, and we registered more than 650, which was the maximum that we can accommodate so we ended up having a waiting list.” According to Dr. Von Roenn, the attendance speaks to the growing importance of the issue of palliative care and the need for a forum for researchers to discuss and learn about current therapies, interventions, and paths forward. The next Palliative Care in Oncology Symposium will accommodate a larger number of attendees and is scheduled for October 2 to 3, 2015, in Boston. To learn more, visit pallonc.org.

Resource Center

early integration of palliative care, and psycho-oncology. Interest in the meeting was evident by the attendance. “Interest in the Palliative Care in Oncology Symposium exceeded our expectations,” Dr. Von Roenn said. “We had planned for about 350 attend-

Save the Date

tation that discusses the workshop’s conclusion that the benefits of using pathologic complete response as a measure for accelerated approvals outweigh the risks. Read the guidance at: www.fda.gov/

For those interested in palliative care who could not attend the symposium, ASCO provides a wide variety of palliative care resources on its website (www.asco.org/pallonc). Members who visit can find out more about upcoming meetings and courses, includ-

Learn how the platform will revolutionize cancer care and find the latest news and updates from the Society on all things CancerLinQ by visiting CancerLinQ.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

ing opportunities to attend workshops or complete online education activities. The website also includes a compilation of relevant guidelines, tools, and resources related to palliative care. Members can access ASCO’s Provisional Clinical Opinion on the integration of palliative care, find out more about Quality Oncology Practice Initiative measures for palliative care, or access other practice improvement resources addressing topics such as emotional well-being, fertility preservation, pain management, and more. Drs. Fisch, Temel, and Von Roenn all stressed that palliative care is an issue that concerns all oncologists. “If we practice in accordance with the Hippocratic Oath, then we have committed to making sure our patients live as well as they can, not just as long as they can,” Dr. Von Roenn said. n © 2014. American Society of Clinical Oncology. All rights reserved.

Gastrointestinal Cancers Symposium

Genitourinary Cancers Symposium

January 15-17, 2015

February 26-28, 2015

Moscone West Building

Rosen Shingle Creek

San Francisco, California

Orlando, Florida

In melanomaâ&#x20AC;Ś

A T CELL IS ONLY AS EFFECTIVE

Dendritic cell

References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol. 2004;172:6074-6079.

AS THE ANTIGEN THAT ACTIVATES IT1

T cell

Tumor-derived antigens (TDAs) set the immune system in motion by priming and activating T cells. Once released, TDAs are processed by dendritic cells and subsequently presented to T cells, initiating an adaptive immune response.1-3 Learn more at

MelanomaAntigens.com

The ASCO Post | DECEMBER 15, 2014

PAGE 60

Perspective Robert Peter Gale, Hillard M. Lazarus, and Peter Wiernik continued from page 1

In China, where government policy means most people with AML do not have a sibling, more than 1,500 HLA haplotype–matched transplants are done annually, many for persons with AML in first remission. That is more procedures of this type than are done in the rest of the world combined. All of this is quite exciting, but one really important question remains unanswered: should anyone with AML, even those with a perfect donor, receive a transplant in first remission? We recently discussed this issue,1 raising the blasphemous thought that transplants in first-remission AML may be inappropriate, even in persons with high-risk AML. All of what follows, of course, hinges on whether we can agree on the definition of “high-risk AML.”

Four Prerequisites Our opinion is based on analyses of data from clinical trials as well as on theoretical considerations. Four conditions are needed to justify transplants for AML in first remission: • (1) We should be able to reasonably precisely identify persons with AML in first remission (usually for a few months) at high risk for relapse. • (2) A transplant in first remission should have a therapeutic advantage over conventional therapy (if any) of a sufficient magnitude to overcome the adverse biologic features of the high-risk leukemia. • (3) A transplant in first remission should confer a substantial survival or leukemia-free survival advantage over waiting to determine if or when a person relapses and then doing a transplant (with or without additional therapy). • (4) We cause little harm to persons in first remission misidentified as likely to relapse and who receive a transplant. Unfortunately, few data support any of these conditions. For example, we Dr. Gale is Visiting Professor of Haematology, Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London and is a part-time employee of Celgene Corporation. Dr. Lazarus is Professor of Medicine at Case Western Reserve University School of Medicine, Director of Novel Cell Therapy at University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, and consultant for Actinium Pharmaceuticals. Dr. Wiernik is a medical oncologist at Cancer Research Foundation of New York, Chappaqua.

are poor at identifying, at the subject level, persons in first remission for a few months likely to relapse subsequently. Receiver-operator curves of prediction accuracy show we exhaust most of our predictive value by this time. A person with high-risk cytogenetics at diagnosis who rapidly achieves a remission and does not relapse in the first 3 to 6 months has a markedly different prognosis than he or she had at diagnosis.

Early vs Late Transplant The third assumption is critical. Are there really convincing data from a randomized study showing a benefit for transplants in first remission vs waiting for relapse and performing transplants only in these persons? No. The correct answer to whether there is a benefit of transplants over conventional therapy can only be derived from a trial starting at a reasonable time into first remission

We may be blasphemers but we are not nihilists, and we support clinical trials to test whether allotransplants in persons with AML in first remission—even those with high-risk leukemia (whatever that is)—are appropriate and needed for us to move forward. —Robert Peter Gale MD, PhD, DSc(hc), FACP, Hillard M. Lazarus MD, FACP, and Peter H. Wiernik MD, FACP, FASCO

This is because the best predictor of remission is remission and the best predictor of relapse is relapse, not cytogenetics. Although the a priori odds may be stacked against you, if you make it to kilometer 40, you are likely to finish the marathon. (Bayesians arise!) As for a therapeutic advantage, most data show that variables (or combinations thereof) predicting an unfavorable outcome with conventional therapy also operate after transplants. This should come as no surprise to hematologists and oncologists. Unfortunately, the adverse impact of bad cancer biology is usually stronger than the favorable impact of new therapies. Even if we assume transplants have a slight antileukemia advantage over conventional therapy, some or all of this benefit is lost to treatment-related mortality. And other bad things can happen, such as chronic graft-vs-host-disease, which may be worse than death from leukemia. To know whether bad cancer biology can be overcome in this setting, we need a study in which high-risk subjects are randomly assigned to receive or not receive the new intervention being tested. Such a study has not been reported, but, fortunately, several are in progress.

(say, 3 months), in which eligible subjects are randomly assigned to what is essentially an early vs late transplant in those who relapse. Such a study, of course, needs to be analyzed on an intent-to-treat basis, as some (many?) persons who relapse may not make it to a transplant and some persons assigned to a transplant may relapse before it can be done. Also, being in second remission should not be a requirement to proceed to a transplant in a person who relapses. Few studies attempting to address this question, even tangentially, are reported. The largest found comparable outcomes with a strategy of delaying transplants in persons with intermediate-risk AML until relapse with the advantage of having to do fewer transplants.2 Let’s call it a wash for now. As for the final condition—primum non nocere—there is little question that performing a transplant in someone already cured by conventional therapy is hardly in his/her interest.

Dubious Nomenclature Consider the nomenclature of AML risk assignment. Saying someone with newly diagnosed AML is “good-risk” seems a stretch. Good-

risk compared to what? A 65-yearold with good-risk AML has a 5-year survival probability of less than 20%. Good-risk in this context ranks close to “military intelligence” and “parental guidance” as a euphemism. People with good-risk AML should not buy an extended warranty on their new washer/dryer. (Consumer Reports suggests none of us do; free advice. Perhaps they know something we don’t.) Finally, some will say our discussion is akin to debating how many angels can dance on the head of a pin— medieval. Now that we have tests of measurable (not minimal) residual disease (MRD),3 can’t we simply reserve transplants for persons in first remission who are MRD-positive? Sadly, this is not so simple. Specificity and sensitivity of MRD tests for AML are quite imperfect. And although there is an association between a positive MRD test and an increased relapse risk, 20% to 40% of persons who are MRD-positive do not relapse, whereas 20% to 30% of persons who are MRDnegative do. In a recent large, well-done study of MRD testing in persons with AML in first remission, test results were informative in making a therapeutic decision in only about 20% of subjects.4 There were also high rates of false-negative and false-positive correlations between MRD test results and clinical outcomes. So asking whether it is better to be MRD-negative than MRD-positive is a bit like asking is it better to be young, beautiful, and rich, or old, ugly, and poor. The answer is simple, but it’s not the whole story. One is reminded of when George Bernard Shaw received this offer from Isadora Duncan: “Will you be the father of my next child? A combination of my beauty and your brains would startle the world.” Shaw replied, “I must decline your offer with thanks, for the child might have my beauty and your brains.”

Complex Biology None of this is surprising given several technical issues including sampling error at low leukemia cell frequencies.5 And then there is the fundamental biologic issue of the clonal diversity of AML at diagnosis, revealed by wholeexome and whole-genome sequencing.6,7 Because persons with AML at diagnosis have multiple clones with diverse mutations and with unknown capacities to proliferate, it seems rather unlikely we can devise an MRD test continued on page 61

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PAGE 61

RSNA 2014 RSNA Awards Gold Medal to Three Leaders in Radiology

he Radiological Society of North America (RSNA) awarded the Gold Medal, the organization’s highest honor, to three individuals at the RSNA 100th Scientific Assembly and Annual Meeting: Gary J. Becker, MD, of Tucson; Allen S. Lichter, MD, FASCO, of Alexandria, Virginia; and Etta D. Pisano, MD, of Charleston, South Carolina.

Gary J. Becker, MD Over the course of his 36-year career in radiology, the name Gary J. Becker, MD, has become synonymous with the word “leader.” In addition to serving as 2009 RSNA President, Dr. Becker served as Executive Director of the American Board of Radiology (ABR) from 2007 until his retirement in mid-2014. Among his many accomplishments, Dr. Becker oversaw ABR’s critical transition from oral to computer-based exams for certification in diagnostic radiology. Dr. Becker completed his residency in diagnostic radiology at Indiana University, where he served as Professor and Chief of the Vascular Section. In 1990, after 20 years at Indiana University, he moved to Miami Cardiac and Vascular Institute serving as Director of Interventional Radiology and ultimately as Assistant Medical Director of the Institute and Medical Director of Clinical Research until 2004. After serving as Branch Chief of Image Guided Intervention in the Di-

Robert Peter Gale, Hillard M. Lazarus, and Peter Wiernik continued from page 60

that will capture this complex biology. Moreover, it might be necessary to develop a different MRD test for each person. Added to this is our lack of knowledge of the phenotype and genotype of the cell(s) with the biologic potential to cause recurrent AML (rather than progeny of the clone). We may be blasphemers but we are not nihilists, and we support clinical trials to test whether allotransplants in

vision of Cancer Treatment and Diagnosis at the National Cancer Institute, Dr. Becker moved to the University of Arizona in 2005, serving as a professor in the interventional section of the Department of Radiology. Founding Editor of the Journal of Vascular and Interventional Radiology, Dr. Becker has served as a manuscript reviewer, editorial board member, associate editor, and editor for more than 20 journals.

Allen S. Lichter, MD, FASCO Allen S. Lichter, MD, FASCO, has served as Chief Executive Officer of ASCO since 2006. With research focusing on breast cancer, Dr. Lichter was an early advocate of the breast-conserving approach and conducted one of the trials that found the use of lumpectomy and radiation therapy to be as effective as mastectomy. This work, along with other trials conducted in the United States and Europe, revolutionized breast cancer treatment standards. Dr. Lichter previously served as the Director of the Radiation Therapy Section of the National Cancer Institute’s Radiation Oncology Branch. As Chair and Professor of Radiation Oncology and Dean of the University of Michigan Medical School, Dr. Lichter introduced an innovative curriculum and oversaw creation of a new Biomedical Science Research facility. At ASCO, Dr. Lichter has overseen persons with AML in first remission— even those with high-risk leukemia (whatever that is)—are appropriate and needed for us to move forward. n Disclosure: Dr. Gale acknowledges support from the NIHR Biomedical Research Centre funding scheme and is a part-time employee of Celgene. Drs. Lazarus and Wiernik reported no potential conflicts of interest.

References 1. Gale RP, Wiernik PH, Lazarus HM: Should persons with acute myeloid leukemia have a transplant in first remission?

Gary J. Becker, MD

Allen S. Lichter, MD, FASCO

Etta D. Pisano, MD

Women, in particular, and radiologists, in general, owe a debt of gratitude to Etta D. Pisano, MD, for her tireless efforts to develop, apply, and test imaging technology for the early detection and diagnosis of breast cancer and other breast problems. Dr. Pisano became the first female Dean of the College of Medicine at the Medical University of South Carolina (MUSC), Charleston, in 2010. Her biggest contributions to radiology have been the research and testing she has done to integrate emerging technology

into breast imaging; her groundbreaking study, Digital Mammographic Imaging Screening Tool (DMIST), was the largest clinical trial ever led by a radiologist and provided essential information about the efficacy of digital mammography. Dr. Pisano served MUSC as Vice President for Medical Affairs and Dean of the College of Medicine from 2010 to 2014. Previously, Dr. Pisano had served in numerous positions at the University of North Carolina (UNC) at Chapel Hill and alsoo served as founding Chief of Breast Imaging at UNC Hospitals. In addition to leading DMIST, Dr. Pisano has served as principal investigator for over 30 other studies. She has authored or coauthored 145 articles appearing in peer-reviewed journals and has been a reviewer for more than a dozen journals, including Radiology and RadioGraphics. The Gold Medal Awards were presented to Dr. Becker, Dr. Lichter, and Dr. Pisano on December 2, 2014, during the RSNA Annual Meeting in Chicago. n

Leukemia 28:1949-1952, 2014. 2. Burnett AK, Goldstone A, Hills RK, et al: Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. J Clin Oncol 31:1293-1301, 2013. 3. Goldman JM, Gale RP: What does MRD in leukemia really mean? Leukemia 28:1131, 2014. 4. Terwijn M, van Putten WL, Kelder A, et al: High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: Data from the HOVON/SAKK AML 42A

study. J Clin Oncol 31:3889-3897, 2013. 5. Butturini A, Klein J, Gale RP: Modeling minimal residual disease (MRD) testing. Leuk Res 27:293-300, 2002. 6. Ding L, Ley TJ, Larson DE, et al: Clonal evolution in relapsed acute myeloid leukemia revealed by whole-genome sequencing. Nature 481:506-510, 2012. 7. Cancer Genome Atlas Research Network: Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368:20592074, 2013.

projects including the CancerLinQ™ rapid learning system and the Quality Oncology Practice Initiative. He was Founding Chairman of the Conquer Cancer Foundation, ASCO’s philanthropic arm. A former coeditor of Oncology, Dr. Lichter also served in editorial positions with the Journal of the National Cancer Institute, International Journal of Radiation Oncology, Biology, Physics, and Journal of Clinical Oncology.

Etta D. Pisano, MD

Visit The ASCO Post website at ASCOPost.com

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

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

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

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

CYRAMZA monotherapy significantly extended overall survival (OS)1

CYRAMZA significantly delayed disease progression1 MAJOR OUTCOME MEASURE

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

Placebo

months

(4.4, 5.7)

(2.8, 4.7)

5.2

0.8

OS PROBABILITY

CYRAMZA

0.6

3.8

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

0.4

CYRAMZA Placebo

0.2

0.0 0

238 117

10 11 12 13

14 15 16 17 18 19

0 1

0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk CYRAMZA Placebo

154 66

92 34

49 20

17 7

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

7 4

3 2

37%

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

INCREASE IN MEDIAN OS

Most Common Adverse Reactions

Use in Specific Populations

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

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

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

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

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

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

CYRAMZA (ramucirumab) injection

PA000IPAM00-BS 9.25x13.25

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

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State of the Art

Palliative Care in 2014

A Conversation With Tracy Batchelor, MD By Piana A Ronald Conversation With Diane E. Meier, MD By Ronald Piana

alliative care expert Diane E. Meier, MD, is the Director of the Center to Advance Palliative Care (CAPC), a national organization devoted to enhancing the number and quality of palliative care programs across the nation. Under her leadership, the number of palliative care programs in the United States has more than tripled over the past 10 years. The ASCO Post recently spoke with Dr. Meier about the evolving role of palliative care throughout the oncology delivery system.

Major Advances Palliative care’s integration into standard of care in oncology has, in some ways, been an uphill battle. What are the biggest advances you’ve seen in this field in your career? The most notable advance has occurred quite recently with the accumulating body of evidence demonstrating that concurrent delivery of palliative care with best practices in cancer care not only improves quality of life for patients and families, it also prolongs life. To the credit of the oncology community, this accumulating body of data is driving change in oncologic delivery and service models. People in the community now understand that palliative is not a nice-to-have service; it’s a musthave part of the cancer care continuum. The first goal of palliative care is to

best serve our patients and families, placing them at the center of our palliative care mission. Naturally, if patients feel better, they are more likely to complete their appropriate cancer treatments. Hence, palliative care extends the patient’s life, and that’s our mission as oncologists. So this important message, backed by data, is now catching on. I think about 87% of [National Cancer Institute]–designated comprehensive cancer centers have integrated high-quality palliative care teams into their delivery model.

People in the community now understand that palliative is not a nice-to-have service; it’s a must-have part of the cancer care continuum. —Diane E. Meier, MD

Moreover, realizing that palliative care was not restricted to end-of-life care was a true paradigm shift in oncology; as a community we finally embraced the notion of treating the whole person with concurrent palliative care intervention, not just treating the disease. It was a huge step forward in patient care.

Pain Management Despite growing awareness by the major cancer organizations, undertreated

Center to Advance Palliative Care

cancer pain is still a serious clinical problem. Where are we in this challenge, and what is the way forward to ensure that all our cancer patients have their pain properly managed? Appropriate management of pain has seen a couple of major pendulum swings in this country. Twenty years ago there was real fear of prescribing opioids. For one thing, doctors dreaded having their offices raided and being handcuffed by drug enforcement agents and hauled off to jail. Following this overreaction, there was a widespread

n the first quarter of 2015, the Center to Advance Palliative Care (CAPC) will become a member-based organization. Member organizations will have unlimited access to CAPC tools, training, and hands-on technical assistance. At that time, CAPC will launch the first of its online curricula, broken into three specialized silos: • Pain Management (eg, pain assessment, opioid conversions, match the drug class to the pain) • Communication Skills (eg, discussing serious news, discussing prognosis, conducting a family meeting) • Operational (eg, what is palliative care, designing your hospital-based program, building a business plan) For more information about CAPC, visit www.capc.org.

movement to educate physicians and the public that opioids were the gold standard of pain control and that pain was a bad symptom that needed to be controlled. However, some people oversold the safety component of opioid analgesics. We then saw some inappropriate use of these drugs by physicians, most of whom were prescribing opioid analgesics for chronic pain as opposed to cancer pain. Unfortunately, during this period, there was a thriving street-drug trade that ultimately led to a series of overdoses and deaths, all of which garnered national attention in the lay press. As a reaction, the pendulum swung back the other way, leading to tighter restrictions and tougher [U.S. Food and Drug Administration] labeling on opioid analgesics. The challenge for us in health care is to achieve a proper balance, and the key to that balance is ensuring that all of the health-care professions with prescribing privileges, from doctors to physician assistants, are properly educated. Appallingly, the vast majority of

people who prescribe opioid analgesics have had little to no training in the safe and effective use of these drugs. Remarkably, it is not a required component in the medical curricula. Consequently, we are graduating doctors and turning them out into the health-care system without these essential skills. There will never be enough palliative care specialists to manage pain, so we need to make sure that every health-care professional who services our patients is trained in the proper use of pain medications.

Training Initiative How do we begin a training initiative of that huge scale? It requires a systematic approach. Because I believe so strongly in this issue, my organization, CAPC, is developing a comprehensive palliative care clinical curriculum aimed at every clinician who cares for people with serious illnesses, with special emphasis on oncologists. For example, there are 12 different interactive courses on safe and effective opioid prescribing—that can be taken on any mobile device—which is 12 times more than anyone got in medical school residency or fellowship. If one passes these courses and receives a CAPC designation, patients and family members can be confident that that the clinician has a firm knowledge of how to properly prescribe and use opioid analgesics. Importantly, in the first quarter of 2015, CAPC will become a membership organization, with membership open to health-care organizations including hospitals, hospices, and nursing homes, as well as home care agencies and payers. Once an organization joins us, all the clinical staff of that organization will have full access to CAPC’s expanded training and technical assistance content, including Continuing continued on page 66

The ASCO Post | DECEMBER 15, 2014

PAGE 66

FDA Update

Ixazomib Receives Breakthrough Therapy Designation for Relapsed or Refractory Systemic Light-Chain Amyloidosis

he U.S. Food & Drug Administration (FDA) has granted Breakthrough Therapy status to Takeda Pharmaceuticals’ investigational, oral proteasome inhibitor, ixazomib (MLN9708), for the treatment of re-

lapsed or refractory systemic light-chain amyloidosis. This is the first proteasome inhibitor and first investigational therapy for systemic light-chain amyloidosis to receive Breakthrough Therapy designation. Systemic light-chain amyloidosis is a rare and aggressive protein misfolding disorder with fewer than 3,000 cases diagnosed in the United States every year. It is characterized by the

deposition of amyloid in bodily organs and tissues. While systemic light-chain amyloidosis can affect different organs in different people, it frequently affects the heart, kidneys, liver, spleen, nervous system, and gastrointestinal tract. There are no approved treatments in the United States or globally for systemic light-chain amyloidosis, representing a significant unmet medical need.

