TAP Vol 6 Issue 10 by Harborside Press LLC

ASCO 2015 News 1, 3-5, 9–13 | Bilateral Prophylactic Mastectomy

| CUSTOM ‘Basket’ Trial

VOLUME 6, ISSUE 10

JUNE 10, 2015

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

Clinical Trials, Drug Costs, and Restoring the Primacy of the Patient Volunteer

ASCO 2015 Plenary Report

CheckMate 067: Dual Checkpoint Blockade Proves Effective in Advanced Melanoma By Caroline Helwick

By Laurence H. Baker, DO

n advanced melanoma, combination treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) more than doubled the median progression-free survival time over ipilimumab alone in the CheckMate 067 trial. That said, single-agent nivolumab proved almost as powerful in patients expressing the programmed cell death ligand 1 (PD-L1). The findings from CheckMate 067, the first phase III trial to evaluate the combination of anti–PD-1 and anti–CTLA-4 agents, were presented at the Plenary Session of the 2015 ASCO Annual Meeting by Jedd Wolchok, MD, PhD, Chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, New York.

Toward Precision Immunotherapy “PD-L1 expression is not a binary discriminator of absolute benefit, but this trial is a first effort to try to introduce a precision aspect to immunotherapy.

In this study, we see it’s a way to initiate meaningful conversations between patients and clinicians about whether a combination [nivolumab/ipilimumab] is the right thing for them, vs nivolumab alone,” he told The ASCO Post. Jedd Wolchok, MD, PhD Some experts, however, were more tempered in their impression of PD-L1 as a potential biomarker. Study discussant Michael B. Atkins, MD, Deputy Director of the Lombardi Cancer Center at Georgetown University, a key figure in the PD-1 research story, said much more work is needed before involving PD-L1 expression in patient selection. “Even with a high threshold for positivity, which greatly enriched the biomarker-positive group in this trial, the

“What’s past is prologue.” ©ASCO/Scott Morgan 2015

continued on page 9

ASCO Annual Meeting

Mismatch Repair Deficiency Predicts Benefit With Pembrolizumab in Colorectal Cancer By Caroline Helwick

Almost two-thirds of colorectal cancer patients whose tumors demonstrated mismatch repair deficiency responded to pembrolizumab (10 mg/kg every 2 weeks), whereas none with mismatch repair– proficient tumors responded, reported Dung T. Le, MD, of the Kimmel Cancer Center at Johns Hopkins University, Baltimore. “This is the first study to use genetics to guide immunotherapy,” Dr. Le noted. “Mismatch repair–deficient tumors are highly responsive to checkpoint blockade This is the first study to use genetics with anti–PD-1 agents.”

©ASCO/Max Gersh 2015

genetic marker to predict response to anti– PD-1 (anti-programmed cell death protein 1) antibodies may have emerged in colorectal cancer, a tumor type that is a newcomer to the anti–PD-1 ballgame. In a phase II study of colorectal cancer patients treated with pembrolizumab (Keytruda), the presence of mismatch repair deficiency within the tumor robustly predicted benefit, investigators reported at the 2015 ASCO Annual Meeting.1

to guide immunotherapy. Mismatch repair–deficient tumors are highly responsive to checkpoint blockade with anti–PD-1 agents.

Send your comments to editor@ASCOPost.com

—Dung T. Le, MD

High Mutational Load May Be Needed

—William Shakespeare

oday, a cancer drug under study in a clinical trial is commonly provided for a finite period of time after the study closes to accrual. If that drug were not yet U.S. Food and Drug Administration (FDA)-approved when the study began, the complimentary drug supply to patients would end following FDA approval. In order to continue therapy with the drug, it would become the patient’s responsibility to purchase it. But this was not always the case. The following commentary is not meant to continued on page 94

Dr. Baker is Professor of Internal Medicine and Pharmacology, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage ASCO Annual Meeting ��1, 3–5, 9–13, 95 ASBS Annual Meeting �� 14, 17 AUA Annual Meeting ��22–24 AACR Annual Meeting ��26 Robert L. Coleman, MD, on Advanced Ovarian Cancer ��28 Direct From ASCO �� 46–49 Kim Margolin, MD, on Immune Checkpoint Inhibition ��53 In Memoriam �� 81 Fracture Risk After Stem Cell Transplant ��87

Mismatch repair deficiency occurs in up to 20% of sporadic colorectal cancers and all colorectal cancontinued on page 10

A Harborside Press® Publication

The ASCO Post | JUNE 10, 2015

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com Cara H. Glynn, Director of Editorial Cara@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

Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com

Jamie Von Roenn, MD American Society of Clinical Oncology

Randi Londer Gould and Susan Reckling, Senior Editors Randi@harborsidepress.com Susan@harborsidepress.com