The development program for ixazomib in this indication progressed directly from a phase I to a phase III clinical trial, TOURMALINE-AL1, which is currently evaluating ixazomib plus dexamethasone in patients with relapsed or refractory systemic lightchain amyloidosis. This is the only phase III trial for relapsed or refractory systemic light-chain amyloidosis and it is recruiting globally. n

FDA Grants Breakthrough Therapy Designation to Investigational CAR T-Cell Therapy

he U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to JCAR015, an investigational chimeric antigen receptor therapy developed by Juno Therapeutics. The designation applies for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia and was filed by Juno’s collabo-

ration partner, Memorial Sloan Kettering Cancer Center, where phase I clinical trials are currently underway. JCAR015 is currently being tested in clinical trials at Seattle Children’s Hospital for relapsed/refractory CD19positive pediatric leukemia and at Fred Hutchinson Cancer Research Center for refractory chronic lymphocytic leuke-

mia, non-Hodgkin lymphoma, and acute lymphoblastic leukemia. Data on these programs will be presented at the 54th Annual Meeting of the American Soci-

ety of Hematology meeting next week in San Francisco. The FDA’s Breakthrough Therapy designation was created to help accelerate the development and review of new drugs for serious or life-threatening conditions. The designation comes with potential benefits, including intensive FDA guidance and eligibility for priority review. n

Diane E. Meier, MD

Closing Thoughts

continued from page 65

Any last thoughts on this field that you’ve dedicated your career to? Palliative care is about meeting the patient and the family and understanding where they are in their particular clinical situation. It’s about understanding patients’ hopes and fears and what matters most to them, and then using the power that our training has given us as doctors to help those people achieve their goals. Each person battling a serious illness has unique priorities, and it is our job to mobilize the health-care system in the service of each patient and fam-

ily. The patient is not just another cog in the system, and we must remember that the sole reason for palliative care is to rekindle the roots of the healing profession. It’s about the patient as a person. The cost element, which is important in overall health care, is not what palliative care is all about. However, there are analyses demonstrating that palliative care intervention prevents many unnecessary emergency room visits, which of course saves the system money. There are other examples where palliative care saves money by addressing

symptoms before they become emergencies. The cost-saving issues are a side effect of delivering better quality of care, but they are not part of the intended role of palliative care. That’s an important distinction because, in palliative care, we often advocate for very expensive therapies if we think they are beneficial for our patients. Delivering the best care possible is what drives palliative care, no matter how much it costs. It’s all about meeting the needs and goals of the patient in front of us. n

Education Units and Continuing Medical Education. We’ll offer a number of value-added courses such as integrating palliative care into the nursing home setting. These courses also help managers, whether they’re clinicians or administrators, understand the components of a high-quality palliative care delivery system. For instance, how can you get paid and measure quality and make sure your staff is adequately trained? The courses offer a full spectrum of valuable and actionable knowledge.

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

ASCOPost.com | DECEMBER 15, 2014

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Announcements

Dr. Matthew J. Ellis Named Director of Lester and Sue Smith Breast Center

atthew J. Ellis, MD, PhD, a renowned clinician scientist in the area of genomics and molecular profiling of breast cancer, was named the new Director of the Lester and Sue Smith Breast Center at Baylor College of Medicine. Dr. Ellis assumed his new role in

addition to the Smith Breast Center team and our mission to improve diagnosis, prevention, and treatment of breast cancer,” said Dr. Osborne. “He will serve as an important link with the Baylor Human Genome Sequencing Center. In addition, he brings with him

a large resource of patient-derived xenografts, which are excellent for testing new therapies and understanding treatment resistance.” Dr. Ellis is a native of the United Kingdom. He completed his medical degree from Queens’ College & School

of Clinical Medicine at the University of Cambridge in England, postgraduate clinical training at the Royal College of Physicians in London, and doctoral training at the Royal Postgraduate Medical School at the University of London. n

Matthew J. Ellis, MD, PhD

September 2014, succeeding C. Kent Osborne, MD, Director of the National Cancer Institute–designated Dan L. Duncan Cancer Center at Baylor. “Dr. Ellis has an excellent track record in leadership, and his research in genomics is outstanding,” said Paul E. Klotman, MD, President, CEO, and Executive Dean of Baylor College of Medicine. “He is the perfect fit for our organization and its goal of bringing new treatments to patients on an accelerated timeline.” Dr. Ellis was recruited from Washington University School of Medicine in St. Louis, where he was Professor of Medicine and Head of the Section of Breast Oncology, a position he had held since 2010. He also had served as Head of Medical Oncology at Washington University School of Medicine and had been a faculty member there since 2003.

Groundbreaking Work Dr. Ellis’ work has unveiled groundbreaking new information about mutations in breast cancer and their clinical relevance. He has been instrumental in developing a genome atlas and therapeutic road map for estrogen receptor–positive breast cancer. More recently, he has found that metastatic breast tumors initially positive for the estrogen receptor frequently harbor mutations and translocations in the receptor, which render the tumor resistant to endocrine therapies used to block estrogen. Several laboratories are now trying to develop new drugs that will block these mutant receptors. His genomic and proteomic studies have been funded by the National Human Genome Institute, the National Cancer Institute, the AVON Foundation, the Breast Cancer Research Foundation, and Susan G. Komen for the Cure. “Dr. Ellis will be an outstanding

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The ASCO Post | DECEMBER 15, 2014

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Announcements

Karmanos Cancer Institute’s Hayley Thompson, PhD, Awarded $1.8 Million Grant to Improve Access to Cancer Survivor Resources

ayley S. Thompson, PhD, Associate Professor, Population Studies and Disparities Research Program at the Barbara Ann Karmanos Cancer Institute, and Department of Oncology,

Wayne State University School of Medicine, was recently awarded a $1.8 million grant from the Agency for Healthcare Research and Quality (AHRQ), which will be given over the next 4 years.

The grant titled “eHealth Activity Among African American and White Cancer Survivors” will study the use of Internet-based and mobile technologies by cancer survivors once their treat-

ment has ended. The study will compare how African American and white cancer survivors access health resources electronically and the impact that has on their cancer survivorship.

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Announcements

Interviews will be conducted with a sample of approximately 1,230 African American and white breast, prostate, and colorectal cancer survivors from the metropolitan Detroit area to assess general eHealth activity, as well as specific eHealth activities, such as searching the Internet for health information, purchasing medication online, or e-mailing one’s physician.

Hayley S. Thompson, PhD

A select subsample of 144 participants will receive in-home visits from the study team to observe personal health information management in the home and examine the role of technology in the context of health information management. The results will guide the development of a mobile app focused on cancer survivorship resources that can be accessed digitally.

“While it is good news that more people are surviving cancer, many of these individuals face different health-related issues,” said Dr. Thompson. “Working with eHealth technologies to help improve the cancer survivor’s access to needed services could help address and prevent some of the overwhelming needs and stresses that cancer survivors experience.” n

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Journal Spotlight Head/Neck Cancer

Antacids Linked to Better Survival in Patients With Head and Neck Cancer

atients with head and neck cancer who used antacid medicines to control acid reflux had better overall survival, according to a study from the University of Michigan Comprehensive Cancer Center. Results of the study were published in Cancer Prevention Research.1

Reflux can be a common side effect of chemotherapy or radiation treatment for head and neck cancer. Doctors at the University of Michigan frequently prescribe two types of antacids, namely proton pump inhibitors or histamine 2 blockers, to help treat this side effect.

Study Details The researchers looked at 596 patients who were treated for head and neck cancer. More than two-thirds of the patients took one or both types of antacid medication after their diagnosis. Patients who were taking antacids

had significantly better overall survival than those who did not take them. Proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole) had the biggest effect, showing a 45% decreased risk of death, compared to patients who did not take antacids. Pa-

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Journal Spotlight

tients taking histamine 2 blockers (eg, cimetidine, ranitidine, famotidine) had a 33% decreased risk of death. “We had suspicions that these medications somehow had a favorable impact on patient outcomes. This led us to review our large cohort of patients and screen them for common medications, focusing on antacids. In fact, our study

did show that people taking antacids are doing better,” said lead study author Silvana Papagerakis, MD, PhD, Research Assistant Professor of Otolaryngology—Head and Neck Surgery at the University of Michigan Medical School and an Adjunct Clinical Assistant Professor at the University of Michigan School of Dentistry.

Next Steps The researchers are not clear why these medications affect the cancer, although they have begun additional work to understand the mechanisms involved. “What this study makes clear is these medications may be more beneficial to the patients than just controlling

side effects,” she said, adding that more studies are needed before antacids can be recommended for all patients with head and neck cancer. n

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

Reference 1. Papagerakis S, et al: Cancer Prev Res 7:1258-1269, 2014.

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The ASCO Post | DECEMBER 15, 2014

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In Memoriam Oncology Worldwide

AACR CEO Discusses the Global Status of Cancer at Seminar in Turin, Italy

argaret Foti, PhD, MD (hc), Chief Executive Officer of the American Association for Cancer Research (AACR), recently spoke at the Institute for Cancer Research and Treatment (IRCC) in Turin, Italy, on November 25. Her lecture was titled “Reflec-

tions on the Global Cancer Research Landscape.” The audience included both senior and junior researchers at the IRCC, a nonprofit scientific and clinical institution in Turin that specializes in all areas of cancer research, especially transla-

tional cancer research. Its mission is to fight cancer through understanding the basics of the disease, offering state-ofthe-art diagnostic and therapeutic services, and leveraging the interface between molecular biology and medicine. Dr. Foti’s comprehensive presenta-

tion on the “Global Cancer Research Landscape” covered three main points: the global status of cancer, the progress and challenges facing the cancer field, and what the AACR is doing to address global cancer incidence and mortality. Advances

Margaret Foti, PhD, MD (hc)

in cancer research, she explained, have led to cures for a number of different cancers, a higher quality of life for cancer survivors, and an extension in the lives of patients whose cancer cannot be cured. Yet the global cancer burden will continue to rise unless cancer becomes a global priority, with governments and the general public committing to more funding, education, and improvements in regulatory science and policy. Dr. Foti emphasized these points by presenting data on cancer incidence and mortality in the world, Europe, and Italy. Major increases in incidence and mortality from cancer are projected to rise significantly by 2035, unless we stem the tide of this complex set of diseases.

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Importance of Collaboration Dr. Foti also discussed the importance of collaborations in tackling the toughest problems in cancer. With more than 35,000 members in 97 countries, the AACR has made collaboration a high priority, both in the United States and internationally. In October 2014, the organization opened its first satellite office outside the United States in Shanghai, with the goal of developing collaborations to maximize progress in the Asia Pacific region and around the world. Further, as the Scientific Partner of Stand Up To Cancer (SU2C), the AACR collaborates with SU2C and cancer research organizations across the globe in the oversight of a number of meritorious research grants. The AACR also partners with international organizations to host scientific meetings and workshops, including the prestigious series of annual meetings on Molecular Targets and Cancer Therapeutics held along with the U.S. National Cancer Institute (NCI) and the European Organisation for Research and Treatment of Cancer (EORTC). n

ASCOPost.com | DECEMBER 15, 2014

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Issues in Oncology Palliative Care

Debate Over Legalizing Physician-Assisted Death for the Terminally Ill

Four experts in ethics and palliative care argue the pros and cons of Death With Dignity laws. By Jo Cavallo

n November 1, 2014, 29-yearold Brittany Maynard ended her life through physician-assisted death, reigniting the controversy surrounding Death With Dignity laws, which allow physicians to prescribe life-ending drugs to terminally ill patients. Diagnosed with glioblastoma multiforme in January, Ms. Maynard was given 6 months to live. Afraid that she would suffer unremitting pain and cognitive and motor loss, she moved from California to Oregon, one of five states with laws legalizing physician-assisted death—often referred to as physicianassisted suicide—so she could choose “death with dignity.” “Having this choice at the end of my life has become incredibly important,” wrote Ms. Maynard in an essay posted on CNN.com.1 “It has given me a sense of peace during a tumultuous time that otherwise would be dominated by fear, uncertainty, and pain.”

Description and Perception Since Oregon’s Death With Dignity Act became law in 1997, 752 patients have participated in physician-assisted death; 400 more people received prescriptions to end their lives but never took the medication. Despite outcries from opponents of assisted death that facilitating suicide in any context devalues human life, there is growing support of the Death With Dignity movement across the country, with 70% of Americans in favor of allowing doctors to hasten a terminally ill patient’s death when the process is described as “ending the patient’s life by some painless means,” according to a 2013 Gallup Poll.2 However, support for the process drops to 51% when it is described as doctors helping patients “commit suicide.” According to the latest information, seven states, including Connecticut, Hawaii, Kansas, Massachusetts, New Hampshire, New Jersey, and Pennsylvania, have pending bills in favor of physician-assisted death.

Arguing the Pros and Cons Although ASCO has taken no official position on physician-assisted suicide, in a 1998 position statement on highquality end-of-life care,3 which neither supported nor condemned the practice, the Society recommended that physicians engage their patients in discussions

about their concerns regarding how they might die; explain what comfort care will be provided; and assure patients that they will not be abandoned. “The most important response to the physician-assisted suicide debate is to take every responsible measure to assure that all physicians are well trained in optimal end-of-life care and to remove all barriers to the delivery of such care,” said the statement. In November 2014, Intelligence Squared U.S. Debates, a nonpartisan, nonprofit organization in New York, argued the ethics of the issue and whether death with dignity laws devalue human life and lead to a slippery slope, where vulnerable patients are pressured to choose death, or are a recognition of everyone’s basic human rights to autonomy and freedom from pain and suffering. The motion “Legalize Assisted Suicide” was argued by four authorities in ethics and palliative care and then voted on by audience members. Arguing for the motion were Peter Singer, MA, BPhil, the Ira W. DeCamp Professor of Bioethics at the University Center for

PRO

Andrew Solomon, PhD Because much of modern medicine prolongs not living but dying, we need to rethink death itself. Making someone die in a way that others approve, that he feels is anathema, is an odious form of tyranny. Aiding dying needs to be tightly regulated, as any life or death matter does, from driving to surgery. However, although no one should be pressed into assisted dying, no one should be categorically denied that right. It’s about dignity. Brittany Maynard, who captured headlines for choosing to end her life at the age of 29 at the end of a battle with brain cancer, said, “It has given me peace. I do not want to die, but I am dying, and I want to die on my own terms.” It’s not about depression. When hope of recovery is gone, when one achieves relief from physical symptoms only at the cost of mental clarity, and once dignity is lost to physical

When hope of recovery is gone, when one achieves relief from physical symptoms only at the cost of mental clarity, and once dignity is lost to physical deterioration, the wish to end one’s life may be rational. ©Annie Leibovitz

Human Values at Princeton University; and Andrew Solomon, PhD, Professor of Clinical Psychology at Columbia University. Arguing against the motion were Baroness Ilora Finlay, FMedSci, Professor of Palliative Medicine at the Institute of Cancer & Genetics at Cardiff University School of Medicine in Wales and President of the British Medical Association; and Daniel P. Sulmasy, MD, PhD, the Kilbride-Clinton Professor of Medicine and Ethics in the Department of Medicine and the Divinity School and Associate Director at the MacLean Center for Clinical Medical Ethics at the University of Chicago Medicine. The ASCO Post has excerpted portions of the debate here. (To watch the full debate, go to http://fora.tv/2014/11/13/ Legalize_Assisted_Suicide.)

—Andrew Solomon, PhD

deterioration, the wish to end one’s life may be rational. Some people may find great meaning in those very final stages, whereas others may not be interested in finding that meaning. And from a nontheological point of view, it can be argued that the meaning people attach to that stage of life is an artifact of the human imagination. It’s not about suicide. Suicide responds to personal disintegration, whereas this precludes it. And it is about the limitations of medicine. It’s nothing short of medical arrogance to say that palliative care and hospice care can adequately deal with the end of every life. Hospice, in fact, can impose an authoritarian, hard, paternalistic view that the hospice way of dying is the only way.

Daniel P. Sulmasy, MD, PhD

CON

Daniel P. Sulmasy, MD, PhD I am a physician, and part of my job is to help people die with dignity and in comfort. However, I don’t want to help you or your daughter or your uncle commit suicide. And you shouldn’t want me to. I urge you to oppose physician-assisted suicide, because it’s bad ethical reasoning, bad medicine, and bad policy. We strongly support the right of patients to refuse treatments and believe that physicians have a duty to treat pain and other symptoms, even to the point of hastening death. However, empowering physicians to assist patients with suicide is quite another matter, striking at the heart not just of medical ethics, but also of ethics itself. That’s because the very idea of interpersonal ethics depends upon our mutual recognition of each other’s equal independent worth, the value that we have simply because we are fellow human beings. Now, is assisted suicide death with dignity? The word “dignity” has at least two senses. Proponents use the word in an attributed sense to denote the value others confer on them or the value they might even confer upon themselves. But there’s a deeper, intrinsic sense of dignity. Human dignity ultimately rests not on a person’s interests, but on the value of the person whose interests they are. I don’t have to ask you what your preferences are to know that you have dignity. Assisted suicide and euthanasia require us to accept that it is morally permissible to act with the specific intention of making a somebody into a nobody, to make the person dead. Intentions, not just outcomes, matter in ethics. Intending that somebody be turned into a nobody violates the fundamental basis of our interpersonal ethics, our intrinsic dignity. Paradoxically, in physician-assisted continued on page 74

The ASCO Post | DECEMBER 15, 2014

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Issues in Oncology Physician-Assisted Death continued from page 73

suicide and euthanasia, patients turn control over to physicians, who assess their eligibility and must provide the means. And, further, since death obliterates all liberty, saying that respect for liberty justifies the obliteration of liberty undermines the value that we place on human freedom.

PRO

Peter Singer, MA, BPhil

©Denise Applewhite/ Princeton University

First, we believe that people should be the ones to decide for themselves whether they think that continued life is worthwhile for them or not. We don’t think that it should be up to anybody else to say, “We think your life is worth-

bert. She’s a retired oncology nurse, so she knows a lot about cancer and about people dying of cancer. She now herself has terminal liver cancer, but she supports this [bill] because she said, “As I battle my illness, I would like the choice and comfort that come with the option of aid in dying.”

CON

Baroness Ilora Finlay, FMedSci I’m a palliative care physician. For more than 25 years, I’ve looked after dying patients. I’ve had countless conversations about death and dying and supported each one individually, not with some type of formula death. It is through compassion that I see how dangerous it is to license doctors to provide lethal drugs. When you normalize physicianassisted suicide, the underlying social dynamic changes. Laws aren’t just regulatory instruments; they send a message. And the message they send is that

For more than 25 years, I’ve looked after dying patients. I’ve had countless conversations about death and dying, and … it is through compassion that I see how dangerous it is to license doctors to provide lethal drugs.

Peter Singer, MA, BPhil

while.” And, second, we think that there is a lot of unnecessary suffering, whether it’s excruciating pain or not; suffering and distress of various sorts will continue in this system, and for the foreseeable future, it could be relieved by a relatively simple legislative reform that has been shown to work. Now, in fact, [the Northeast] region took a little step closer to that. The New Jersey State Assembly voted to pass the Aid in Dying for the Terminally Ill Act, which is similar to the other legislation that we’ve been discussing. It voted 41 to 31—a fairly clear majority. Of course, it still has to go to the Senate, where it would need the assent of the governor, so it still has some way to go. I want to quote one of the supporters of the bill whose name is Janet Col-

about 1 in 20 [patients] is found to have died of something different from the condition for which he or she was treated. Forty percent of seriously ill people have some mental disturbance often attributed to the illness, anxiety, or treatment. And in 13% to 14% [of the cases], this is a major, treatable depression. Yet Oregon’s own research shows that about 25% of those seeking assisted suicide have depression, which is sometimes missed or overlooked. [Outside] pressures [on the patient] may be more difficult to pick up than depression. Coercion can be subtle—the costs of care, life insurance about to expire, or just caregiver fatigue (the person who picks up that their family is stressed and doesn’t want to be thought of badly). And what of doctors? For the doctor under pressure, it is all too easy to give into the pressure to prescribe. Doctors must recognize dying, not impose futile treatments, and relieve distress.

—Baroness Ilora Finlay, FMedSci

if you’re terminally ill, ending your life is something that you ought to think about. Changing the law isn’t simple and straightforward. So, what are some of the problems? Let’s look at prognosis. Prognoses are notoriously inaccurate. Even the most expert [at predicting when death will occur] has a 50/50 chance of being wrong about a life expectancy of 6 months. Oregon’s law requires a prognosis of 6 months or less [to be eligible for assisted death], yet 2 years, 9 months from request to death has been recorded. Pathologists tell us that at postmortem,

It’s all too easy to be swayed by emotion and fear, but human beings are uniquely interconnected. If I accede to the request to provide lethal drugs, I actually give the message, “Yeah, I think you’re right. You’d be better off dead.” I don’t give the message that you are of worth. I’ve been there myself. My own mum was in a hospice dying, angry, terribly angry that I was opposing the assisted suicide that she wanted. She thought it was the answer. This fiercely independent lady dreaded dependence. It broke my heart, and I

was torn apart by it. So, she battled with us and then went home. To everyone’s surprise, she didn’t die; she lived 4 more years. And in those 4 years, she saw her two great grandsons born. And she said they were the richest years of her life. They were important to her and to us all. [Assisted suicide] is not like in the movies. Assisted suicide isn’t straightforward and clean and quick. Some people take a long time to die, up to 104 hours. That’s not dignified. Don’t vote for this dangerous law that actually deprives people of the possibility of having their dignity and having doctors who have to work to improve their quality of life. This law allows them to throw in the towel.

Results of the Debate An audience vote before the debate showed that 65% were in favor of the motion to “Legalize Assisted Suicide”; 10% were against the motion; and 25% were undecided. After the debate, 67% voted for the motion. According to the rules of the debate, the opposing side had to pick up 2 or more percentage points to win the debate. In the final tally, 22% of the audience participants voted against the motion, an increase of 12 percentage points over the original vote, and the side arguing against physician-assisted suicide was declared the winner. n References 1. Maynard B: My right to death with dignity at 29. November 2, 2014. Available at http://www.cnn.com/2014/10/07/ opinion/maynard-assisted-suicide-cancer-dignity. Accessed December 1, 2014. 2. U.S. support for euthanasia hinges on how it’s described. Gallup, May 29, 2013. Available at http://www.gallup. com/poll/162815/support-euthanasiahinges-described.aspx. Accessed December 1, 2014. 3. Cancer care during the last phase of life. J Clin Oncol 16:1986-1996, 1998.

Don’t Miss These Important Reports in This Issue of The ASCO Post Tony S. K. Mok, MD, on crizotinib in ROS1-rearranged NSCLC see page 35

F. Stephen Hodi, MD, and colleagues, on metastatic melanoma see page 38

Visit The ASCO Post online at ASCOPost.com

Jennifer A. Ligibel, MD, on relieving fatigue in cancer survivors see page 46

ASCOPost.com | DECEMBER 15, 2014

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Announcements Hematology

ASH Releases Second List for Choosing Wisely Campaign

he American Society of Hematology (ASH) has announced five additional commonly used tests, treatments, and procedures in hematology that physicians and patients should question in certain circumstances. The additional items join an initial list of five practices to question that the Society released this past year as part of the Choosing Wisely ® campaign, an initiative of the American Board of Internal Medicine Foundation. These new practices to question are also highlighted in a recent issue of Blood.1

Recommendations ASH’s new Choosing Wisely recommendations include the following five practices: • Don’t treat with an anticoagulant agent for more than 3 months in a patient with a first venous thromboembolism that has occurred in the setting of a major transient risk factor. • Don’t routinely transfuse patients with sickle cell disease for chronic anemia or uncomplicated pain cri-

sis without an appropriate clinical indication. • Don’t perform baseline or routine surveillance computed tomography scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia. • Don’t test or treat for suspected heparin-induced thrombocytopenia in patients with a low pretest probability of heparin-induced thrombocytopenia. • Don’t treat patients with immune thrombocytopenic purpura in the

absence of bleeding or a very low platelet count.

Evidence-Based Methodology The second ASH Choosing Wisely list was developed using a rigorous evidence-based methodology that incorporated suggestions from ASH members and prioritized avoiding harm to patients above all other considerations. The goal of the list is to start conversations both within the hematology community and among physicians and their

ASH developed its second Choosing Wisely list to help hematologists manage the utilization and delivery of patient-care resources, and the Society encourages hematologists to consider these recommendations in all facets of their work, including patient care, teaching, innovation, and research. —Lisa Hicks, MD

patients about how everyone can maximize the quality of hematologic care. “Unnecessary treatments or tests not only add waste to the health-care system, but in some cases they also expose our patients to a risk of harm,” said Lisa Hicks, MD, of St. Michael’s Hospital and the University of Toronto and Chair of the ASH Choosing Wisely Task Force. “ASH developed its second Choosing Wisely list to help hematologists manage the utilization and delivery of patient-care resources, and the Society encourages hematologists to consider these recommendations in all facets of their work, including patient care, teaching, innovation, and research,” she added. n To learn more about Choosing Wisely and to view ASH’s 10 items to question, visit www.ChoosingWisely.org. Reference 1. Hicks LK, Bering H, Carson KR, et al: The second ASH choosing wisely campaign: Five hematologic tests and treatments to question. Blood. December 3, 2014 (early release online).

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

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APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown. RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.” mCRC = metastatic colorectal cancer; OS = overall survival. WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Important Safety Information • In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. • A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory. • Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving

FOLFOX alone (HR = 1.16, 95% CI: 0.94–1.41). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for treatment with Vectibix®. • Progressively decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. • In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. • Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. • Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. • In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4 • The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone • Prespecified major efficacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02) • Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC • Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm (n = 331) (HR = 0.83; 95% CI: 0.70, 0.98) • There were no OS or PFS benefits in Vectibix®-treated patients with mutant KRAS/RAS mCRC • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. • Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis. • In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/ acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). • NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. • As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. • Advise patients of the need for adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus, and has the potential to cause fetal

harm when administered to pregnant women. • Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®. • Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. • In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. • In Study 3, the most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inﬂammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-aﬂibercept) prescribing information, sanoﬁ-aventis. Avastin® is a registered trademark of Genentech, Inc. Erbitux® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap® is a registered trademark of Regeneron Pharmaceuticals, Inc. Please see Brief Summary of full Prescribing Information on adjacent page. ©2014 Amgen Inc. All rights reserved. 10/14 61007-R7-V1

Visit www.vectibix.com

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Vectibix (panitumumab) ®

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Growth of eyelashes GASTROINTESTINAL DISORDERS Nausea Diarrhea Vomiting Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue Mucosal inﬂammation INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea Cough SKIN AND SUBCUTANEOUS TISSUE DISORDERS Erythema Pruritus Acneiform dermatitis Rash Skin ﬁssures Exfoliative rash Acne Dry skin Nail disorder Skin exfoliation Skin ulcer

Study 1 Vectibix® Plus Best Supportive Care Best Supportive Care (N = 234) (N = 229) Any Grade Grade 3-4 Any Grade Grade 3-4 n (%) n (%) n (%) n (%) 13 (6) 52 (23) 49 (21) 43 (19) 15 (7)

2 (< 1) 4 (2) 6 (3)

37 (16) 26 (11) 28 (12) 2 (< 1)

1 (< 1)

60 (26) 15 (7)

10 (4) 1 (< 1)

34 (15) 2 (< 1)

7 (3)

57 (25)

4 (2)

41 (18) 34 (15)

12 (5) 1 (< 1)

30 (13) 17 (7)

8 (3)

150 (66) 132 (58) 131 (57) 51 (22) 45 (20) 41 (18) 31 (14) 23 (10) 22 (10) 21 (9) 13 (6)

13 (6) 6 (3) 17 (7) 3 (1) 3 (1) 4 (2) 3 (1)

2 (< 1) 4 (2) 2 (< 1) 2 (< 1) 1 (< 1)

2 (< 1)

2 (< 1) 1 (< 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%). In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix ®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)]. In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix ®-treated patients [see Dosage and Administration (2.3)]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported. Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®. Table 2: Adverse Reactions (≥ 5% Difference) Observed in Patients with Wild-type (WT) KRAS Tumors Treated with Vectibix® and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone (Study 3)

SYSTEM ORGAN CLASS Preferred Term EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS Diarrhea Stomatitis GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inﬂammation Asthenia INFECTIONS AND INFESTATIONS Paronychia INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Anorexia Hypomagnesemia Hypokalemia Dehydration RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

FOLFOX Alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

58 (18)

5 (2)

10 (3)

201 (62) 87 (27)

59 (18) 15 (5)

169 (52) 42 (13)

29 (9) 1 (< 1)

82 (25) 79 (25)

14 (4) 16 (5)

53 (16) 62 (19)

1 (< 1) 11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

116 (36) 96 (30) 68 (21) 26 (8)

14 (4) 21 (7) 32 (10) 8 (2)

85 (26) 26 (8) 42 (13) 10 (3)

46 (14)

30 (9)

6 (2) 1 (< 1) 15 (5) 5 (2)

Vectibix® Plus FOLFOX (n = 322) Any Grade Grade 3-4 n (%) n (%)

FOLFOX Alone (n = 327) SYSTEM ORGAN CLASS Any Grade Grade 3-4 Preferred Term n (%) n (%) SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash 179 (56) 55 (17) 24 (7) 1 (< 1) Acneiform dermatitis 104 (32) 33 (10) Pruritus 75 (23) 3 (< 1) 14 (4) Dry skin 68 (21) 5 (2) 13 (4) Erythema 50 (16) 7 (2) 14 (4) Skin fissures 50 (16) 1 (< 1) 1 (< 1) Alopecia 47 (15) 30 (9) Acne 44 (14) 10 (3) 1 (< 1) Nail disorder 32 (10) 4 (1) 4 (1) Palmar-plantar erythrodysesthesia 30 (9) 4 (1) 9 (3) 2 (< 1) syndrome Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix ®. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Vectibix®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-7726436) to enroll. Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. Geriatric Use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix ® monotherapy. Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. Patient Counseling Information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix ® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

This brief summary is based on the Vectibix® Prescribing Information v22, 10/14. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2014 Amgen Inc. All rights reserved. 80748-R2-V1 – v22 10/14

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INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)]. Limitation of Use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Vectibix® in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)]. RAS is defined as exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereon is referred to as “RAS.” DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix ®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix ®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS- and KRAS-Mutant mCRC A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Vectibix® and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory [see Indications and Usage (1.2)]. Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter OS compared to 219 patients receiving FOLFOX alone (HR = 1.16, 95% CI: 0.94-1.41). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®. Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix ® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix ®. Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)]

• Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)] • Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are presented from two clinical trials in which patients received Vectibix®: Study 1, an openlabel, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix® Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 1)

ASCOPost.com | DECEMBER 15, 2014

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JADPRO LIVE at APSHO 2014 Second Annual JADPRO Live Conference Attracts 400 Advanced Practitioners in Oncology From Across the Nation By Jo Cavallo

he second annual JADPRO Live: Transforming Oncology Practice was held October 30 to November 2 in Orlando, Florida. The conference drew nearly 400 nurse practitioners, physician assistants, clinical nurse specialists, advanced-degree nurses, hematology/oncology nurses, pharmacists, and physicians. A meeting of the Journal of the Advanced Practitioner in Oncology, JADPRO Live was held in conjunction with the first annual meeting of t he Advanced Practitioner Society for Hematology and Oncology (APSHO)—a newly formed society for nurse practitioners, physician assistants, pharmacists, clinical nurse specialists, and advanced degree nurses.

Grand Rounds lectures on several cancers, including non-Hodgkin lymphoma; chronic myelogenous leukemia; chronic lymphocytic leukemia; basal cell carcinoma; gynecologic malignancies; and lung, prostate, and breast cancers. The Grand Rounds discussion on non-Hodgkin lymphoma was presented by Julie M. Vose, MD, MBA,

Although recent clinical experience has shown significant cardiotoxicity posttrial with cancer therapies, we have also seen resolution of toxicity using evidence-based cardiology guidelines.

Diverse Educational Program The 4-day interactive, educational program included 25 sessions on such diverse topics as bone marrow aspiration, lumbar puncture, Ommaya reservoir placement, punch biopsy, and suturing (a hands-on skills workshop); genetics and BRCA mutations; infection management; pain management; cardiotoxicity; avoiding common drug interactions and reactions; and an update on oncology drugs. The conference also presented

of Nebraska Medical Center. The session focused on current treatment and medical progress in non-Hodgkin lymphoma; the role of genomics in the therapeutic treatment of the disease; and strategies for the management of treatment-related toxicities in patients within the context of a multidisciplinary team. During this discussion, the present-

—Jean-Bernard Durand, MD, FCCP, FACC

FASCO, the Neumann M. and Mildred E. Harris Professional Chair and Chief of the Oncology/Hematology Division in the Department of Internal Medicine at the University of Nebraska Medical Center and ASCO’s President-Elect; and Katherine L. Byar, MSN, APN, BC, BMTCN, a hematologic malignancy nurse practitioner at the University

Save the Date November 5-8, 2015 JW Marriott Phoenix Desert Ridge

For conference exhibitor or sponsorship opportunities, contact David Horowitz at 631-935-7658 or email at david@harborsidepress.com

A CE/CME Conference for Advanced Practitioners in Oncology

Learn more at jadprolive.com

ers stressed the importance of understanding the specific cytogenetic and molecular abnormalities of each lymphoma subtype in determining treatment options for patients and of establishing a comprehensive care plan as patients transition from active treatment to survivorship.

Addressing Cardiotoxicity While advances in treatment for cancer have helped boost the overall number of cancer survivors to 14 million, according to the National Cancer Institute, cancer treatment–related cardiotoxicity is the leading cause of treatment-associated mortality in survivors of pediatric and adolescent cancers after disease recurrence and second or subsequent malignancies and is one of the most common post-treatment issues among 5- to 10-year survivors of adult cancer.1 To help conference attendees bridge the scientific knowledge gaps on the problem of treatment-related cardiotoxicity, Jean-Bernard Durand, MD, FCCP, FACC, Associate Professor in the Department of Cardiology at The University of Texas MD Anderson Cancer Center, gave a lecture on “Treat-

ment- and Disease-Related Cardiotoxicity in the Oncology Setting.” During this session, Dr. Durand discussed the prevention of cardiotoxicity; emerging new concepts to consider with cardiotoxicity; how to recognize common treatment-related cardiac abnormalities, including appropriate tools for diagnostic evaluation; and applying the principles of risk analysis, prevention, early identification of signs and symptoms, and individualized treatment planning for patients with cancer at risk of developing disease- or treatment-related cardiac events. To reduce the incidence of treatment-related cardiotoxicity, “cardiologists and oncologists must collaborate,” said Dr. Durand. “Although recent clinical experience has shown significant cardiotoxicity posttrial with cancer therapies, we have also seen resolution of toxicity using evidence-based cardiology guidelines.”

Earning CE Credits The conference offered triple accreditation, and attendees were able to earn up to 16 continuing education (CE) credit/contact hours for sessions that met the educational criteria for nurse contact hours through the American Nurses Credentialing Center (ANCC) and the California Board of Registered Nursing (CBRN, provider 13164); pharmacist contact hours through the Accreditation Council for Pharmacy Education (ACPE); and physician AMA PRA Category 1 Credits™ through the Accreditation Council for Continuing Medical Education. n

Disclosure: Drs. Vose, Byar, and Durand reported no potential conflicts of interest.

Reference 1. Cancer Treatment-Related Cardiotoxicity: Understanding the Current State of Knowledge and Developing Future Research Priorities. National Cancer Institute, Epidemiology and Genomics Research; March 20–21, 2013. Available at epi. grants.cancer.gov/events/cardiotoxicity/. Accessed December 2, 2014.

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Integrative Oncology

By Jyothirmai Gubili, MS

Aloe Vera Scientific names: Aloe vera, Aloe barbadensis, Aloe capensis Common names: Burn plant, lily of the desert, elephant’s gall, cape aloe, first aid plant, ghai kunwar, Sabila

he use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidencebased information on integrative and complementary therapies commonly used by patients with cancer. We chose Aloe vera for this issue because of its growing popularity among cancer patients.

Compiled by Barrie R. Cassileth, PhD, and Jyothi Gubili, MS, Memorial Sloan Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, MBA, LAc, Memorial Sloan Kettering Cancer Center.

Overview

A perennial succulent plant, Aloe vera belongs to the lily family and resembles a cactus. It is prevalent in Asia, Africa, and other tropical areas and is easily propagated in dry climate. Aloe has a long history of traditional medicinal use, dating back to ancient Egypt, where it was used as a remedy for burns and skin conditions. Aloe leaves are the source of a clear thick gel, which is used topically to treat burns, psoriasis, and frostbite as well as for wound healing. It is used orally for ulcerative colitis, diabetes, and constipation. Aloe is marketed in the form of juice, softgels, capsules, and ointments. It is

OF NOTE Physicians should be aware of the potential for diarrhea as a consequence of oral aloe use and of possible interactions with some prescription medications.

also a common ingredient in many cosmetics including lotions and creams. Although aloe is used to relieve constipation, the U.S. Food and Drug Administration ruled its use as a stimulant laxative unsafe.1 Aloe products are promoted to patients with cancer, especially for use against radiation-induced skin toxicity, despite the absence of strong evidence.

The Science

Aloe demonstrated antioxidant, anti-inflammatory,2 immunomodulatory, and anticancer3,4 properties in vitro. Aloe emodin, a compound in aloe, was shown to enhance the effects of radiation in HeLa cells.5 The anthracenes and anthraquinones are responsible for aloe’s antiproliferative effects, whereas the immunostimulating property is conferred mainly by acemannan.6 In a study of patients with second-degree burns, topical

The ASCO Post | DECEMBER 15, 2014

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 offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices.

Herb-Drug Interactions

Cytochrome P450 substrates: Aloe juice was found to inhibit CYP3A4 and CYP2D6 in vitro and may affect the intracellular concentration of drugs metabolized by these enzymes.16 (It has been estimated that CYP3A4 metabolizes about half of all drugs on the market, and CYP2D6 metabolizes about 20% of these drugs.)n

Disclosure: Ms. Gubili reported no potential conflicts of interest.

aloe was found to be superior to the commonly used silver sulfadiazine cream.7 An aloe gel complex was shown to benefit obese individuals with early untreated diabetes by affecting reductions in body weight and insulin resistance.8 The anticancer potential of aloe has been investigated in a few studies. The concurrent use of oral aloe with chemotherapy resulted in tumor regression and improved survival in patients with metastatic cancers.6 Results of a systematic review suggested that aloe also may help to prevent chemotherapy-induced oral mucositis.9 However, data are inconsistent about whether it can help repair radiation therapy–induced skin damage.10,11

Adverse Effects

Inappropriate use of aloe supplements has been linked to thyroid dysfunction.12 A case of hypokalemia was reported with use of aloe during chemotherapy.13 Toxic hepatitis was seen following use of aloe preparations; liver function was normalized after discontinuation of aloe.14 A National Toxicology Program study showed that long-term exposure to aloe was carcinogenic in rats,15 although studies in humans have not been conducted.

References 1. Food and Drug Administration. Status of Certain Additional Over-the-Counter Drug Category II and III Active Ingredients. http:// www.fda.gov/ohrms/dockets/98fr/050902a. htm. Accessed November 26, 2014. 2. Yagi A, Kabash A, Okamura N, et al: Antioxidant, free radical scavenging and antiinflammatory effects of aloesin derivatives in Aloe vera. Planta Med 68:957-960, 2002. 3. Pugh N, Ross SA, ElSohly MA, Pasco DS: Characterization of Aloeride, a new highmolecular-weight polysaccharide from Aloe vera with potent immunostimulatory activity. J Agric Food Chem 49:1030-1040, 2001. 4. Lee KH, Kim JH, Lim DS, Kim CH: Anti-leukaemic and anti-mutagenic effects of di(2ethylhexyl)phthalate isolated from Aloe vera Linne. J Pharm Pharmacol 52:593-598, 2000. 5. Luo J, Yuan Y, Chang P, et al: Combination of aloe-emodin with radiation enhances radiation effects and improves differentiation in human cervical cancer cells. Mol Med Rep 10:731-736, 2014. 6. Lissoni P, Rovelli F, Brivio F, et al: A randomized study of chemotherapy versus biochemotherapy with chemotherapy plus Aloe arborescens in patients with metastatic cancer. In Vivo 23:171-175, 2009. 7. Khorasani G, Hosseinimehr SJ, Azadbakht M, et al: Aloe versus silver sulfadiazine creams for second-degree burns: A random-

ized controlled study. Surg Today 39:587591, 2009. 8. Choi HC, Kim SJ, Son KY, et al: Metabolic effects of aloe vera gel complex in obese prediabetes and early non-treated diabetic patients: Randomized controlled trial. Nutrition 29:1110-1114, 2013. 9. Worthington HV, Clarkson JE, Bryan G, et al: Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev Apr 13;(4):CD000978, 2011. 10. Heggie S, Bryant GP, Tripcony L, et al: A phase III study on the efficacy of topical aloe vera gel on irradiated breast tissue. Cancer Nurs 25:442-451, 2002. 11. Olsen DL, Raub W Jr, Bradley C, et al: The effect of aloe vera gel/mild soap versus mild soap alone in preventing skin reactions in patients undergoing radiation therapy. Oncol Nurs Forum 28:543-547, 2001. 12. Pigatto PD, Guzzi G: Aloe linked to thyroid dysfunction. Arch Med Res 36:608, 2005. 13. Baretta Z, Ghiotto C, Marino D, Jirillo A: Aloe-induced hypokalemia in a patient with breast cancer during chemotherapy. Ann Oncol 20:1445-1446, 2009. 14. Yang HN, Kim DJ, Kim YM, et al: Aloe-induced toxic hepatitis. J Korean Med Sci 25:492-495, 2010. 15. Boudreau MD, Beland FA, Nichols JA, Pogribna M: Toxicology and carcinogenesis studies of a nondecolorized [corrected] whole leaf extract of Aloe barbadensis Miller (Aloe vera) in F344/N rats and B6C3F1 mice (drinking water study). Natl Toxicol Program Tech Rep Ser Aug(577):1-266, 2013. 16. Djuv A, Nilsen OG: Aloe vera juice: IC50 and dual mechanistic inhibition of CYP3A4 and CYP2D6. Phytother Res 26:445451, 2012.

For additional information, visit the “About Herbs” website at http://www.mskcc.org/ cancer-care/herb/aloe-vera.

ASCOPost.com | DECEMBER 15, 2014

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FDA Update

FDA Approves Blinatumomab to Treat Rare Form of Acute Lymphoblastic Leukemia

he U.S. Food and Drug Administration (FDA) today granted accelerated approval to blinatumomab (Blincyto) for the treatment of patients with Philadelphia chromosome–negative, relapsed or refractory precursor B-cell acute lymphoblastic leukemia (B-cell ALL). Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that activates endogenous T cells when bound to the CD19-expressing target cell. Precursor B-cell ALL is a rapidly growing type of cancer in which the bone marrow makes too many B-cell lymphoblasts. The Philadelphia chromosome is an abnormality that sometimes occurs in the bone marrow cells of leukemia patients. Blinatumomab is the first approved drug that engages the body’s T cells to destroy leukemia cells. The drug acts as a connector between the CD19 protein, which is found on the surface of most B-cell lymphoblasts, and CD3, a protein on T-cell lymphocytes. It is intended for patients with relapsed or refractory disease. “Immunotherapies, especially blina-

tumomab with its unique mechanism of action, are particularly promising for patients with leukemia,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Recognizing the potential of this novel therapy, the FDA worked proactively with the sponsor under our Breakthrough Therapy designation program to facilitate the approval of this novel agent.”

ment and encephalopathy or other side effects in the nervous system. The most common side effects seen in blinatumomab-treated participants were pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, fatigue, constipation, diarrhea, and tremor.