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

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

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

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

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

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

Jay S. Cooper, MD Maimonides Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

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

Rakesh Chopra, MD Artemis Health Institute Gurgaon, India Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

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

Sarah McGullam, Web Editor Sarah@harborsidepress.com Michael Buckley, Art Director Michael@harborsidepress.com Regine M. Lombardo, Senior Graphic Designer Regine@harborsidepress.com Terri Caivano, Layout Artist Terri@harborsidepress.com Gail van Koot, Editorial Coordinator Gail@harborsidepress.com Elizabeth Janetschek, Editorial Assistant Elizabeth@harborsidepress.com Norman Virtue, Production Manager Norman@harborsidepress.com Shannon Meserve, Circulation Manager Shannon@harborsidepress.com Jeannine Coronna, Vice President, Director of Operations Jeannine@harborsidepress.com

Jacek Jassem, MD Medical University of Gdansk, Poland

Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

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

Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com

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

Anthony Cutrone, President Anthony@harborsidepress.com

E. David Crawford, MD University of Colorado

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

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel

Steven T. Rosen, MD City of Hope National Medical Center

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January by Harborside Press®, LLC, 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 ©2015 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

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ASCOPost.com | JUNE 10, 2015

PAGE 3

ASCO Annual Meeting Thoracic Oncology

Second-Line Nivolumab Therapy Improves Survival in Patients With Nonsquamous Non–Small Cell Lung Cancer By Alice Goodman

nti–programmed cell death protein 1 (PD-1) immunotherapy with nivolumab (Opdivo) extended survival in patients with the most common form of lung cancer—nonsquamous non–small cell lung cancer (NSCLC). Patients whose disease progressed on standard platinum doublet therapy who were treated with nivolumab lived an average of 3 months longer than those treated with docetaxel in this setting.1 “Nivolumab is the first PD-1 inhibitor to significantly improve overall survival vs docetaxel in previously treated patients with advanced nonsquamous NSCLC. Nivolumab appears to be particularly active in patients with PD-1 ligand (PDL1)–positive tumors. Nivolumab significantly improved response rates, with objective response rates as high as 36% in PD-L1 expressors. Overall survival approximately doubled with nivolumab vs

docetaxel across the PD-L1–expressing continuum,” said Luis Paz-Ares, MD, PhD, Professor of Medicine at Hospital Universitario 12 de Octubre in Madrid. Dr Paz-Ares emphasized that nivolumab is a “kinder, gentler” treatment compared with second-line docetaxel. He reported the results of the phase III CheckMate 057 trial at a press conference during the 2015 ASCO Annual Meeting.

disease that progressed on previous platinum-based chemotherapy to treatment with nivolumab vs docetaxel. In addition, patients were allowed a prior tyrosine kinase inhibitor treatment in cases of EGFR mutation or ALK rearrangement. Patients were unselected for PD-L1 expression.

Nivolumab is the first PD-1 inhibitor to significantly improve overall survival vs docetaxel in previously treated patients with advanced nonsquamous NSCLC.

Study Details CheckMate 057 is the first phase III study to show that immunotherapy is active against nonsquamous NSCLC. Also presented at the Annual Meeting, a separate trial (CheckMate 017) found that nivolumab improved overall survival vs docetaxel in advanced squamous cell NSCLC.2 CheckMate 057 randomly assigned 582 patients with stage IIIB or IV advanced

EXPERT POINT OF VIEW

“R

esults of CheckMate 057 represent excellent progress, but they are not truly ‘checkmate,’” said Roy S. Herbst, MD, PhD, Chief of Medical Oncology, Director of the Thoracic Oncology Research Program, Associate Director for Translational Research at Yale Cancer Center in New Haven, Connecticut. “Nivolumab [Opdivo] is in my opinion the new standard of care for previously treated patients, but we still have work to do on the endgame, because the results are likely not as good in biomarker-negative patients,” he added. “We

Nivolumab is a new standard of care, but we still have work to do on the endgame, because the results are not as good in biomarker-negative patients. —Roy S. Herbst, MD, PhD

therefore need to develop better biomarkers than PD-L1.” Roche, Merck, and other industry and academic investigators are working on this, he said. “Nivolumab appears to be more effective than docetaxel and is less toxic. I will consider nivolumab after front-line chemotherapy in most of my patients with lung cancer,” he continued. “In the absence of a reliable biomarker, I will offer it to all my patients right now who are suitable candidates (with no immune-related contraindications and reasonable performance status), but as we had to do before with the introduction of EGFR inhibitors, we will have to continue to work, explore, and identify a reliable biomarker for improved response and survival, to identify a group of patients who might then benefit from other combination or alternative therapies. At this point, nivolumab seems to have more robust efficacy data in a large population of patients than we had with EGFR inhibitors.” n Disclosure: Dr. Herbst reported no potential conflicts of interest.

also substantially higher with nivolumab compared with docetaxel in those with PD-L1 ≥ 5% and ≥ 1%. No difference in median overall survival was observed between the two treatment arms in those with low PDL1 expression (< 10% of cells).