Approval Process The FDA granted blinatumomab Breakthrough Therapy designation, Priority Review, and Orphan Product

Clinical Trial The safety and effectiveness of blinatumomab were evaluated in a clinical study involving 185 adults with Philadelphia chromosome-negative relapsed or refractory precursor B-cell ALL. All participants were treated with blinatumomab for at least 4 weeks via infusion. Results showed 32% of participants achieved complete remission for approximately 6.7 months. Blinatumomab carries a boxed warning alerting patients and health-care professionals that some clinical trial participants experienced cytokine-release syndrome at the start of the first treat-

designation because the sponsor, Amgen, demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies; the drug had the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and the drug is intended to treat a rare disease, respectively. Blinatumomab is

being approved more than 5 months ahead of the prescription drug user fee goal date of May 19, 2015, the date the agency was scheduled to complete review of the application. Blinatumomab is being approved under the FDA’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials. The FDA is requiring blinatumomab’s manufacturer to conduct a study to verify that the drug improves survival in participants with relapsed or refractory Philadelphia-negative precursor B-cell ALL. The FDA approved blinatumomab with a Risk Evaluation and Mitigation Strategy (REMS), which consists of a communication plan to inform health care providers about the serious risks and the potential for preparation and administration errors. n

Necuparanib Receives Fast Track Designation From the FDA for the Treatment of Metastatic Pancreatic Cancer

he U.S. Food and Drug Administration (FDA) has granted Fast Track designation to the investigation of necuparanib as a first-line treatment in combination with paclitaxel and gemcitabine in patients with metastatic pancreatic

cancer. Necuparanib is a novel oncology drug candidate engineered from unfractionated heparin to have significantly reduced anticoagulant activity while preserving relevant antitumor properties associated with heparins. The FDA’s Fast Track Drug Development Program is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.

Clinical Trial Underway In October 2014, Momenta Pharmaceuticals completed the Part A dose-escalation component of the phase I/II clinical trial evaluating necuparanib in combination with paclitaxel and gemcitabine in patients with advanced metastatic pancreatic cancer, and reported positive top-line data. Part B of the phase I/II trial, currently underway, is a randomized, controlled,

proof-of-concept study to evaluate the antitumor activity of necuparanib in combination with paclitaxel plus gemcitabine vs paclitaxel plus gemcitabine alone. The company expects data from Part B to be available in the first half of 2017. Necuparanib received Orphan Drug designation from the FDA for the treatment of pancreatic cancer in June 2014. n

Download

The ASCO Post iPad App FREE from iTunes today!

Bristol-Myers Squibb. Research that leads the way in Immuno-Oncology.

What if you could help the body’s own immune system combat cancer? Bristol-Myers Squibb is researching ways to make this possible. At Bristol-Myers Squibb, we’re committed to Immuno-Oncology (I-O), a rapidly evolving field that enlists the immune system in the fight against cancer. As we learn more about how cancer evades the immune system, the growing potential of Immuno-Oncology continues to drive our research efforts. To find out more about Immuno-Oncology and our leading-edge research, visit ImmunoOncologyHCP.com.

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; DECEMBER 15, 2014

PAGE 84

Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Soft-Tissue Sarcomas Compiled by Jo Cavallo

he information contained in this Clinical Trials Resource Guide includes details of actively recruiting clinical studies of children and adults with various types of soft-tissue sarcoma, including nonrhabdomyosarcoma, Ewing sarcoma, gastrointestinal stromal tumor, and Kaposi sarcoma. The studies presented here are interventional, nonrandomized, and randomized and include pilot, phase I, phase I/ II, phase II, and phase II/III studies investigating gene therapy; toll-like receptor 4 (TLR4) agonist GLA-SE and radiation therapy; diagnostic imaging; single-agent and combination chemotherapies; and vaccine therapy. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.org.

PILOT Study Type: Interventional/singlegroup assignment Study Title: A Pilot Study to Determine the Safety of the Combination of Stable-Emulsion Formulation of Glucopyranosyl Lipid A (GLA-SE) With Radiation in Patients With Metastatic Sarcoma Study Sponsor and Collaborators: Fred Hutchinson Cancer Research Center; National Cancer Institute Purpose: To study the side effects of toll-like receptor 4 (TLR4) agonist glucopyranosyl lipid A-stable-emulsion when given together with radiation therapy in the treatment of patients with sarcoma that has metastasized Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Incidence of severe adverse events, defined as any grade 3 or higher adverse advent according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (time frame: up to week 9) Principal Investigator: Seth Pollack, MD, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 206-667-6629 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02180698

Study Type: Interventional/singlegroup assignment Study Title: Quantitative Imaging Biomarkers of Treatment Response in Osteosarcoma and Ewing Sarcoma Study Sponsor and Collaborators: Vanderbilt-Ingram Cancer Center; National Cancer Institute Purpose: To use changes in 3 Tesla MRI measurements of tumor protein content, cell density, and microvessel perfusion obtained before and after a single cycle of neoadjuvant chemotherapy (NAC) to predict eventual tumor response observed at the conclusion of NAC in patients with osteosarcoma or Ewing sarcoma Ages Eligible for Study: 13 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Percent change in MRI metrics (time frame: pretreatment and end of neoadjuvant cycle 1) Principal Investigator: Vicky Keedy, MD, Vanderbilt-Ingram Cancer Study. Contact: VICC Clinical Trials Information Program at 800-811-8480. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01882231 Study Type: Pilot/interventional/ single-group assignment Study Title: Pilot Study: Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) for Assessing Tumor Vascularity and Permeability in Soft-Tissue Sarcoma Treated With Preoperative Radiotherapy Followed by Surgical Resection Study Sponsor and Collaborators: University of Utah Purpose: To determine the diagnostic value of dynamic contrast enhancing MRI (DCE-MRI) in soft-tissue sarcoma for assessment of tumor radiographic changes in vascular permeability and microvessel density before and after preoperative radiotherapy Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Feasibility (time frame: 36 months) Principal Investigator: Ying Hitchcock, MD, Huntsman Cancer Institute. Contact: Crelley Mackey; 801-5813916, crelley.mackey@hci.utah.edu. For More Information: Visit Clini-

calTrials.gov and refer to this study by its identifier: NCT01575951 Study Type: Interventional/singlegroup assignment Study Title: A Pilot Study to Test Whether Systemic Interferon Gamma Increases Tumor Class I MHC Expression in Patients With Synovial Sarcoma and Myxoid/ Round Cell Liposarcoma Study Sponsor and Collaborators: Fred Hutchinson Cancer Research Center; National Cancer Institute Purpose: To study the effect of recombinant interferon gamma on tissue in treating patients with soft-tissue sarcoma Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Change in class 1 MHC expression after treatment with IFN gamma as determined by immunohistochemistry (time frame: baseline up to 2 weeks postsurgery) Principal Investigator: Seth Pollack, MD, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 206-667-6629 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01957709 Study Type: Interventional/randomized/parallel assignment Study Title: The Effect of Antiangiogenic Therapy With Pazopanib Prior to Preoperative Chemotherapy for Subjects With Extremity Soft-Tissue Sarcomas: A Randomized Study to Evaluate Response by Imaging Study Sponsor and Collaborators: University of Washington; National Cancer Institute Purpose: To assess pazopanib hydrochloride followed by chemotherapy and surgery in treating patients with soft-tissue sarcoma. Giving pazopanib hydrochloride and chemotherapy before surgery may make the tumor smaller and reduce the amount of tissue that needs to be removed. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Absolute values and changes in maximum standardized uptake value of tumors measured by FDG-PET pre- and post-

receipt of pazobanib vs placebo, and post-receipt of two courses of preoperative chemotherapy (time frame: at baseline and 14 days) Principal Investigator: Robin L. Jones, MD, MRCP, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 206288-7439 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01446809

PHASE I Study Type: Phase I/interventional/single-group assignment Study Title: A Study To Determine the Feasibility of Treating Synovial Sarcoma and Myxoid/Round Cell Liposarcoma Using Autologous NY-ESO-1 Specific CD8+ T Cells With Cyclophosphamide Pre-Conditioning but Without the Use of IL-2 Study Sponsor and Collaborators: Fred Hutchinson Cancer Research Center; National Cancer Institute Purpose: To study the side effects and best way to give genetically engineered NY-ESO-1-specific T lymphocytes after cyclophosphamide in the treatment of patients with advanced synovial sarcoma or myxoid/round cell liposarcoma Ages Eligible for Study: 18 to 85 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Incidence of grade 3 or greater toxicity according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (time frame: up to 10 weeks) Principal Investigator: Seth Pollack, MD, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 206-667-6629 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02059850 Study Type: Phase I/interventional/single-group assignment Study Title: Phase I Study of Dasatinib in Combination With Ipilimumab for Patients With Advanced Gastrointestinal Stromal Tumor and Other Sarcomas Study Sponsor and Collaborators: National Cancer Institute Purpose: To investigate the side ef-

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Clinical Trials Resource Guide

fects and best dose of dasatinib when given in combination with ipilimumab in the treatment of patients with gastrointestinal stromal tumors or other sarcomas that cannot be removed by surgery or have metastasized Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximum tolerated dose defined as the highest dose studied for which the observed incidence of dose-limiting toxicity is less than 33% according to the National Cancer Institute Common Toxicity Criteria (time frame: up to week 12) Principal Investigator: Richard D. Carvajal, MD, Memorial Sloan Kettering Cancer Center; 646-888-4161, carvajar@mskcc.org. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01643278 Study Type: Phase I/interventional/single-group assignment Study Title: A Phase I Trial Combining Decitabine and Vaccine Therapy for Patients With Relapsed Neuroblastoma and Sarcoma Study Sponsor and Collaborators: University of Louisville; Solving Kids’ Cancer Purpose: To test the effectiveness of an autologous cancer testis (CT) antigen specific dendritic cell vaccine preceded by decitabine as a demethylating chemotherapy in patients with relapsed high-risk neuroblastoma, Ewing sarcoma, osteogenic sarcoma, rhabdomyosarcoma, or synovial sarcoma Ages Eligible for Study: 1 to 17 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Tolerance of study treatment (time frame: 2 years) Principal Investigator: Kenneth G. Lucas, MD, University of Louisville, Kosairs Children Charities Pediatric Clinical Research Unit; 502-582-0043, k0luca01@louisville.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01241162 Study Type: Phase I/interventional/nonrandomized/parallel assignment Study Title: A Phase I Trial of Dendritic Cell Vaccination With and Without Inhibition of Myeloid Derived Suppressor Cells by Gemcitabine Pre-

Treatment For Children And Adults With Sarcoma Study Sponsor and Collaborators: University of Miami Purpose: To test whether the use of adjuvant vaccination with autologous dendritic cells matured in situ after being loaded with tumor lysates derived from autologous refractory sarcoma tissue will be safe, feasible, and potentially beneficial for patients with sarcoma Ages Eligible for Study: 1 year and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Number of participants with adverse events as a measure of safety and tolerability (time frame: 3 years) Principal Investigator: John Goldberg, MD, University of Miami; jgoldberg2@med.miami.edu. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01803152

PHASE I/II Study Type: Phase I/II/interventional/nonrandomized/parallel assignment Study Title: Phase I/II Trial of Mithramycin in Children and Adults With Refractory Extracranial Solid Tumors (Phase I) or Ewing Sarcoma and EWSFLI1 Fusion Transcript (Phase II) Study Sponsor and Collaborators: National Cancer Institute Purpose: To study whether mithramycin is safe and effective against solid tumors and Ewing sarcoma in children and adults Ages Eligible for Study: 1 year and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Determine the tolerability, toxicity, and recommended dose of mithramycin in pediatric patients with extracranial tumors (time frame: 2 years) Principal Investigator: Brigitte C. Widemann, MD, National Cancer Institute; 301-496-7387, widemanb@pbmac.nci.nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01610570 Study Type: Phase I/II/interventional/nonrandomized/single-group assignment Study Title: A Phase I/II Study of the Safety, Pharmacokinetics and Ef-

ficacy of Pomalidomide (CC-4047) in the Treatment of Kaposi Sarcoma in Individuals With or Without HIV Study Sponsor and Collaborators: National Cancer Institute Purpose: To test whether pomaldomide is a safe and effective treatment for Kaposi sarcoma in people with or without HIV Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Assess the safety, tolerability, and pharmacokinetics of pomalidomide in people with Kaposi sarcoma, whether HIV associated or not, at a dose derived from solid tumor studies (time frame: 6-12 months) Principal Investigator: Robert Yarchoan, MD, National Cancer Institute; 301-496-0328, robert.yarchoan@nih. gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01495598

PHASE II Study Type: Phase II/interventional/nonrandomized/single-group assignment Study Title: Phase II Study of Cediranib (AZD2171) in Patients With Alveolar Soft Part Sarcoma Study Sponsor and Collaborators: National Cancer Institute Purpose: To determine whether AZD2171 is effective in young patients with alveolar soft part sarcoma, a type of cancer that develops in tissues that connect, support, or surround other organs in the body Ages Eligible for Study: Up to 16 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To determine if pediatric patients with alveolar soft part sarcoma will experience at least a minimal response rate when treated with AZD2171 (time frame: 2 cycles) Principal Investigator: Shivaani Kummar, MD, National Cancer Institute; 301-435-0517, kummars@mail. nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00942877 Study Type: Phase II/interventional/single-group assignment Study Title: Proton Radiation for the Treatment of Pediatric Bone and

Non-Rhabdomyosarcoma Soft-Tissue Sarcomas Study Sponsor and Collaborators: Massachusetts General Hospital; Brigham and Women’s Hospital, Children’s Hospital Boston, Dana-Farber Cancer Institute, National Institutes of Health Purpose: To assess the short- and long-term side effects of proton beam radiation for pediatric bone and nonrhabdomyosarcoma soft-tissue sarcomas Ages Eligible for Study: Up to 30 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Acute and late toxicities (time frame: 3 years) Principal Investigator: Torunn Yock, MD, Massachusetts General Hospital; 617-724-1836 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00592293

PHASE II/III Study Type: Phase II/III/interventional/randomized/parallel assignment Study Title: Pazopanib Neoadjuvant Trial in Non-Rhabdomyosarcoma Soft-Tissue Sarcomas (PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib Study Sponsor and Collaborators: National Cancer Institute Purpose: To test how well pazopanib hydrochloride, combination chemotherapy, and radiation therapy work and compares to radiation alone or in combination with pazopanib hydrochloride or combination chemotherapy in the treatment of newly diagnosed non-rhabdomyosarcoma soft-tissue sarcomas that can be removed by surgery Ages Eligible for Study: 2 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Potential benefit for chemoradiotherapy plus pazopanib hydrochloride defined as protocol week 13 pathologic response (phase II) (time frame: week 13) Principal Investigator: Aaron R. Weiss, DO, Children’s Oncology Group; 207-396-8090, wrighd@mmc. org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02180867 n

The ASCO Post | DECEMBER 15, 2014

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Book Reviews

Internal Medicine: A Doctor’s Stories By Ronald Piana

“T

his book is the story of a residency in internal medicine. I wrote it over a period of 10 years, beginning just after my own residency ended…. I wrote this book primarily in an attempt to make sense of the process of becoming a doctor.” So begins the introduction of Internal Medicine: A Doctor’s Stories, the compelling new book by Terrence Holt, MD, a professor and internist at the University of North Carolina, Chapel Hill. Dr. Holt is an accomplished writer. His previous book, In the Valley of Kings: Stories, was a finalist for the PEN/Robert W. Bingham Award for distinguished literary achievement, His abundant talent is on full display in each of the nine chapters in this concisely drawn book, which entices the reader to travel along with the young intern as he journeys through the corridors of medicine, capturing the drama of sickness, suffering, and death. The book opens on Dr. Holt’s first call night as an intern, when he runs into Dr. M, one of the senior attendings he’d known for years. Dr. Holt writes, “How’s it going?” he asked me. I told him I was on call. “First call?” He smiled. “I remember my first call. About 10 o’clock that night, my resident said

to me, ‘I’m going to be just behind that door. Call me if you need me. But remember—it’s a sign of weakness.’”

Medical School Is Over Dr. M’s message, although delivered tongue-in-cheek, is loud and clear: Medical school is over. And from the onset, the reader feels the pulse and heartbeat of the hospital wards and the “frantic milling about that makes up an intern’s day.” This is real-life medicine and doctoring right down to the futile reality of watching patients die and not being able to do a damn thing about it. A 26-year-old woman with scleroderma is in respiratory distress, but she refuses to wear an oxygen mask because it makes her “feel claustrophobic.” As the night progresses, she begins to fade, and the interplay between the young doctor and a seasoned nurse is at once tender and perfunctory in its depiction of the hospital ward reality. At one point, Dr. Holt puts the young patient’s oxygen mask on his own face, inhaling deeply to rejuvenate himself from fatigue. “I can’t breath,” says the young woman, as Dr. Holt places the mask back on her face and deftly brings her to life on the pages. “The light

Bookmark Title: Internal Medicine: A Doctor’s Stories Author: Terrence Holt, MD Publisher: Liveright Publishing Corporation Publication Date: September 2014 Price: $24.95; hardcover, 288 pages

in the room was golden, the late sun of the July evening slanting through the high window. The face that turned to me had a stretched and polished look, her features immobile, the entire effect disturbingly like a doll’s face … only her eyes were mobile, following me as I moved.” She died during the night. Whether at the bedside of a hospice patient in a chapter called, “The Surgical Mask,” or in the nightmarish world of the psychiatric hospital depicted in

the chapter, “Iron Maiden,” the doctorpatient relationship is fully realized, revealing how human complexities and vulnerabilities are the foundation of caring for the sick. Internal Medicine: A Doctor’s Story is the unvarnished story of what it means to be a doctor—and to be human. Every doctor can relate to the gritty and tender stories in Dr. Holt’s impressive book. The beleaguered intern’s narrative is a gripping read from cover to cover. n

Working Stiff: Two Years, 262 Bodies, and the Making of a Medical Examiner By Ronald Piana

ust as the sun came up over a Manhattan construction site, a group of hard hats were sitting on the sidewalk sipping coffee before their morning shift started. A noise punctuated the hum of the city streets. A metallic creak turned into a menacing groan, scattering the construction workers as the derrick of a 383-foot-

tall crane fell from the roof and crashed down on James Friarson’s head, a worker who ran the wrong way. “The steel boom had punched a foot-deep hole in the sidewalk when it came down on Mr. Friarson. A hard hat was still there, lying on its side in a pool of blood and brain, coffee and doughnuts,” writes Judy Melinek,

Bookmark Title: Working Stiff: Two Years, 262 Bodies, and the Making of a Medical Examiner Authors: Judy Melinek, MD, and T.J. Mitchell Publisher: Scribner, a Division of Simon & Schuster, Inc Publication Date: August 2014 Price: $25.00; hardcover, 272 pages

MD, and T. J. Mitchell, authors of the recently published book Working Stiff: Two Years, 262 Bodies, and the Making of a Medical Examiner. Just 2 months before the September 11 terrorist attacks, Dr. Melinek began her training as a New York City forensic pathologist, and Working Stiff chronicles her 2 years of training. It takes the reader past the police tape of horrific scenes of death and into the morgue, where the depictions of autopsies and startling revelations viewed on such shows as Law & Order are debunked.

Storytelling Collaboration Dr. Melinek’s coauthor, T. J. Mitchell, is also her husband, and the intimacy of their storytelling collaboration is evident. Mr. Mitchell, a professional writer, does a good job of keeping the pace hopping and mixing multiple storylines into a cohesive narrative. Humans have a natural fascination with death and with those who deal with it on a daily basis, which gives the authors an interesting topic to write about.

However, books that tackle a subject like this also run the risk of being repetitive and perhaps appear better suited for a long magazine article. At times, Working Stiff seems to drift off topic, but that is a small gripe for a book that is both entertaining and informative, especially for those in the medical profession. Forensic pathology is a tough field, and Dr. Melinek’s entry into it couldn’t have come at a tougher time: 9/11. The chapter dealing with the catastrophe is the centerpiece of the book. “DM01000041 was a crushed head and torso. It was the first body from the attack I would handle. I was immediately overwhelmed…the body was pulverized. Major organs were eviscerated, some still attached by blood vessels and connective tissue, but others were missing entirely.” This is tough stuff, and it’s written in clear, strong language. This book is a good reminder that the people out there with MD behind their names care for us from cradle to grave, and it’s not easy. Readers of The ASCO Post should enjoy the read. n

VOTRIENT for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.1

LIGHTING A WAY FORWARD Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

Please see additional Important Safety Information for VOTRIENT on subsequent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

VOTRIENT demonstrated signiﬁcant improvement in PFS in a Phase 3 trial1 • VOTRIENT provided a 65% reduced risk of progression or death compared with placebo (HR 0.35; 95% CI 0.260.48; P<0.001)1

Proportion Progression Free

PFS in overall study population (N=369)1

1.6

MONTHS Median PFS

1.0

4.6

VOTRIENT (n=246)

MONTHS Median PFS

Placebo (n=123)

• The efficacy efficacy of VOTRIENT for the treatment of patients with adipocytic STS or GIST has not been demonstrated1

HR 0.35 (95% CI 0.26-0.48) P<0.001

0.8 0.6 0.4 0.2 0.0 0

Months Randomized, double-blind, placebo-controlled, multicenter, Phase 3 trial to evaluate the efﬁcacy and safety of VOTRIENT in patients (N=369) with advanced STS. The Phase 3 trial population excluded patients with adipocytic sarcoma or GIST. Patients were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.1,2

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the randomized STS trial, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT had congestive heart failure, which did not resolve in 1 patient. Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Hemorrhagic events have occurred and can be fatal. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thromboembolic Events: Arterial thromboembolic events have occurred and can be fatal. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, VTEs were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal

pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms. • 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. • Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT 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 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. 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. • 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, gastrointestinal 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 post-natal 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.

VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.1

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In soft tissue sarcoma, a dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced STS trial, 58% of patients on VOTRIENT required a dose interruption; 38% of patients on VOTRIENT had their dose reduced • 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 • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • 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

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • The most common adverse reactions (≥20%) in patients with advanced soft tissue sarcoma who received VOTRIENT were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, hair color changes, vomiting, tumor pain, dysgeusia, headache, musculoskeletal pain, myalgia, gastrointestinal pain, and dyspnea Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

• For additional information on dosing modifications modifications based on drug interactions, please see Sections 2.2 and 7 of accompanying Brief Summary of Prescribing Information

Important Safety Information for VOTRIENT (cont’d) • 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 healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs. 0% in the placebo group). • Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) 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 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 STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions.

Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages. www.GSKSource.com ©2014 GSK group of companies. All rights reserved. Printed in USA. 66601R0 June 2014

VOTRIENT.com/HCP/aSTS

The most common adverse reactions (≥20%) in patients who received VOTRIENT versus placebo were fatigue (65% vs 48%), diarrhea (59% vs 15%), nausea (56% vs 22%), decreased weight (48% vs 15%), hypertension (42% vs 6%), decreased appetite (40% vs 19%), hair color changes (39% vs 2%), vomiting (33% vs 11%), tumor pain (29% vs 21%), dysgeusia (28% vs 3%), headache (23% vs 8%), musculoskeletal pain (23% vs 20%), myalgia (23% vs 9%), gastrointestinal pain (23% vs 9%), and dyspnea (20% vs 17%). Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in patients receiving VOTRIENT versus placebo included increases in AST (51% vs 22%), ALT (46% vs 18%), glucose (45% vs 35%), alkaline phosphatase (32% vs 23%), total bilirubin (29% vs 7%), and potassium (16% vs 11%); decreases in albumin (34% vs 21%) and sodium (31% vs 20%); and leukopenia (44% vs 15%), lymphocytopenia (43% vs 36%), thrombocytopenia (36% vs 6%), and neutropenia (33% vs 7%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Data on file. GlaxoSmithKline, 2011.

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated. 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 STS, a decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized STS trial, ALT >3 X ULN was reported in 18% and 5% of the VOTRIENT and placebo groups, respectively. ALT >8 X ULN was reported in 5% and 2% of the VOTRIENT and placebo groups, respectively. 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% (4/240) of patients on VOTRIENT and <1% (1/123) on placebo. Four-tenths percent (0.4%) of patients (1/240) in the randomized STS trial died of hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the randomized STS trial, 0.4% (1/240) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 123 patients who received placebo on the trial had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the randomized STS trial, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared to baseline or a decline in LVEF of ≥10%

compared to baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) of patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents 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 STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. 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 STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and

lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, doubleblind, placebo-controlled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. 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 STS who Received VOTRIENT

Adverse Reactions Fatigue Diarrhea Nausea Weight decreased Hypertension Appetite decreased Hair color changes Vomiting Tumor pain Dysgeusia Headache

VOTRIENT

Placebo

(N=240)

(N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 65 13 1 48 4 1 59 5 0 15 1 0 56 3 0 22 2 0 48 4 0 15 0 0 42 7 0 6 0 0 40 6 0 19 0 0 39 0 0 2 0 0 33 3 0 11 1 0 29 8 0 21 7 2 28 0 0 3 0 0 23 1 0 8 0 0

Musculoskeletal pain

Myalgia

Gastrointestinal pain

Dyspnea Exfoliative rash Cough Peripheral edema Mucositis Alopecia Dizziness Skin disorderb

20 18 17 14 12 12 11 11

5 <1 <1 2 2 0 1 2

<1 0 0 0 0 0 0 0

17 9 12 9 2 1 4 1

5 0 <1 2 0 0 0 0

1 0 0 0 0 0 0 0

Skin hypopigmentation

Stomatitis 11 <1 0 3 0 0 Chest pain 10 2 0 6 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. b 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia. Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0%), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus <1%), chills (5% versus 1%), vision blurred (5% versus 2%), and nail disorder (5% versus 0%).

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=240)

Parameters Hematologic Leukopenia Lymphocytopenia Thrombocytopenia Neutropenia Chemistry AST increased ALT increased Glucose increased Albumin decreased Alkaline phosphatase increased Sodium decreased Total bilirubin increased

Placebo (N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 44 43 36 33

1 10 3 4

0 0 1 0

15 36 6 7

0 9 0 0

0 2 0 0

51 46 45 34

5 8 <1 1

3 2 0 0

22 18 35 21

2 2 2 0

0 1 0 0

Potassium 16 1 0 11 0 0 increased a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

T:13”

B:14.25”

S:12.5”

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. 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. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. Bradycardia: In the randomized trial of VOTRIENT for the treatment of STS, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (45/238) of patients treated with VOTRIENT and in 4% (5/121) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (4/240) of patients treated with VOTRIENT compared to <1% (1/123) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs That Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and Cmax). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, shortacting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to

avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and postimplantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/ maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist

of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal). VOTRIENT is a registered trademark of the GSK group of companies.

GlaxoSmithKline Research Triangle Park, NC 27709

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2015

2015 Oncology Meetings January 2015

February

Melanoma 2015: 25th Annual Cutaneous Malignancy Update January 10-11 • San Diego, California For more information: www.scripps.org/events/melanomaannual-cutaneous-malignancyupdate-january-10-2015

26th International Congress on Anti-Cancer Treatment February 3-5 • Paris, France For more information: http://www.icact.fr

7th Breast Gynecological International Cancer Conference January 15-16 • Cairo, Egypt For more information: www.bgicc.eg.net/Home.aspx Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org 13th Oncology Update: Advances and Controversies January 16-19 • Steamboat Springs, Colorado For more information: www.mdanderson.org 11th Annual Clinical Breakthroughs and Challenges in Hematologic Malignancies January 17 • Lake Buena Vista, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

7th Annual T-cell Lymphoma Forum January 29-31 • San Francisco, California For more information: www.tcellforum.com

Translation of the Cancer Genome February 7-9 • San Francisco, California For more information: www.aacr.org AACR-SNMMI Joint Conference: State-of-the-Art Molecular Imaging in Cancer Biology and Therapy February 11-14 • San Diego, California For more information: www.aacr.org 2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11-15 • San Diego, California For more information: www.asbmt.org 5th International Conference on Innovative Approaches in Head & Neck Oncology February 12-14 • Nice, France For more information: www.estro.org/congressesmeetings/items/5th-ichno 15th Annual Targeted Therapies of The Treatment of Lung Cancer February 18-21 • Santa Monica, California For more information: www.iaslc.org/events/15th-annualtargeted-therapies-treatment-lungcancer The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 19-21 • San Diego, California For more information: www.imedex.com/antiangiogenesis-and-immunetherapies/ Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org

6th Current Concepts in the Management of Thyroid and Parathyroid Neoplasms February 26-28 • Houston, Texas For more information: www.mdanderson.org 32nd Annual Miami Breast Cancer Conference® February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/32nd-AnnualMiami-Breast-Cancer-Conference

Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial SloanKettering Cancer Center March 6-9 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse Advanced Prostate Cancer Consensus Conference March 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

Society of Interventional Radiology February 28-March 5 • Atlanta, Georgia For more information: www.sirmeeting.org

March

13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers March 5-8 • Orlando, Florida For more information: www.aacr.org 16th European Congress: Perspectives in Lung Cancer March 6-7 • Torino, Italy For more information: www.imedex.com Advances in the Management of Multiple Myeloma March 6-7 • Saint Petersburg, Florida For more information: http://moffitt .org/for-physicians-healthcareprofessionals/conferences/ conferences

NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp 8th Annual Interdisciplinary Prostate Cancer Congress™ March 14 • New York, New York For more information: http://www.gotoper.com/ conferences/ipcc/meetings/8thAnnual-Interdisciplinary-ProstateCancer-Congress 25th Annual Interdisciplinary Breast Center Conference March 14-18 • Las Vegas, Nevada For more information: www2.breastcare.org American Society of Preventive Oncology (ASPO) Annual Meeting March 15-17 • Birmingham, Alabama For more information: http://aspo.org/annual-meeting ACCC 41st Annual National Meeting March 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ calendar.asp 14th St. Gallen International Breast Cancer Conference March 18-21 • Vienna, Austria For more information: www.oncoconferences.ch

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2015

2015 Oncology Meetings State-of-the-Art Neuro-Oncology Conference: 3rd Annual Meeting March 19-20 • Clearwater Beach, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences 21st Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 19-21 • Stevenson, Washington For more information: www.ohsu.edu/bbb Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/ EORTC-EANO-ESMO 2015 March 27-28 • Istanbul, Turkey For more information: www.ecco-org.eu/Events/EORTC_ EANO_ESMO-2015 46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

Save the Date

13th International Conference on Malignant Lymphoma (ICML) June 17–20, 2015 Lugano, Switzerland The 13-ICML will bring 3,000 physicians to Lugano from all over the world: hematologists, clinical oncologists, radiation oncologists, pediatricians, pathologists, and leading researchers involved in the study and treatment of lymphoid neoplasms. For more information, visit www.lymphcon.ch/imcl/index.php

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

3rd ESTRO Forum April 23-28 • Barcelona, Spain For more information: http://www.estro.org/congressesmeetings/items/3rd-estro-forum

May

Hematologic Malignancies: New Therapies and the Evolving Role of Transplant April 10-11 • Chicago, Illinois For more information: www.mayo.edu/cme/hematologyand-oncology-2015r919

The 28th Annual Meeting of the American Society of Pediatric Hematology/Oncology May 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/content/ annualmeeting.html

7th Asian Oncology Summit and the 11th Annual Conference of the Organisation for Oncology and Translational Research April 10-12 • Shanghai, China For more information: www.asianoncologysummit.com

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

HPV-induced Head and Neck Cancer: Screening, Detection and Less Invasive Therapies April 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ELCC2015-Lung-Cancer Multidisciplinary Spine Oncology Symposium April 17-18 • New York, New York For more information: www.mskcc.org/events/cme/ multidisciplinary-spine-oncologysymposium/form American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org ONS 40th Annual Congress April 23–26 • Orlando, Florida For more information: www.ons.org/conferences/ congress-2015

ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

June International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/ 2015 Clinical Update: 21st Century Prevention of HPV-Associated Cancer June 5-7 • Baltimore, Maryland For more information: www.asccp .org/Education/2015-21st-CenturyPrevention-of-HPV-Associated-Cancer Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org

13th International Conference on Malignant Lymphoma (ICML) June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2 Anticancer Drug Action and Resistance: from Cancer Biology to the Clinic June 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015 International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/ MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July 7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp NRG Oncology Meeting July 10-13 • Chicago. Illinois For more information: www.gog.org/meetinginformation .html 14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com/conferences/ibc/ meetings/14th-Annual-InternationalCongress-on-the-Future-of-BreastCancer

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

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

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

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

39% 29

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

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

53%

47% No relevant family history Relevant family history

32%

71%

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

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

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

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

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

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Top 10 Articles From The ASCO Post in 2014 Most-Viewed Online at ASCOPost.com

he following list presents those articles published in 2014 that were observed most often by visitors to ASCOPost.com, as measured by the number of views.a To view the full version of the articles listed below, visit ASCOPost.com and enter the URL provided below each entry.

1. Continuous Lenalidomide/ Low-Dose Dexamethasone: A New Option for Older Patients With Newly Diagnosed Myeloma January 15, 2014, Volume 5, Issue 1 First-line treatment of newly diagnosed multiple myeloma using the Rd regimen (continuous lenalidomide [Revlimid] plus low-dose dexamethasone) was superior to standard triplet treatment with MPT (melphalan, prednisone, and thalidomide [Thalomid]) for 72 weeks, according to the initial results of the FIRST (Front-Line Investigation of Revlimid/Dexamethasone vs Standard Thalidomide) trial presented at the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans. Visit http://bit.ly/1vhFjjQ

2. Delaying Androgen Deprivation Therapy May Not Compromise Survival in Men With Prostate Cancer and PSAOnly Relapse June 10, 2014, Volume 5, Issue 9

In men with prostate cancer and a prostate-specific antigen (PSA)-only recurrence after curative surgery or radiation, delaying androgen deprivation therapy for at least 2 years or until clinical progression (ie, new symptoms, metastasis by imaging techniques or short PSA doubling time) did not appear to impact survival or prostate cancer–specific survival compared with immediate initiation of androgen deprivation therapy within 3 months of PSA-only recurrence. These results of a large, population-based study, developed jointly by the Harvard School of Public Health and University of California, San Francisco, are suggestive and can be included in discussions with patients, but they are by no means definitive, say experts. The study was presented at the 2014 ASCO Annual Meeting. Visit http://bit.ly/1B9KTbm

3. FDA Programs to Expedite Drug and Biologic Product Development February 15, 2014, Volume 5, Issue 3 With the advent of the Breakthrough Therapy designation, there are now four FDA programs to expedite the development of promising new agents: Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval. These programs complement one another and serve a common goal: to speed the approval of effective treatments for serious conditions. In this

Additional Articles of Note ■■ Adjuvant Bisphosphonates in Early Breast Cancer: Practice-Changing Findings January 15, 2014, Volume 5, Issue 1 Visit http://bit.ly/1rUM8CS ■■ HER2-Positive Breast Cancer Patients With Small Tumors Benefit From Low-Toxicity Regimen January 15, 2014, Volume 5, Issue 1 Visit http://bit.ly/1tA6UZ4 ■■ Mounting Success in Trials of Genetically Engineered T Cells to Treat Leukemias and Lymphomas January 15, 2014, Volume 5, Issue 1 Visit http://bit.ly/1yDvnRu ■■ Common Mutations May Impact Neoadjuvant Treatment Outcomes in Breast Cancer February 1, 2014, Volume 5, Issue 2 Visit http://bit.ly/1tICcMB ■■ Issues in the Management of the Axilla in Patients With Breast Cancer June 25, 2014, Volume 5, Issue 10 Visit http://bit.ly/1yfpdrS

article, FDA reviewers Drs. Kluetz and Donoghue address questions relating to the role of expedited programs for the development of cancer therapies. Visit http://bit.ly/1vcR5qF

4. The Future of Biomedical Research March 1, 2014, Volume 5, Issue 4 In January, Congress approved a $1 trillion appropriations bill for the rest of fiscal year 2014. While the new bill includes $29.9 billion for the National Institutes of Health (NIH)—$1 billion above FY2013 levels after sequestration—including $4.9 billion for the National Cancer Institute (NCI), it does not restore NIH funding to presequestration spending levels. In addition, the budget leaves the NIH with about 10% less purchasing power in current dollars compared to FY2007. In a wide-ranging interview with The ASCO Post, Francis S. Collins, MD, PhD, Director of the National Institutes of Health, addressed the impact that budget stagnation is having on biomedical research and on the careers of young investigators, his optimism for the future, and the outlook for improvements in global health care. Visit http://bit.ly/15NOcbh

5. A New Era in the Management of Advanced HER2-Positive Breast Cancer June 25, 2014, Volume 5, Issue 10 Approximately 20% of all breast cancers are human epidermal growth factor receptor 2 (HER2)-positive. Prior to the era of HER2-targeted therapy, HER2-positive breast cancer was characterized by a poor prognosis. The development of the first HER2-targeted therapy, trastuzumab (Herceptin) led to dramatically improved outcomes for this population in both the early-stage and metastatic settings. In recent years, outcomes for women with advanced HER2-positive breast cancer have improved further with the development and approval of three additional HER2-targeted therapies—lapatinib (Tykerb), pertuzumab (Perjeta), and ado-trastuzumab emtansine (Kadcyla). With the addition of these agents to the therapeutic armamentarium, metastatic HER2-positive breast cancer is no longer characterized by a rapid disease course but rather by median survival rates in excess of 3 years. Visit http://bit.ly/1ycho7M

6. NCCN Clinical Practice Guidelines in Oncology: 2014 Updates May 15, 2014, Volume 5, Issue 8 At the 19th Annual Conference of the National Comprehensive Cancer Network (NCCN), held in Hollywood, Florida, NCCN Panel members presented updates for several tumor types, briefly summarized in this article. Visit http://bit.ly/1B9MU7u

7. ‘Double-Hit’ Lymphomas a Challenge for the Oncologist April 15, 2014, Volume 5, Issue 6 “Double-hit” lymphomas remain challenging tumors, and the best means of treatment remains somewhat elusive, according to studies presented at the 2013 ASH Annual Meeting in New Orleans, and experts who commented on these findings at the 2014 Highlights of ASH in North America meeting in Miami. Visit http://bit.ly/1yc4lhA

8. PREVAIL Trial Shows Enzalutamide to Be a Promising Option for Metastatic Castration-Resistant Prostate Cancer March 1, 2014, Volume 5, Issue 4 Encouraging results of the large phase III PREVAIL trial represent another positive milestone for men with metastatic castration-resistant prostate cancer. Enzalutamide (Xtandi) improved overall survival by 29% and reduced the risk of radiographic progression of disease by 81% in men who had not received chemotherapy. An interim analysis of the trial data in 2013 was so favorable that the Independent Data Monitoring Committee halted the trial prematurely and offered all placebo recipients enzalutamide. Complete trial results were reported at the 2014 Genitourinary Cancers Symposium in San Francisco. Visit http://bit.ly/1iw0l4H

9. Addition of Neoadjuvant Carboplatin in Triple-Negative Breast Cancer Supported by SABCS Studies February 1, 2014, Volume 5, Issue 2 The achievement of a pathologic complete response in patients with triple-negative breast cancer was boosted by the addition of carboplatin to a standard neoadjuvant chemotherapy regimen, and by the addition of veliparib,

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Year in Review

an investigational oral PARP inhibitor, plus carboplatin to a standard chemotherapy regimen, in studies presented at the 2013 San Antonio Breast Cancer Symposium. Visit http://bit.ly/1m0gi4S

10. Maintenance Therapy in Multiple Myeloma May 1, 2014, Volume 5, Issue 7 S. Vincent Rajukumar, MD, reported that in 2012, three randomized placebo-controlled trials reported a significant prolongation of progression-free survival with lenalidomide (Revlimid) as maintenance therapy for multiple

myeloma. Two of these trials tested lenalidomide maintenance after stem cell transplantation, and one investigated maintenance following conventional melphalan-based therapy. One of the three trials, a post-transplant study conducted in the United States, found an improvement in overall survival, while in the others no survival benefit was

seen. All three trials showed a significant increase in the incidence of second cancers. Following the publication of these trials, there has been some controversy on the implications of these findings. Some experts have endorsed routine maintenance, at least in the post-transplant setting, while others have argued

that additional data are needed before such therapy might be recommended. Frequent updates of these study results at subsequent meetings have not clarified the issues, but rather, have given rise to new misconceptions. Visit http://bit.ly/1tA3y8y n a

Last Updated: Tuesday, December 2, 2014

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The ASCO Post Editorial Correspondence

May 29-June 2, 2015

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The ASCO Post | DECEMBER 15, 2014

PAGE 98

Reflections

The Wedding Picture By Fadlo R. Khuri, MD, FACP

Never Give Up The following essay by Fadlo R. Khuri, MD, FACP, is excerpted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories (May 2014), coedited by Stan Winokur, MD, and Vincent Coppola. The book is available on Amazon.com and thebigcasino.org.

ife and hope are why we go into this most challenging and rewarding of professions in the first place. Recently, as I was opening Christmas and other holiday cards, I spied an envelope with a name and address that I did not recognize. It turned out to be a note from the mother of a former patient of mine with a grand surprise: a picture of her daughter, whom I had cared for almost a decade earlier. The picture showed my former patient, KK, in her wedding dress, crossing Massachusetts Avenue, walking down Commonwealth Avenue in my native Boston, arm in arm with her new groom. In the note, the mother thanked me for starting her daughter on the right course of therapy and let me know that, thanks to my clinical judgment (her words, not mine), her daughter had been able to obtain her PhD and had just gotten married! She also wanted to remind me that she thought it both ironic and pleasing that her daughter and her husband had in fact moved to Boston, where she knew I had done my training. She was sure I would remember her daughter and thought I would enjoy the picture. Of those two facts, there can be no doubt.

My clinical judgment: If only that were the complete story! I will never forget the first time I saw this young woman, KK, a 23-year-old student studying for her master’s in public health, who noticed that her voice was getting raspier and that she was becoming increasingly short of breath. I saw her in my clinic shortly after she had a tracheostomy performed, after a major neck dissection and an operation to debulk her disease had proven necessary but largely futile. She had, in fact, an aggressive form of medullary thyroid cancer and turned out not to have the hereditary component, but she did have a RET gene mutation (in simple terms, a mutation in a particular gene identified as a risk factor for this type of thyroid cancer). She was sent to me by a long-standing colleague, for whom I have nothing but admiration, a head and neck surgeon who has never

pleaded. I thought hard and remembered from my limited experience treating thyroid cancers at MD Anderson Cancer Center with Dong Moon Shin, MD, FACP [now Professor and Executive Vice Chair, Department of Hematology and Medical Oncology at Emory University School of Medicine], and Andy Burgess, MD [Deputy Chairman in the Department of Melanoma/Sarcoma Medical Oncology], that we had placed some patients with thyroid cancers on clinical trials of several new compounds, agents targeting the Ras/Raf pathway. At the time, we had a trial of one such agent, sorafenib (Nexavar). Although other agents targeting the Ras/Raf pathway act specifically on just one protein within the network, sorafenib acts on several proteins. Being intimately aware of the progress seen with patients who had been treated with this class of targeted ther-

When I was asked … what had been the highlight of my year, it was no contest. It was the wedding picture of my patient, sent to me by her mother, and a sign that even the longest of shots based on the best extrapolations we can make from science can pay off. —Fadlo R. Khuri, MD, FACP

said “no” to a patient in his 35-plus years practicing in Georgia. Bill Grist, MD [Associate Professor of Otolaryngology–Head and Neck Cancer at Emory Healthcare] called me and said, “Fadlo, I need you to take a look at this young girl. We really have nothing to offer her, but it’s hard for me to give up. I know chemotherapy is not much of a help for these patients, but I think she is willing to try anything, and so am I.” When I first met our patient, she was as full of life as she would be in that wedding picture almost a decade later but was unquestionably scared. “What could we try?” she asked. Surely, with all the science and the clinical trials ongoing in cancer, there must be something we could try, she

apies, I thought it made sense to try to treat her with the “dirtiest” inhibitor that was available to me. I had no honest idea that sorafenib could target the Ret mutation, but I figured it was worth a shot.

Extending Life We started KK on the drug, and within weeks, her tumor began to shrink. Still, I indicated to her that this was no cure, and we had no idea how long it would benefit her. After a year under my care, she moved to Maryland to be closer to her family, assuming that although the worst would happen, she would remain optimistic, always hoping for the best. She wanted to spend more quality

time with her family. Her disease had shrunk dramatically in the time I had treated her, and she had started to gain a little weight. Her mother, who had some training in science and joined her on several visits, also thought it would be best for her to be close to her family. She finished her master’s degree and moved north to Maryland. I arranged for her to see Ed Sausville, MD, PhD, FACP, at the University of Maryland Greenebaum Cancer Center, a friend and colleague of many years and a thought leader in drug development throughout his career at the National Cancer Institute. Ed continued sorafenib and would send me occasional e-mails to tell me how well KK was doing. The years passed and I lost touch with her. I always wondered what had happened to her until I received the wedding picture.

The Most Meaningful Award This past year was a remarkable year, ironic in that our work was recognized with an award from the American Association for Cancer Research named after the late Richard Rosenthal. Mr. Rosenthal was a philanthropist who died of lung cancer, making this a particularly poignant award for me, as I have spent the bulk of my career working on the prevention and treatment of lung and head and neck cancers. I also received an award from the Arab-American community as the high-achieving individual in Georgia who inspired others by his work, also a deeply meaningful award for me. When I was asked toward the end of this past year what had been the highlight of my year, however, it was no contest. It was the wedding picture of my patient, sent to me by her mother, and a sign that even the longest of shots based on the best extrapolations we can make from science can pay off. Life and hope are why we go into this most challenging and rewarding of professions in the first place. n Fadlo R. Khuri, MD, FACP, is Professor and Roberto C. Goizueta Chair in Cancer Research and Deputy Director of the Winship Cancer Institute of Emory University in Atlanta.

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

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

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

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

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

Percentage surviving

80 60 40 20 0

7 8 OS (months)

ZELBORAF (n=337)

Dacarbazine (n=338)

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

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

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

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

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

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

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

75%

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

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

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | DECEMBER 15, 2014

PAGE 102

FDA Update

FDA Approves Ruxolitinib to Treat Patients With Polycythemia Vera

he U.S. Food and Drug Administration (FDA) approved a new use for ruxolitinib ( Jakafi) to treat patients with polycythemia vera, a chronic type of bone marrow disease. Ruxolitinib, a JAK inhibitor, is the first drug approved by the FDA for this condition.

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

ADRs

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

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

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

37 33 45 23 24 9 8 19 5 14

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

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

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

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

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

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

clots in the veins near the skin surface. In addition, it puts patients at increased risk of stroke or heart attack. Ruxolitinib’s new use is intended to treat polycythemia vera patients who have an inadequate response to or cannot tolerate hydroxyurea, which

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

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

is often prescribed to reduce the number of red blood cells and platelets in the blood. The drug’s approval to treat polycythemia vera will help decrease the occurrence splenomegaly and the need for phlebotomy.

Clinical Trial Ruxolitinib’s safety and effectiveness to treat polycythemia vera were evaluated in a clinical study involving 222 participants who had the disease for at least 24 weeks, had an inad-

equate response to or could not tolerate hydroxyurea, had undergone a phlebotomy procedure and exhibited an enlarged spleen. Participants were randomly assigned to receive ruxolitinib or the best available therapy, as determined by the investigator on a participant-by-participant basis. The study was designed to measure the reduced need for phlebotomy beginning at week 8 and continuing through week 32, in addition to at least a 35% reduction in spleen volume at week 32. Results showed 21% of ruxolitinib-treated participants experienced a reduction in the need for a phlebotomy and a reduction in spleen volume, compared to 1% of participants who received best available therapy. The most common side effects associated with use of ruxolitinib in participants with polycythemia vera were anemia and thrombocytopenia. The most common non-hematologic side effects were dizziness, constipation, and shingles. The FDA reviewed ruxolitinib use for polycythemia vera under the agency’s priority review program because, at the time the application was submitted, the drug demonstrated the potential to be a significant improvement in safety or effectiveness over available therapy in the treatment of a serious condition. In 2011, the FDA approved ruxolitinib for treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. n

Safety:10"

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

Polycythemia vera occurs when too many red blood cells are made in the bone marrow. Patients may also experience an increase in white blood cells and platelets. An overabundance of blood cells can cause the spleen to Safety:7" swell, bleeding problems, and blood

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In the News Supportive Care

Appetite-Enhancing Agent Helps Patients Treated for NSCLC Gain Weight and Lean Body Mass and Feel Better By Charlotte Bath

“P

eople have an image of stage III or IV lung cancer patients getting chemotherapy or chemoradiation, and they look terrible; they are losing weight. The fact is, when they respond, they can gain weight,” according to Philip Bonomi, MD, MS. He is the lead author of a phase III study showing that the investigational agent anamorelin hydrochloride significantly increased weight and lean body mass and improved anorexia-cachexia symptoms among patients with unresectable stage III/IV non–small cell lung cancer (NSCLC). The patients were underweight or had lost more than 5% of body weight at the time of diagnosis. More than 50% had not received prior treatment. During the trial, most of the patients were being treated with chemotherapy or radiation, and some were treated with both. Dr. Bonomi presented the results of ROMANA 1, an international doubleblind randomized trial,1 at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology and expanded on

the clinical implications in an interview with The ASCO Post. Dr. Bonomi is Director of the Division of HematologyOncology at Rush and Alice Pirie Wirtz Professor of Medicine at Rush University Medical Center.

‘Would You Prescribe That for Your Patients?’ Following Dr. Bonomi’s presentation, the discussant, Jeffrey Crawford, MD,

ter, Durham, North Carolina, commented on the clinical benefit of anamorelin, as shown in the ROMANA 1 trial. “If we ask ourselves this question: If you had a drug today that improved appetite with the resultant improvement in body weight and lean body mass, with minimal toxicity, would you prescribe that for your patients with cancer cachexia? For the patients we deal with on a daily basis in our clinic and their fam-

The pathway to regulatory approval of anamorelin would be a major step forward in the management of patients with cancer cachexia. —Jeffrey Crawford, MD

Chief of the Medical Oncology and Transplantation Division and Associate Director of Clinical Research at Duke University Comprehensive Cancer Cen-

ily members, I think the overwhelming answer to that is yes.” According to Dr. Crawford, “The pathway to regulatory approval of anamorelin would be a ma-

jor step forward in the management of patients with cancer cachexia.” Calling ROMAMA 1 “a very important trial,” Dr. Crawford lauded the inclusion of supportive care issues in the symposium agenda. Supportive care issues have continued to be in the news, as their value in quality of life and survivorship have gained more widespread recognition.

A Common and Debilitating Condition The cancer anorexia-cachexia syndrome is a common and debilitating condition among patients with advanced NSCLC and is characterized by loss of appetite and decreased body weight, mainly through the loss of lean body mass (skeletal muscle), Dr. Bonomi explained. Cachexia “is associated with poor overall survival and worse quality of life,” he added. “All of us who have treated these patients have tried many things, with very limited success. So we definitely have an unmet need.” continued on page 104

Expect Questions About Cancer Cachexia From Patients and Family Members By Charlotte Bath

“C

achexia is estimated to be the immediate cause of death in 20% to 40% of cancer patients,” and by the time of diagnosis, “60% of patients with lung cancer have already experienced a significant weight loss, according to the National Cancer Institute.1 “All of us who have treated these patients have tried many things, with very limited success,” noted Philip Bonomi, MD, Director of the Divi-

Philip Bonomi, MD

sion of Hematology/Oncology at Rush and Alice Pirie Wirtz Professor of Medicine at Rush University Medical Center. He is also the lead author of

ROMANA 1, a phase III study showing that the investigational agent anamorelin hydrochloride significantly increased weight and lean body mass and significantly improved anorexiacachexia symptoms among patients with unresectable stage III/IV non– small cell lung cancer (NSCLC).2 Often, Dr. Bonomi noted, it the patient’s family members who express the most concern about the patient not eating, leaving the patient to grapple with physiologic reasons for not eating and the added pressure from family members to eat. In the functional assessment portion of the ROMANA 1 trial, patients reported improvements in appetite and less pressure from family members to eat. Patients randomized to receive anamorelin had a median increase of 1.10 kg in lean body mass and of 2.20 kg in body weight.

So Few Alternatives Current treatment for cachexia

has very limited efficacy and is associated with  potential risks. The side effects of glucocorticoids “are not minor,” Dr. Bonomi said. “You’re trying to make somebody feel stronger, and one of the major side effects of those drugs is proximal muscle weakness.” This can affect hips and thigh, “so getting out of a chair, getting out of a low car, lifting your leg to go up a stair, those are profoundly weakened in some patients.” None of the progestational agents “works very well. There is not a headto-head comparison, but in my experience, they don’t,” Dr. Bonomi stated. Cannabis “may help some people but is not especially good either,” he added. “There really isn’t a good choice for these patients.”

Other Potential Uses In addition to combating cachexia, anamorelin has other potential uses, Dr. Bonomi reported. People with

“any disease associated with wasting” might benefit, he said. A major indication would be for chronic obstructive pulmonary disease. Other indications may include serious rheumatoid arthritis, chronic renal disease, and conditions related to aging. “There are many potential places where this could help,” he said, “but it probably has to be in conjunction with [physical] training.” n

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

References 1. Nutrition in Cancer (PFQ®) Health Professional Version. National Cancer Institute. Last modified September 9, 2104. 2. Bonomi P, Temel J, Currow D, et al: Anamorelin for the treatment of cancer anorexia-cachexia in advanced NSCLC: Results from ROMANA 1, a pivotal phase 3 study. 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. Abstract 5. Presented October 31, 2014.

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In the News Appetite-Enhancing Agent continued from page 103

Cachexia is seen even in patients with early-stage disease. “When you see weight loss in somebody who has stage I or II lung cancer, that is a bad prognostic factor. It usually means there is disease out there; you just can’t find it. As the disease progresses, these patients continue to lose weight.” Patients can, however, gain weight during the course of their treatment. He cited a study “looking across 2,300 patients entered on three different phase III trials, and no matter what the regimen was, about 18% of patients or more gained about 5% of their starting body weight, and those patients had a significantly longer survival.” The patients had stage IV lung cancer, and not all of them had been losing weight at the time of their diagnosis. He noted that an abstract of the study was included at the World Lung Conference in Sydney, Australia, in 2013, and a manuscript is in preparation but has not yet been submitted.

Concomitant Cancer Therapy Anamorelin is a novel, orally active, selective ghrelin receptor agonist with appetite-enhancing and anabolic activity. Released by the stomach, gherlin stimulates multiple pathways that regulate body weight, lean body mass, appetite, and metabolism. Anamorelin is being developed by Helsinn Therapeutics, which supported the study. Patients were randomized 2:1 to take a 100-mg pill daily for 12 weeks or placebo. They could not be taking prescription medications intended to increase appetite or treat weight loss. Most patients were 61 to 62 years old, and 16% to 20% had a performance status score of 2. More than 75% of participants were male, and close to 99% were Caucasian. The patients were from Eastern and Western Europe, the United States, and Canada. Dr. Bonomi conjectured that the predominance of Caucasian patients was probably related to the patient popu-

lation of the participating centers. At the time of enrollment, 52.6% of the patients in the anamorelin group and 54.7% of those in the placebo group had not received prior treatment for NSCLC. During the trial, at the discretion of the treating physician, 89.2% of patients taking anamorelin were receiving concomitant chemotherapy and 11.5% were receiving radiation therapy. Among those in the placebo group, 86.3% were receiving concomitant chemotherapy, and 11.2 % were receiving radiation therapy.

Significant Benefits Patients receiving anamorelin had a median increase of 1.10 kg in lean body mass, one of the study’s two coprimary endpoints, and 2.20 kg in body weight vs a 0.44-kg median decrease in lean body weight and a 0.14-kg median weight increase among those receiving placebo (P < .001). In the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire, where patients could register concerns about appetite, looking too thin, vomiting, and stomach pain, scores significantly improved for patients receiving anamorelin. FAACT scores at week 12 were 4.12 ± 0.8 vs 1.92 ± 0.8 for patients receiving placebo (P = .004). The significant benefits in lean body mass, body weight, and FAACT scores were also observed in the identically designed ROMANA 2 study, “highlighting the consistency between these two independent trials,” Dr. Bonomi noted. (Combined results from ROMANA 1 and 2 were summarized at the European Society for Medical Oncology [ESMO] 2014 Congress in Madrid and reported in the November 1 issue of The ASCO Post.2) Survival data are expected in 2015. “Patients’ symptoms and concerns about fatigue appeared to improve slightly or stabilize among patients receiving anamorelin and worsen among those receiving placebo, according to their responses to the Functional As-

sessment of Chronic Illness Therapy– Fatigue (FACIT–F) 2 questionnaire. Differences in scores attained statistical significance at week 9 (0.33 ± 0.9 in the anamorelin group vs −1.50 ± 1.0 in the placebo group, P = .331) and at week 12 (0.48 ± 1.0 vs −2.10 ± 1.0, P = .0244).

Not Strong on Strength Handgrip strength, the other coprimary endpoint, actually decreased in both groups: -1.00 kg in the anamorelin group and -2.69 in the placebo group. “Training is another important variable. If you put muscle mass on and don’t have some associated training, are you going to see a change in grip or strength? My suspicion is you are not going to see it unless you train. And these patients did not do any training,” at least as part of the study, Dr. Bonomi noted. “The handgrip not only didn’t correlate with gaining any muscle mass, it didn’t correlate with how the patients felt. The FAACT, which is a highly validated instrument, showed patients had significant improvements in cancer cachexia/anorexia. The scores went up by 3 or 4 points. Those are considered clinically meaningful by gurus in that area.”

Little Toxicity “Anamorelin was well tolerated when administered daily over 12 weeks,” Dr. Bonomi reported. The most common drug-related adverse events were hyperglycemia, occurring in 5.3% of patients, and nausea, occurring in 3.8%. Treatment-emergent adverse events of any kind occurred in 14.4% of patients receiving anamorelin vs 9.3% of patients receiving placebo. Grade 3/4 drug-related adverse events occurred in < 1.5% of patients in both groups. Among the 979 total patients in both ROMANA 1 and 2, about 55% continued on to the ROMANA 3 trial. That trial is looking at the effects of anamorelin and its tolerability in patients who take it for an additional 3 months. Although uncertain when the ROMANA

3 investigators will release results, Dr. Bonomi said, “I expect that results of ROMANA 3 will be described in an abstract submitted to ASCO for the 2015 Annual Meeting.”

Additional Studies An ongoing study at Rush University Medical Center is looking at skeletal muscle mass index, as determined by serial CT scans of lean body masses of patients being treated with chemotherapy or chemoradiation, and correlating that with their response to therapy and survival. “We have already seen that increased weight correlates with longer survival. Now what we would like to see is, does increased weight, including increased lean body mass, correlate with regression of the tumor? Our clinical impression is yes, but we are going to do all the measurements,” Dr. Bonomi reported. Noting that the investigators do not have a direct intervention for muscle mass, Dr. Bonomi commented, “Since anamorelin increases muscle mass, if we interfere with the muscle breakdown— and I realize I may be getting carried away, but I am the eternal optimist— might this anabolic effect have a positive impact on survival? I look forward to seeing the survival data from the ROMANA studies. If anamorelin doesn’t affect survival, its effects on appetite and energy level are big positives for lung cancer patients.”n

Disclosure: Dr. Bonomi received honoraria from Helsinn for participation in advirosry boards. Dr. Crawford reported no potential conflicts of interest.

References 1. Bonomi P, Temel J, Currow D, et al: Anamorelin for the treatment of cancer anorexia-cachexia in advanced NSCLC: Results from ROMANA 1, a pivotal phase 3 study. 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. Abstract 5. Presented October 31, 2014. 2. Goodman A: Novel oral agent treats cachexia in patients with non-small cell lung cancer. The ASCO Post November 1, 2014.

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ASCOPost.com | DECEMBER 15, 2014

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Announcements

Regis Chair for Breast Cancer Research Established

n partnership with the Regis Foundation for Breast Cancer Research, Regis Corporation, a leader in beauty salons and cosmetology, has announced that the Masonic Cancer Center at the University of Minnesota, Minneapolis, has established the Regis Chair for Breast Cancer Research. This milestone will help the Masonic Cancer Center attract, retain, and support the work of leading breast cancer researchers. Renowned surgical oncologist Todd M. Tuttle, MD, has been named the inaugural chair holder. “I am grateful to the Regis Foundation for its dedication to improving the life of anyone touched by breast cancer,” said Dr. Tuttle. “Research is the key to discovering better ways to prevent, diagnose, and treat this disease. It is an honor to hold the Regis Chair for Breast Cancer Research, and I thank the Regis Corporation employees and guests who made this generous support possible.” Endowed chairs are among the most important investments made in academics because they continue to give—forever. The Regis Chair for Breast Cancer Research will be used to support leading research to develop new methods for breast cancer detection and treatment options.

Clip for the Cure “We’re very proud of our partnership with the Masonic Cancer Center and are honored that Dr. Tuttle will be advancing the center’s breast cancer research,” said Dan Hanrahan, Regis Corporation President and CEO. “At Regis, we’re able to support breast cancer research because of our Clip for the Cure campaign, which is made possible by the tremendous generosity and commitment from our stylists, guests, and business partners across the country.” The primary fundraiser for the Regis Foundation for Breast Cancer Research is Regis Corporation’s annual Clip for the Cure haircutting event, which was held this year on Saturday, October 18. To support the event, more than 7,000 Regis corporate salons and 50,000 stylists participated in the daylong fundraiser, welcoming approximately 220,000 guests to salons across the country. Regis Corporation donated 10% of proceeds from each haircut to the Foundation. In September and October, guests also donated funds to support the Regis Foundation for Breast Cancer Research,

while salons helped raise awareness for the cause by selling limited-edition pink rings and bracelets, with net proceeds going to the Foundation. Throughout the year, the Foundation also works on a local level to support centers and institutions that assist

and treat patients with breast cancer. It has supported San Francisco’s UCSF Helen Diller Family Comprehensive Cancer Center, Pittsburgh’s Hillman Cancer Center, the Chesapeake Regional Health Foundation in Virginia, and Columbia St. Mary’s Founda-

2015

tion in Wisconsin. The Foundation has plans for additional partnerships throughout 2014 and 2015. n For more information on Clip for the Cure and the Regis Foundation for Breast Cancer Research, visit ClipForTheCure.com.

Annual Conference

ADVANCING THE STANDARD OF CANCER CARE TM

March 12 – 14, 2015 The Diplomat • Hollywood, Florida

Track Session Topics* – New this year! Breast Cancer

Early Stage | HER2-Positive and Triple Negative Cancer | New Therapies for Hormone-Sensitive Advanced Disease

Gastrointestinal (GI) Cancers Esophageal | Metastatic Colorectal Cancer | Pancreatic Cancer

Genitourinary (GU) Cancers

Castration-Recurrent Prostate Cancer | Bladder Cancer | Kidney Cancer

Hematologic Malignancies

Chronic Myelogenous Leukemia | Chronic Lymphocytic Leukemia | Multiple Myeloma | B-cell Lymphomas

Early Bird DEADLINE!

Monday, February 2, 2015

Lung Cancers

Non-Small Cell Lung Cancer: Minimally Invasive Techniques | Adjuvant Therapy and Treatment of Metastatic Disease | Small Cell Lung Cancer: Role of Radiation Therapy

Skin Cancers

Localized and Advanced Melanoma | Dermatologic Toxicities Associated with Targeted Therapies

Supportive Care

Fertility | Smoking Cessation | Anthracycline-Induced Cardiac Toxicity

* Subject to change.

Visit NCCN.org/AC2015 to register

or to view more information for this educational program. JNCCN-N-0201-1214

The ASCO Post | DECEMBER 15, 2014

PAGE 106

Lab Notes

Ongoing Molecular Research in the Science of Oncology TARGETED THERAPY Functional Kinomics Identifies WEE1 Kinase as Target in Head and Neck Cancer In a study reported in Clinical Cancer Research, Moser and colleagues used RNA interference kinase viability screens to identify survival kinases (involved in G2-M cell-cycle checkpoint, SFK, PI3K, and FAK pathways) in p53-mutant head and neck squamous cell carcinoma. Selected kinase targets were tested against a panel of kinase inhibitors. Study of the WEE1 kinase showed that both RNA interference-mediated knockdown and a specific kinase inhibitor (MK1775) produced significant inhibition of cell viability and apoptosis. Sensitivity to the WEE1 kinase inhibitor was determined in part by p53 mutational status and was due to unscheduled mitotic entry. The inhibitor was active as a single agent and potentiated the activity of cisplatin in a p53-mutant head and neck squamous cell carcinoma xenograft model. The investigators concluded: “WEE1 kinase is a potential therapeutic drug target for [head and neck squamous cell carcinoma]. This study supports the application of a functional kinomics strategy to identify novel therapeutic targets for cancer.” Moser R, et al: Clin Cancer Res 20:4274-4288, 2014.

Lipophilic Bisphosphonate Plus Rapamycin Active in KRAS-Mutant Lung Cancer KRAS-mutant lung adenocarcinoma has not been successfully targeted therapeutically. In a study reported in Science Translational Medicine, Xia and colleagues found that the combination of lipophilic bisphosphonates and rapamycin exhibited promising activity in this setting. Lipophilic bisphosphonates inhibit farnesyl and geranylgeranyl diphosphate synthases, inhibiting prenylation of KRAS and other small G proteins (heterotrimeric GTP-binding protein, heterotrimeric guanine nucleotide-binding proteins) important to tumor growth and cell survival. Rapamycin is an mTOR inhibitor. Bisphosphonate treatment of tumor cells induced autophagy but subsequently led to p62 accumulation and consequent NF-κB activation, yielding little efficacy in the KRAS G12D mouse lung model. In addition to inhibiting the mTOR pathway, rapamycin induced autophagy and prevented p62 accumulation-induced NF-κB activation and tu-

mor cell proliferation. The combination showed far greater efficacy in the KRAS G12D model than either agent alone. The investigators concluded: “Overall, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations.” Xia Y, et al: Sci Transl Med 6:263ra161, 2014.

Dual HER2 Targeting Inhibits HER2-Amplified Uterine Serous Carcinoma In a study reported in Clinical Cancer Research, Groeneweg and colleagues found that dual HER2 targeting showed greater activity than a single agent in HER2-amplified uterine serious carcinoma. In the study, ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab (Herceptin) or lapatinib (Tykerb), and mice with xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human tumor samples were treated with vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Single-agent trastuzumab produced little effect in all models. Lapatinib reduced proliferation in all cell lines and inhibited growth of HER2-amplified ARK2 and EnCa1 xenografts. Dual therapy produced significant antitumor activity in ARK2 and EnCa1 xenografts. Overall, dual therapy induced alteration of downstream MAPK and PI3K pathway mediators only in HER2-amplified models and was associated with increased apoptosis and decreased proliferation. The investigators concluded: “Although trastuzumab alone did not impact [uterine serous carcinoma] growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified [uterine serous carcinoma] and may be a promising avenue for future investigation.” Groeneweg JW, et al: Clin Cancer Res 20:1-12, 2014.

IMMUNOTHERAPY Intraperitoneal Oxidative Stress Induces Tumoricidal Immune Response in Papillomavirus-Linked Head/Neck Cancer In a study reported in Clinical Cancer Research, Rossmann and colleagues found that induction of

oxidative stress via O3/O2 pneumoperitoneum treatment in the papillomavirus-associated rabbit auricular VX2 carcinoma model of head and neck cancer resulted in a tumoricidal immune response that could be adoptively transferred. Auricular VX2 tumors that regressed after O3/O2 pneumoperitoneum treatment exhibited increased levels of CD3-positive tumor infiltrating lymphocytes, as well as increased expression of genes encoding receptors involved in pattern recognition, molecules required for antigen presentation and T-cell activation, and inflammatory mediators. Adoptive cell transfer of peripheral blood lymphocytes from rabbits with regressing tumors to rabbits with newly implanted VX2 tumors resulted in acquired resistance to tumor growth and produced tumor regression. The investigators concluded: “Intraperitoneal oxidative stress effectively converts the immune response against the papillomavirus-associated rabbit VX2 carcinoma from tumor permissive to tumoricidal and leads to a sustainable, adoptively transferable oncolytic immune response.” Rossmann A, et al: Clin Cancer Res 20:4289-4301, 2014.

Checkpoint Blockade Immunotherapy Targets Tumor-Specific Mutant Antigens In a study reported in Nature, Gubin and colleagues showed that the effects of CTLA-4 (cytotoxic T-lymphocyte–associated protein-4) and PD-1 PD-1 (programmed cell death protein-1) inhibitors (checkpoint blockade) are achieved through targeting of tumor-specific mutant antigens. In the study, genomic and bioinformatic approaches identified tumor-specific mutant proteins as a major class of T-cell rejection antigens following anti–PD-1 or anti–CTLA-4 treatment of mice with progressively growing sarcomas. Synthetic therapeutic long-peptide vaccines incorporating the mutant epitopes resulted in tumor rejection comparable to that observed with checkpoint blockade immunotherapy. It was observed that although mutant tumor antigen-specific T cells were present in progressively growing tumors, they were reactivated with anti–PD-1 or anti–CTLA-4 antibody treatment; the T cells displayed some

overlapping transcriptional profiles but primarily expressed treatmentspecific profiles that were associated with tumor rejection. The investigators concluded: “These results reveal that tumor-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.” Gubin MM, et al: Nature 515:577581, 2014.

COMBINATION THERAPY WEE1 Inhibition Sensitizes Pancreatic Cancer to PARP Inhibitor Radiosensitization In a study reported in Clinical Cancer Research, Karnak and colleagues found that WEE1 kinase inhibition increased the sensitivity of pancreas cancer to the radiosensitizing effects of poly(ADP-ribose) polymerase (PARP) inhibition. Treatment of human pancreatic cancer AsPC-1 and MiaPaCa-2 cells with either the WEE1 inhibitor AZD1775 or the PARP inhibitor olaparib resulted in modest radiosensitization, with the combination significantly increasing radiosensitization. Use of the combination was associated with G2 checkpoint abrogation and persistent DNA damage, and WEE1 inhibition was found to reduce homologous recombination repair and prevent radiation-induced Rad51 focus formation. In MiaPaCa-2 xenografts, olaparib produced no radiosensitization, and AZD1775 had a moderate effect (P < .05). However, the combination produced highly significant radiosensitization (P < .0001) that translated into a 13-day delay in tumor-volume doubling vs radiation alone and complete eradication of 20% of tumors. The authors concluded: “Taken together, these results demonstrate the efficacy of combined inhibition of WEE1 and PARP inhibitors for radiosensitizing pancreatic cancers and support the model that WEE1 inhibition sensitizes cells to PARP inhibitormediated radiosensitization through inhibition of [homologous recombination repair] and abrogation of the G2 checkpoint, ultimately resulting in

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Lab Notes

IMMUNE RESPONSE PD-L1 Expression by Tumor Infiltrating Cells Associated With Activity of Anti–PD-L1 Antibody in Multiple Cancer Types Programmed cell death protein ligand 1 (PD-L1) interferes with anticancer immune response by binding programmed PD-1 and B7.1 (CD80), negative regulators of T-cell activation. In a study reported in Nature, Herbst and colleagues showed that treatment with an anti–PDL1 antibody (MPDL3280A) produced responses across multiple cancer types in patients with tumors expressing high levels of PD-L1 and particularly when PD-L1 was expressed by tumor-infiltrating immune cells. Responses were also associated with T-helper type 1 gene expression, CTLA-4 (cytotoxic T-lymphocyte–associated protein-4) expression, and absence of fractalkine (CX3CL1) in baseline tumor samples. The investigators concluded: “[T] hese data suggest that MPDL3280A is most effective in patients in which preexisting immunity is suppressed by PD-L1 and is reinvigorated on antibody treatment.” More detailed information about this study may be found on page 48 in this issue of The ASCO Post. Herbst RS, et al: Nature 515:563567, 2014.

being confirmed by mass spectrometry. The identified peptides were structurally modeled bound to MHC-I, with the mutations that were solvent-exposed and thus accessible to T-cell antigen receptors being predicted to be immunogenic. Every predicted immunogenic peptide produced a therapeutically active T-cell response when used as a vac-

cine in mice. The predictions also permitted development of peptide-MHC-I dextramers, which allowed monitoring of kinetics and distribution of the antiBLEED:8.375” tumor T-cell response before and after TRIM:7.875” vaccination. SAFETY:7” concluded: The investigators “These findings indicate that a suitable prediction algorithm may provide an

approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.” n Yadav M, et al: Nature 515:572-576, 2014. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

Now enrolling for alectinib

NCT 02075840 BO28984

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

Randomize 1:1

unrepaired, lethal DNA damage and radiosensitization.” Karnak D, et al: Clin Cancer Res 20:5085-5096, 2014.

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

Primary Endpoint:

Alectinib1

Crizotinib

Secondary Endpoints:

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

• Objective response rate, investigator-assessed,

by RECIST 1.1

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

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

PHARMACODYNAMIC MONITORING Predicting Immunogenic Tumor Neoantigens With Combined Mass Spectrometry and Exome Sequencing Peptides containing tumor somatic mutations are potentially immunogenic if presented on major histocompatibility complex class I molecules (MHCI), and it has been shown that such mutant peptides act as T-cell epitopes. In a study reported in Nature, Yadav and colleagues developed an approach combining whole-exome and transcriptome sequencing analysis with mass spectrometry, which enabled them to identify neoepitopes in two common mouse tumor models. Of the >1,300 amino acid changes identified, approximately 13% were predicted to bind MHC-I, with a small fraction of these

• Patient-reported outcomes

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Advanced, recurrent, or metastatic ALK-positive NSCLC

• Prior malignancy in past 3 years

• Life expectancy ≥12 weeks

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

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

metastatic disease • Measurable disease by RECIST 1.1

a prior therapy

• Baseline QTc >470 ms or symptomatic

bradycardia <45 beats per minute • Concomitant strong cytochrome P4503A

inhibitors/inducers or QT-prolonging medications

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

The ASCO Post | DECEMBER 15, 2014

PAGE 108

In the Literature

Emerging Clinical Data on Cancer Management LEUKEMIA Obinutuzumab May Have Synergistic Action With New Tyrosine Kinase Inhibitors Final results from the phase I/II GAUGUIN study showed that obinutuzumab (Gazyva) monotherapy was active in patients with heavily pretreated relapsed or refractory chronic lymphocytic leukemia, European researchers reported in Blood. In phase II, median progression-free survival was 10.7 months, and median duration of response was 8.9 months. “For clinical use, obinutuzumab monotherapy is likely to be suitable in situations where rituximab [Rituxan] or ofatumumab [Arzerra] monotherapy are currently used, due to its higher propensity for B-cell depletion, and in patients not suitable for cytotoxic chemotherapy,” the researchers wrote. “However, arguably the most exciting development for obinutuzumab will lie in its potential for combination with new kinase inhibitors such as ibrutinib [Imbruvica] or idelalisib [Zydelig], where its efficiency with regard to eliminating circulating B cells may be synergistic with the strong ability of such kinase inhibitors to induce the migration of clonal cells from lymph node and bone marrow to the blood.” During the phase I dose escalation portion of the study, 13 patients from 7 centers across France received obinutuzumab at 400 to 1,200 mg

(days 1 and 8 of cycle 1; day 1 of cycles 2–8). In the phase II portion, 20 patients from 20 centers across France and Germany received a fixed dose of 1,000 mg (days 1, 8, and 15 of cycle 1; day 1 of cycles 2–8). The median ages of the patients were 64 in phase I and 62.5 in phase II. The median number of previous treatments was three for patients in both phases of the study. Ten patients (50%) in phase II had received prior rituximab treatment. The overall end-of-treatment response rates (all partial responses) were 62% in phase I and 15% in phase II, and the respective best overall response rates were 62% and 30%. The researchers speculated that lower best overall response in phase II was “possibly due to higher baseline tumor burden resulting in lower treatment exposure.” Nearly all patients had infusionrelated reactions, although few were grade 3/4. Adverse events were independent of dose, and no dose-limiting toxicities were reported. Cartron G, et al: Blood 124:21962202, 2014.

COLORECTAL CANCER Patients With Metastatic Colorectal Cancer Have Improved Outcome With FOLFOXIRI and Bevacizumab Patients with untreated metastatic colorectal cancer who received

OLFOXIRI (folinic acid, fluoroF uracil, oxaliplatin, irintotecan) plus bevacizumab (Avastin) had improved survival compared with patients who received FOLFIRI (folinic acid, fluorouracil, irintotecan) plus bevacizumab in a phase III randomized trial conducted at 34 Italian centers. “The median progression-free survival was prolonged by 2.4 months, reaching 12.1 months,” for patients treated with FOLFOXIRI plus bevacizumab, Fotios Loupakis, MD, PhD, of Azienda Ospedaliero–Universitaria Pisana and Università di Pisa, Italy, and colleagues reported in The New England Journal of Medicine. For patients treated with FOLFIRI plus bevacizumab, median progression-free survival was 9.7 months (hazard ratio [HR] for disease progression, 0.75; 95% confidence interval [CI], 0.62–0.90; P = .003). “Moreover, an absolute increase of 12.0% in response rate was reported, and median overall survival was extended, but not significantly so, by 5.2 months, from 25.8 to 31.0” months in the FOLFOXIRI group, the researchers reported. The objective response rates were 65% with FOLFOXIRI vs 53% with FOLFIRI (P = .006). “The intensification of the treatment was associated with a significant increase in the rates of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia. However, no significant differences between treatment groups in the rates of febrile neutropenia, serious adverse events, or deaths due to treatment-related toxic effects were observed,” the investigators wrote. “In our opinion, early recognition and active management of adverse events are crucial.” A total of 508 patients were randomly assigned to receive FOLFIRI plus bevacizumab (control group, 256 patients) or FOLFOXIRI plus bevacizumab (experimental group, 252 patients). “Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression,” the investigators stated. Patients had unresectable metastatic colorectal cancer and had not received chemotherapy or biologic therapy for metastatic disease, although 12.6% had received adjuvant chemotherapy earlier in their disease course. “Demographic and baseline characteristics of the patients were similar in the two groups,” the investigators noted, “but a higher percentage of pa-

tients in the experimental group than in the control group had a primary tumor in the right colon (34.9% vs 23.8%, P = .02).” Among all patients, 79.3% had multiple sites of metastases and 20.7% had disease limited to he liver. The median age was 60 in the FOLFIRI group and 60.5 in the FOLFOXIRI group. Grade 3/4 neutropenia occurred in 50% of patients receiving FOLFOXIRI vs 20.5% of patients receiving FOLFIRI. Higher rates with FOLFOXIRI vs FOLFIRI also occurred for several other grade 3/4 adverse events, including diarrhea (18.8% vs 10.6 %), febrile neutropenia (8.8% vs 6.3%), stomatitis (8.8% vs 4.3%), and peripheral neuropathy (5.2% vs 0%). The only grade 3/4 adverse event with a higher incidence reported for FOLFIRI was nausea, but the incidences were low and the differences slight. “The incidence of serious adverse events was similar in the two groups (19.7% in the control group and 20.4% in the experimental group, P = .91),” the researchers stated. “A total of 142 (91.6%) of the deaths in the control group and 121 (92.4%) of the deaths in the experimental group were attributed to disease progression. In each group, a similar number of patients died as a result of adverse events (4 [1.6%] in the control group and 6 [2.4%] in the experimental group).” Loupakis F, et al: N Engl J Med 371:1609-1618, 2014.

Small Risk-Adjusted Variation in Hospital Readmissions Following Colorectal Cancer Surgery “Little risk-adjusted variation exists in hospital readmission rates after colorectal surgery,” according to an analysis of data from 44,822 patients who underwent colorectal resection for cancer at 1,401 U.S. hospitals between 1997 and 2002. “The use of readmission rates as a high-stakes quality measure for payment adjustment or public reporting across surgical specialties should proceed cautiously and must include appropriate risk adjustment,” concluded Donald L. L ucas, MD, MPH, and colleagues from Walter Reed National Military Medical Center, Bethesda, and Johns Hopkins University School of Medicine, Baltimore. continued on page 110

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In the Literature Emerging Clinical Data continued from page 108

“Readmission has become a major hospital quality metric, but it is unclear whether there is much difference in readmission among hospitals after appropriate risk adjustment,” the authors wrote in JAMA Surgery. To assess the variability in riskadjusted readmission rates following colorectal surgery, the researchers performed a hierarchical multivariable logistic regression analysis of observational data obtained from the Surveillance, Epidemiology, and End Results Medicare–linked database. The authors pointed out that compared with multivariable analyses, hierarchical models “better account for the statistical uncertainty related to low case volumes seen at the hospital level.” In addition, “hierarchical modeling for hospital profiling has been endorsed by the Committee of Presidents of Statistical Societies,” as well as the Centers for Medicare & Medicaid Services and the American College of Surgeons National Surgical Quality Improvement Program. The median age of the study patients was 78 years; 87.1% were nonHispanic white; and 55.2% were female. Most patients (37,228 [83.1%]) underwent a colectomy, most commonly a right colectomy (20,881 patients [46.6%]), and 7,534 patients (16.8%) underwent a proctectomy. On adjusted analysis, risk of readmission increased progressively with age and among patients of black race. Operations most associated with readmission were total abdominal colectomy and abdominoperineal resection. Patients undergoing sigmoid colectomy had a decreased risk of readmission. Comorbidities associated with increased readmission included congestive heart failure, chronic obstructive pulmonary disease, and cerebrovascular disease. The overall 30-day readmission rate was 12.3%. “Looking at hospitals that performed at least five operations annually, we found marked variation in raw readmission rates, with a range of 0% to 41.2% (interquartile range [IQR], 9.5%–14.8%). However, after adjusting for patient characteristics, comorbidities, and operation types in a hierarchical model, no significant variability was found in readmission rates among hospitals, with a range of 11.3% to 13.2% (IQR, 12.1%– 12.4%),” the investigators stated. Lucas DJ, et al: JAMA Surg. October 22, 2014 (early release online).

Personalized Genetic and Environmental Risk Assessment Does Not Increase Use of Colorectal Cancer Screening Individualized genetic and environmental risk assessment of susceptibility to colorectal cancer does not influence adherence to screening in average-risk persons, according to results from a two-group, randomized, controlled trial. Among patients who received genetic and environmental risk assessment and those who did not, approximately onethird completed colorectal screening during the 6-month follow-up. “These findings raise concern about the effectiveness of moderately predictive assessment of genetic risk to promote favorable health care behavior,” D avid S. Weinberg, MD, MSc, of Fox Chase Cancer Center, Philadelphia, and colleagues stated in the Annals of Medicine. “Unlike with genetic testing for high-risk persons, such as those with familial adenomatous polyposis, little is known about the impact on health behaviors or the psychological effects of providing average-risk persons with moderately predictive genetic information,” the authors wrote. “Understanding the benefits and harms of such testing in average-risk persons is important because similar testing is marketed directly to the public in an unsupervised fashion.” The study involved 783 participants from four medical school–affiliated primary care practices. At the time they entered the study, the participants were considered at average risk for colorectal cancer but were not adherent to colorectal cancer screening recommendations. Average risk was defined as “being asymptomatic and having no personal history of colorectal adenomas, cancer, or inflammatory bowel disease or no family history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or colorectal cancer in a first-degree relative.” Nonadherence to colorectal cancer screening guidelines was defined as “not having had home fecal occult blood testing in the past 12 months, barium enema or flexible sigmoidoscopy in the past 5 years, or colonoscopy in the past 10 years.” Participants completed baseline surveys of demographic characteristics, multivitamin use, and psychometric and knowledge characteristics. There were no significant

differences in any of these variables between participants randomly assigned to usual care or genetic and environmental risk assessment. Most patients were aged 50 to 59, and 56% were white. In addition to the baseline survey, patients assigned to genetic and environmental risk assessment met with a specially trained nurse to discuss the purpose of genetic and environmental risk assessment. These participants were told that their results would be classified as average or elevated, but that “an average result did not ensure protection against colorectal cancer now or in the future” and an elevated result “did not guarantee disease but was only one potential risk factor for colorectal cancer, suggesting modestly increased risk compared with that of a similarly aged person.” The study nurse emphasized that genetic and environmental risk assessment was not intended to be a substitute for screening. Genetic and environmental risk assessment “evaluated methylenetetrahydrofolate reductase polymorphisms and serum folate levels. On the basis of prespecified combinations of polymorphisms and serum folate levels, genetic and environmental risk assessment recipients were told that they were at elevated or average risk for colorectal cancer,” the researchers explained. The primary outcome of the study was colorectal cancer screening within 6 months of entering the study. “Overall screening rates for colorectal cancer did not statistically significantly differ between the usual care (35.7%) and genetic and environmental risk assessment (33.1%) groups. After adjustment for baseline participant factors, the odds ratio for screening completion for genetic and environmental risk assessment vs usual care was 0.88 (95% confidence interval [CI], 0.64–1.22),” the researchers reported. Within the genetic and environmental risk assessment group, screening rates did not significantly differ between average-risk (38.1%) and elevated-risk (26.9%) participants. Odds ratios for elevated-risk vs average-risk participants remained nonsignificant after adjustment for covariates (odds ratio [OR], 0.75 [CI, 0.39–1.42]).” The researchers also investigated whether baseline factors may have confounded their results. “Black participants were significantly more

likely than white participants to be at elevated risk, presumably because of well-described differences in allele distribution frequency across race (OR, 5.92 [CI, 3.26–10.74]),” the researchers noted. “That regular multivitamin use was significantly inversely associated with elevated-risk status (OR, 0.24 [CI, 0.13–0.44]) was also expected, because regular multivitamin users may have higher serum folate levels.” Other significant differences included generally lower education levels in the elevated-risk group and less baseline knowledge about colorectal cancer screening and genetics and diet. Using a multivariate logistic model to adjust for potential confounding did not alter the conclusion that genetic and environmental risk assessment risk classification had no significant effect on screening. Although feedback from a single personalized genetic and environmental risk assessment was not positively associated with colorectal cancer screening in average-risk persons, the investigators noted that “additional studies will be required to evaluate whether other approaches to providing genetic and environmental risk assessment affect screening utilization differently.” “We should not look toward personalized medicine and genomics to refine risk estimates in ways that will, on their own, motivate substantial behavior change,” according to an editorial accompanying the article. “Instead, we should utilize such information to identify patients who are most in need of such screening and then rely on proven persuasion techniques to encourage patients to undergo screening (for example, default screening appointments and videos that make the harms of not screening salient). The editorial was written by J. S. Blumenthal-Barby, PhD, MA, and  Amy L. McGuire, JD, PhD,  Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, and Peter A. Ubel, MD, Fuqua School of Business and Sanford School of Public Policy, Duke University, Durham, North Carolina. n Weinberg DS, et al: Ann Intern Med 161:537-545, 2014. Blumenthal-Barby JS, McGuire AL, Ubel PA: Ann Intern Med 161:605606, 2014. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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PAGE 112

Pioneers in Oncology Vincent T. DeVita, Jr, Helped Usher in the Era of Chemotherapy, Turning Lethal Cancers Into Curable Ones By Jo Cavallo

lthough Vincent T. DeVita, Jr, MD, harbored fantasies as a young child of becoming an ice deliveryman when he grew up, his love of chemistry and biology, as well as admonitions from his mother, Isabel, “to become a doctor,” propelled him toward a career in medicine. Now, more than 6 decades later, Dr. DeVita’s contributions to the science of cancer are heralded as leading to some of the most significant breakthroughs in the progress against the disease since President Richard Nixon launched the “War on Cancer” in 1971. Born on March 7, 1935, in the Bronx, New York, Dr. DeVita studied chemistry and biology at the College of William and Mary, a school he choose partly to honor his maternal grandfather, Ernest LoNano, a master antique restorer, who restored Colonial Williamsburg in Williamsburg, Virginia, where the college is located, to its historic form. While there, he met Mary Kay Bush, whom he married soon after their graduation in 1957. The couple then moved to Washington, DC, where Dr. DeVita attended George Washington University School of Medicine. A couple of years into his studies, Dr. DeVita was invited by his physiology professor to spend the summer at Mount Desert Island Biological Laboratory in Bar Harbor, Maine. While there, he met David P. Rall, MD, PhD, then Chief of Chemical Pharmacology at the National Cancer Institute (NCI), who offered Dr. DeVita a job. “I had done extremely well in my pharmacology course in medical school and when I received my national board grades, Dr. Rall asked me to come to the NCI, where I could also fulfill my national service time,” said Dr. DeVita. “The Vietnam War was going on then, and working at the NCI counted as time spent in military service and allowed me to avoid the draft. It was a coveted position, and I took advantage of it.” Dr. DeVita would spend the majority of his medical career in various positions at the NCI, including Senior Investigator, Head of the Solid Tumor Service, Chief of the Medical Branch, Director of the Division of Cancer Treatment, Clinical Director, and then Director of the NCI from 1980 to 1988. Although cardiology was Dr. DeVita’s initial choice as a medical spe-

cialty during his residency, when he saw the investigations being done in cancer drug development at the NCI, he switched his focus to oncology and “was hooked.” During his first year there, Dr. DeVita became interested in Hodgkin lymphoma. His investigation of the disease would come to dominate his early research efforts and lead to the era of curative chemotherapy in oncology care.

Proving Chemotherapy Is a Viable Cancer Therapy In the early- to mid-1960s, the field of cancer therapy centered on its two top weapons, surgery and radiation, despite the fact that neither was effective against stopping the systemic spread of solid tumors or halting the progression in blood cancers like leukemia. The result was cure rates stuck at a dismal 33%.

0% to 80%. The remission rates were so unheard of and such a testament to the feasibility of curing cancer with drugs, data from the MOMP and MOPP studies were presented at meetings of the American Association for Cancer Research (AACR) in 1965 and 1967, respectively. In 1970, the final results from the MOPP study were published in the Annals of Internal Medicine.1 “We didn’t have a lot of molecular tools in those days, so we designed the protocol based on the growth characteristics of the mouse and human bone marrow and assumptions about the growth kinetics of human tumors and what we knew of the mechanism actions of the drugs,” said Dr. DeVita. “We had to translate the data from mice to humans based on the limits of their growth characteristics, so it was a clever design for the time, and it worked. The

There is no better reward than seeing patients who have lived more than 40 years who might have died. It is a great feeling and one of the benefits of growing older. —Vincent T. DeVita, Jr, MD

Then, in 1965, after mouse studies by Howard Skipper, PhD, a mathematical biologist at the Southern Research Institute in Birmingham, Alabama, produced the first curative treatment of a mouse leukemia using combination chemotherapy, Dr. DeVita and his colleagues at the NCI began researching combination chemotherapies in the treatment of Hodgkin lymphoma, a then fatal disease, often treated with single alkylating agents. First, they developed the MOMP protocol, which combined nitrogen mustard, vincristine, methotrexate, and prednisone, followed by the MOPP protocol, which omitted methotrexate and added procarbazine, a drug Dr. DeVita had been studying. Initially derided within the National Institutes of Health Clinical Center as too big a departure from the norm, MOPP began showing impressive results in early clinical trials. In a study of MOPP in 188 patients with advanced Hodgkin lymphoma, the complete remission rate went from

principles used in the MOPP program have become part of the protocols used in chemotherapy drug combinations ever since.”

Attaining Remarkable Remissions In 44 years of follow-up studies of the original 188 patients in the MOPP study, 60% of the patients who attained a complete remission have remained cancer-free, and only one patient developed a secondary leukemia. “If patients are treated with MOPP alone, they don’t have a high risk of developing secondary tumors,” said Dr. DeVita. “It’s when you add radiotherapy to the treatment that patients develop second tumors mostly in the radiation field.” The importance of the MOPP discovery, said Dr. DeVita, was not just that it was successful in curing Hodgkin lymphoma—today, cure rates for this disease top 90%—but that the treatment proved advanced cancer in major organ systems in adults could be cured

using drugs. “There is no better reward than seeing patients who have lived more than 40 years who might have died. It is a great feeling and one of the benefits of growing older,” said Dr. DeVita. In 1972, Dr. DeVita received the Albert Lasker Clinical Medical Research Award for his pioneering work in the development of combination chemotherapy in the treatment of Hodgkin lymphoma. And, in September 2014, ASCO named the MOPP protocol among the Top 5 Advances in 50 Years of Modern Oncology.

From Triumph to Tragedy The success of MOPP marked a turning point in Dr. DeVita’s career, resulting in an appointment as Head of NCI’s Solid Tumor Service in 1968, followed 3 years later by a promotion to Chief of its Medicine Branch. But a year later, in 1972, personal tragedy struck when Dr. DeVita’s son, Ted, just 9 at the time, developed the lethal and rare bone marrow disorder aplastic anemia. Ted was taken to a laminar airflow room at the NCI clinic in Bethesda, Maryland, where he lived for 8 years until his death in 1980. “The area outside Ted’s room became our living room,” said Dr. DeVita. The family, including Ted’s younger sister, Elizabeth, and his mother, Mary Kay, would visit every day, with Dr. DeVita often staying until late at night teaching Ted to play the guitar and chess. After Ted went to sleep, Dr. DeVita retreated to his lab to pursue his research. It was during this time that Dr. DeVita, in collaboration with George Canellos, MD, developed the protocol for CMF (cyclophosphamide, methotrexate, and fluorouracil) in the adjuvant setting for breast cancer. The protocol has since contributed to a significant decline in breast cancer mortality, establishing another major accomplishment in cancer advancement. “Work was a great escape for me, but it was a very difficult time,” said Dr. DeVita. “Mary Kay bore the brunt of caring for Ted and Elizabeth. She is a very strong woman.” The heartbreak of losing a young child served to make Dr. DeVita an even more compassionate physician and cemented his determination to find cures for life-threatening diseases. “Los-

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Pioneers in Oncology ing Ted had a big effect on me,” said Dr. DeVita. “When I started in the field, I took care of young kids with leukemia, and there is no more trying experience than watching little kids go through cancer and its treatment. In those days, most of them died, so I had seen the devastation firsthand. I thought I knew what those parents were going through and when I had to go through it, I found it to be even worse than I thought. I became a little more dedicated in trying to solve this problem. If I needed motivation, and I didn’t need much, losing Ted gave me more.”

The Power of Music If medicine is Dr. DeVita’s vocation, opera is his passion, one that he inherited from both his grandfather and his mother, who played opera arias on the piano when he was growing up. It is also his salvation. During the turbulent times of the late 1970s and early 1980s, when expectations for curing cancer

were running high and the War on Cancer was faltering, as Director of the NCI and the National Cancer Program, Dr. DeVita became the target of immense criticism. “Opera became a form of escapism for me,” said Dr. DeVita. “I get involved in the story, and it is a way for me to forget where I am. When I was having difficulty at the NCI with politics and cancer, I would go away for a weekend and see four operas. By the second opera, I would forget all about Washington.”

In Celebration of a Stellar Career After leaving the NCI in 1988, Dr. DeVita was appointed Physician-inChief and Attending Physician at Memorial Sloan Kettering Cancer Center in New York and later served as Director of the Yale Cancer Center from 1993 to 2003. He is currently the Amy and Joseph Perella Professor of Medicine at Yale Cancer Center and Profes-

sor of Epidemiology and Public Health at Yale School of Medicine in New Haven, Connecticut. In acknowledgment of Dr. DeVita’s accomplishments in the advancement of oncology care, he was elected to the European Academy of Sciences in 2002; awarded the Distinguished Medical Science Award, Friends of the National Library of Medicine in 2009; elected President of the American Cancer Society in 2012 and was named an ASCO fellow that same year; and was elected as a fellow of the AACR Academy in 2014. Dr. DeVita has published more than 450 scientific articles and is the coeditor of Cancer: Principles & Practice of Oncology (Lippincott Williams & Wilkins, 2014), widely regarded as the definitive source of cancer information, now in its 10th edition. He is currently cowriting a book with his daughter Elizabeth DeVita-Raeburn, on the history and aftermath of the War on Cancer, the con-

cept of which set unrealistic goals for cure that still haunt the research community today, said Dr. DeVita. “There are still a lot of people critical about the ‘War on Cancer,’ but the criterion that was imposed, to eradicate all cancer, was impossible to meet. We are never going to eradicate all cancers, but we have been successful in decreasing the overall mortality by 25%, and we are on our way to converting many cancers to chronic diseases. Contrary to what some people think, there has been a lot of measurable progress, but the best is still to come,” said Dr. DeVita. “This is a very, very exciting time in cancer research.” n

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

Reference 1. Devita VT Jr, Serpick AA, Carbone PP: Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 73:881-895, 1970.

Awards

ASH Honors Senator Barbara Mikulski and Patient Advocate Kathy Giusti

he American Society of Hematology (ASH) recognized Senator Barbara Mikulski (D-MD) and Kathy Giusti, Founder of the Multiple Myeloma Research Foundation, with awards for their outstanding support and advocacy for biomedical research

Award, an award recognizing unparalleled leadership by an elected public official on issues of importance to hematology research and/or practice, to honor her significant efforts to increase funding for the National Institutes of Health (NIH). As the Chair of the Senate Appropriations Committee, which oversees all federal discretionary spending, Senator Mikulski has distinguished herself as a congressional champion and vocal supporter of biomedical research. First elected to the Senate in 1986, Senator Mikulski has spent her career Senator Barbara Mikulski Kathy Giusti advocating for sustained bioand the practice of hematology at the medical research funding that helps 56th ASH Annual Meeting in San fuel research discoveries that save lives Francisco. and improve the quality of American Senator Mikulski was presented health care. She was a strong force bewith the 2014 ASH Public Service hind the bi-partisan effort to double

the NIH budget between 1998 and 2003 and has most recently urged Congress to restore federal funding to pre-sequestration levels to ensure the continuation of biomedical research. Kathy Giusti will receive received the 2014 ASH Outstanding Service Award, an honor recognizing effective, “behind-the-scenes” leadership in areas relevant to the mission of the Society, for her efforts to raise public awareness and increase research for multiple myeloma. After she was diagnosed with multiple myeloma in 1998, Ms. Giusti and her sister founded the Multiple Myeloma Research Foundation (MMRF). At the time, little research was being done in the area of multiple myeloma and no effective treatments existed; the life expectancy for newly diagnosed patients was just three years. Through the MMRF, Ms. Giusti focused on identifying barriers slow-

ing drug development and developed patient-centered, collaborative models to overcome those obstacles, leveraging her Harvard Business School training and previous leadership role at a large pharmaceutical company. Since its founding by Ms. Giusti more than 15 years ago, the MMRF has become the world’s top private funder of multiple myeloma research and a valuable resource for patients. “Individuals like Senator Mikulski and Kathy Giusti are invaluable to the hematology field,” said ASH President Linda J. Burns, MD, of the University of Minnesota. “Their passion for advancing research opportunities is truly inspirational, especially in the midst of today’s challenging research landscape. ASH is grateful for their significant efforts and commitment to improve the care of patients with blood disorders.” n

Visit The ASCO Post website at ASCOPost.com

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AVASTIN® (bevacizumab)

Year in Review

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

2014

Featured Columnists The ASCO Post wishes to acknowledge and thank all contributors to the publication during 2014. Here we recognize those who shared their personal thoughts in our Op-Ed department. If you are interested in contributing to The ASCO Post in 2015, write to editor@ASCOPost.com. •• Robert Peter Gale, MD, PhD, DSc(hc), FACP, Hillard M. Lazarus, MD, FACP, and Peter H. Wiernik, MD, FACP, FASCO, on Transplants for AML in First Remission: A Great Leap Forward, Sideways, or Backward? December 15, 2014 •• John F. Smyth, MD, on When Should We Stop Prescribing? December 1, 2014 •• Martin S. Tallman, MD, on The Next-to-Last Frontier in Managing Acute Promyelocytic Leukemia, November 15, 2014 •• Stephan Stilgenbauer, MD, on Linking Biology and Therapy in Chronic Lymphocytic Leukemia, November 1, 2014 •• Hagop Kantarjian, MD, and David P. Steensma, MD, on Relevance of the Hippocratic Oath in the 21st Century, October 15, 2014 •• Robert Peter Gale, MD, PhD, DSc(hc), FACP, on Will Oncologists Be the First to Cure Heart Disease? September 15, 2014 •• Peter Paul Yu, MD, FASCO, as told to Jo Cavallo, on My Priorities for the Year Ahead, September 1, 2014 •• Hagop Kantarjian, MD, on Does the United States Have the Best Health-Care System in the World? August 15, 2014 •• Clifford Hudis, MD, FACP, on Take-Home Messages From ASCO’s Immediate Past President, July 25, 2014 •• Richard J. Boxer, MD, FACS, on Prostate Cancer Biomarkers: Improvement in Predicting Clinically Significant Disease, July 25, 2014 •• Jimmie C. Holland, MD, and James F. Holland, MD, on The More Things Change, the More They Stay the Same, July 10, 2014 •• James L. Mulshine, MD, on Time to Move Forward With Lung Screening, June 25, 2014 •• Carolyn B. Hendricks, MD on Small Practices Like Mine, June 10, 2014 •• Clifford A. Hudis, MD, FACP, on Reflecting on the Past Year and Looking Ahead to the Next, May 15, 2014 •• Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, on Beyond the Cystoscope: Thinkers and Technicians, May 15, 2014 •• Eduardo Cazap, MD, PhD, FASCO, on A Vision of Independent Clinical Research in South America, May 15, 2014 •• S. Vincent Rajkumar, MD, on Maintenance Therapy in Multiple Myeloma, May 1, 2014 •• Paul Kalanithi, MD, on I Refuse to Capitulate to Cancer, March 15, 2014 •• Francis Collins, MD, PhD, on The Future of Biomedical Research, March 1, 2014 •• Jo Cavallo, on Jamie Von Roenn, MD, and ASCO’s Education and Professional Development Services, February 15, 2014 •• Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, on Cancer Genes, Promiscuity, and the National Debt, February 1, 2014 •• Allen S. Lichter, MD, FASCO, on ASCO’s 50th Anniversary and the Road Ahead, January 15, 2014

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 3.2%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occur up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 1.5 Persistent, Recurrent, or Metastatic Carcinoma of the Cervix Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix. [See Clinical Studies (14.6).] 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations and Fistulae Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 3.2% across clinical studies. [See Adverse Reactions (6.1).] From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in <1% of Avastin‑treated patients. The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin. Permanently discontinue Avastin in patients with gastrointestinal perforation. In Avastin clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer but were also reported less commonly in patients with other types of cancer. In a cervical cancer trial (Study 9), the incidence of gastrointestinal‑vaginal fistulae was 8.2% in Avastin‑treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Non‑Gastrointestinal Fistulae Serious and sometimes fatal fistula formation involving tracheo‑ esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. Uncommon (<1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post‑marketing experience. Most events occurred within the first 6 months of Avastin therapy. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), 1.8% of Avastin‑treated patients and 1.4% of control patients were reported to have had non‑gastrointestinal vaginal, vesical, or female genital tract fistulae. Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.3 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).] 5.4 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 0.4 to 6.9 %. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑ squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

AVASTIN® (bevacizumab) In clinical studies in non−small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%−5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3−4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Venous Thromboembolic Events Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade ≥ 3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. Permanently discontinue Avastin in patients with life‑threatening (Grade 4) VTE, including pulmonary embolism. [See Dosage and Administration (2.4), Adverse Reactions (6.1).] 5.7 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.8 Posterior Reversible Encephalopathy Syndrome (PRES) PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of PRES. Discontinue Avastin in patients developing PRES. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing PRES is not known. [See Dosage and Administration (2.4).] 5.9 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).] Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] 5.10 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.11 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations and Fistulae [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Non-Gastrointestinal Fistulae [See Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Venous Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Posterior Reversible Encephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.9).] • Infusion Reactions [See Dosage and Administration (2.4), Warnings and Precautions (5.10)] • Ovarian Failure [See Warnings and Precautions (5.11), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4817 patients with CRC, non‑squamous NSCLC, glioblastoma, mRCC, or cervical cancer, including controlled (Studies 1, 2, 4, 5, 8 and 9) or uncontrolled, single arm trials (Study 6) treated at the recommended dose and schedule for a median of 6 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 59 years), 44% male and 85% White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of

T:10.25" S:9.5"

Arm 1 IFL+ Placebo (n = 396) NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

AVASTIN® (bevacizumab) and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo Preferred terma (n = 304) Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Arm 2 IFL+ Avastin (n = 392)

74%

87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) 55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

26% 1%

32% 6%

40% 32% 25% 6% 6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/ embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and PRES (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). Persistent, Recurrent, or Metastatic Carcinoma of the Cervix All grade adverse reactions were collected in Study 9. Grade 1‑4 adverse reactions occurring where the incidence difference is ≥ 5% in patients receiving Avastin plus chemotherapy compared to chemotherapy alone are presented in Table 4. Table 4 NCI‑CTC Grades 1‑4 and 3‑4 Adverse Reactions in Study 9 (Incidence Difference of ≥ 5% Between Treatment Arms in Chemo + Avastin vs. Chemo Alone) Grade 1‑4 Grade 3‑4 reactions reactions Chemo Chemo+ Chemo Chemo+ Alone Avastin Alone Avastin (n=222) (n=218) (n=222) (n=218) Metabolism and Nutrition Disorders Decreased Appetite 26% 34% Hyperglycemia 19% 26% Hypomagnesemia 15% 24% Hyponatremia 10% 19% Hypoalbuminemia 11% 16% General Disorders and Administration Site Conditions Fatigue 75% 80% Edema Peripheral 22% 15% Investigations Weight Decreased 7% 21% Blood Creatinine Increased 10% 16% Infections and Infestations Urinary Tract Infection 14% 22% Infection 5% 10% Vascular Disorders Hypertension 6% 29% 0.5% 11.5% Thrombosis 3% 10% 2.7% 8.3% Nervous System Disorders Headache 13% 22% Dysarthria 1% 8% Gastrointestinal Disorders Stomatitis 10% 15% Proctalgia 1% 6% Anal Fistula — 6% Blood and Lymphatic System Disorders Neutropenia 6% 12% Lymphopenia 5% 12% Psychiatric Disorders Anxiety 10% 17% Reproductive System and Breast Disorders Pelvic Pain 8% 14% Respiratory, Thoracic and Mediastinal Disorders Epistaxis 1% 17% Renal and Urinary Disorders Proteinuria 3% 10% Grade 3 or 4 adverse reactions occurring at a higher incidence ( ≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone were abdominal pain (11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%), proctalgia (2.8% vs. 0%), urinary tract infection 8.3% vs. 6.3%), cellulitis (3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%), hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8% vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic pain (5.5% vs. 1.4%). There were no Grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, PRES, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort

AVASTIN® (bevacizumab) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.11), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients. 17 PATIENT COUNSELING INFORMATION Advise patients: • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated. • To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting. • Of increased risk of wound healing complications during and following Avastin. • Of increased risk of an arterial thromboembolic event. • Of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following last dose of Avastin. • Of the increased risk for ovarian failure following Avastin treatment.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

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Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

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Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β-HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.11), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized,

AVASTIN® (bevacizumab) double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

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AVASTIN® (bevacizumab) 9 doses of Avastin, 337 mRCC patients who received a median of 16 doses of Avastin, and 218 cervical cancer patients who received a median of 6 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, and 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. There were no patients with Grade 5 VTE. [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%. Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.9).]

Now Approved in Cervical Cancer for women with persistent, recurrent, or metastatic disease Avastin plus chemotherapy demonstrated a statistically significant increase in median OS vs chemotherapy alone in the GOG 240 study (16.8 vs 12.9 months)1

3.9-month increase

1.0

in median OS (HR=0.74 [95% CI, 0.58–0.94], P=0.0132)

Proportion Surviving

0.8 0.6

Avastin plus chemotherapy (n=227) Chemotherapy alone (n=225)

0.4 0.2 0

Months Chemotherapy included either cisplatin/paclitaxel or topotecan/paclitaxel. OS=overall survival; HR=hazard ratio; CI=confidence interval.

Indication

Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix.

Most common adverse events

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 3.2% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 6.9% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — GI fistulae (up to 2%) — Non-GI fistulae (≤1.8%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — GI-vaginal fistulae occurred in 8.2% of patients in a cervical cancer trial — Venous thromboembolism (grade 3–4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with Avastin — Hypertension (grade 3–4, 5%–18%) — Posterior reversible encephalopathy syndrome (PRES) (<0.5%)

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

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Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In CC, grade 3 or 4 adverse reactions in study GOG 240, occurring at a higher incidence (≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone, were abdominal pain (11.9% vs 9.9%), diarrhea (5.5% vs 2.7%), anal fistula (3.7% vs 0%), proctalgia (2.8% vs 0%), urinary tract infection (8.3% vs 6.3%), cellulitis (3.2% vs 0.5%), fatigue (14.2% vs 9.9%), hypertension (11.5% vs 0.5%), thrombosis (8.3% vs 2.7%), hypokalemia (7.3% vs 4.5%), hyponatremia (3.7% vs 1.4%), dehydration (4.1% vs 0.5%), neutropenia (7.8% vs 4.1%), lymphopenia (6.0% vs 3.2%), back pain (5.5% vs 3.2%), and pelvic pain (5.5% vs 1.4%). There were no grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. CC=persistent, recurrent, or metastatic cervical cancer. Reference: 1. Avastin Prescribing Information. Genentech, Inc. August 2014.