—Luis Paz-Ares, MD, PhD

The study met the primary endpoint of overall survival. Median overall survival was 12.2 months for nivolumab vs 9.4 months for docetaxel. This represents a significant 27% decrease in the risk of death for patients who received nivolumab (P = .0015), Dr. Paz-Ares said. One-year overall survival was 51% for nivolumab-treated patients vs 39% for docetaxel recipients. Objective response rates were improved from 12.4% with docetaxel to 19.2% with nivolumab (P = .0246). The duration of response was significantly longer with nivolumab (median, 17.2 vs 5.6 months). Median progression-free survival was not significantly different between treatment arms: 2.3 months with nivolumab vs 4.2 months with docetaxel. The 1-year progression-free survival rate was 19% vs 8%, respectively.

PD-L1 Expression PD-L1 expression was measured using a validated Dako/Bristol-Myers Squibb automated immunohistochemistry assay. Cutoffs for PD-L1 expression were ≥ 1%, ≥ 5%, and ≥ 10%. In the subgroup of patients with the highest level of PD-L1 expression (≥ 10% of cells), median overall survival with nivolumab was 19 months, compared with 8 months for those treated with docetaxel. Median overall survival was

“These results suggest that PD-L1 expression is predictive of the survival benefit of nivolumab, with a huge benefit observed in those with positive expression: a 41% to 60% reduction in the risk of death, which was not found in patients with low or undetectable PD-L1 levels,” Dr. Paz-Ares noted. “The survival benefit for nivolumab was huge compared to docetaxel in PDL1–positive patients, with a median survival ranging from an unprecedented 17.2 months to 19.4 months, depending on level of expression,” Dr. Paz-Ares said.

Adverse Events Treatment-related adverse events were much higher with docetaxel. Any treatment-related adverse event was experienced by 69% of the nivolumab group vs 88% of the docetaxel group. The rate of grade 3/4 adverse events was 10% in the nivolumab group vs 54% of the docetaxel group. Serious adverse events were reported in 7% vs 20%, respectively; the rate of grade 3/4 serious adverse events was 5% vs 18%, respectively. Treatment-related discontinuations occurred in 5% of nivolumab recipients and 15% of docetaxel recipients. PD-L1 expression may have limited usefulness as a biomarker to select patients who will benefit from nivolumab. continued on page 4

Role of Nivolumab in Lung Cancer ■■ In nonsquamous NSCLC that has progressed on standard platinumcontaining doublet therapy, nivolumab extended survival vs docetaxel. ■■ Survival and response rates were even more impressive in patients whose tumors expressed PD-L1.

The ASCO Post | JUNE 10, 2015

PAGE 4

ASCO Annual Meeting Head/Neck Cancer

Clinically Meaningful Preliminary Results With Pembrolizumab in Recurrent Head and Neck Cancer By Alice Goodman

embrolizumab (Keytruda) is making inroads into head and neck cancer, with encouraging results in heavily pre-treated patients with recurrent or metastatic squamous cell carcinoma of the head and neck, according to a report on the expansion-cohort KEYNOTE-012 study presented at the 2015 ASCO Annual Meeting.1 In these poor-prognosis patients who were heavily pretreated, pembrolizumab achieved tumor shrinkage in 57%, and 24.8% had a partial or complete response. Responses were seen in both human papillomavirus (HPV)-positive and HPV-negative tumors.

‘Remarkable’ Efficacy “The efficacy we saw was remarkable. This is the largest experience with immunotherapy in head and neck cancer. Pembrolizumab was roughly twice as effective when measured by response as we have seen with cetuximab [Erbitux], our only approved targeted therapy for head and neck cancer. Responses are durable, which has not been seen before in head and neck cancer and pembrolizumab seems to be broadly active regardless of HPV status, PD-L1 status, or prior treatment,” said lead author Tanguy Y. Seiwert, MD, Assistant Professor of Medicine and Associate Program Leader for Head and Neck Cancer at the University of Chicago. He noted that recent data suggest that cetuximab and other EGFR inhibitors may be less effective against HPV-positive tumors, so the fact that robust activity were seen in this group is encouraging. “Furthermore the side effect profile was favorable. We have high hopes that immunotherapy will change the way we treat

Second-Line Nivolumab continued from page 3

Although PD-L1 expression predicted for survival benefit, some patients without PD-L1 still benefit from nivolumab, Dr. Paz-Ares noted. Tanguy Y. Seiwert, MD, Assistant Professor of Medicine and Associate Program Leader for Head and Neck Cancer at the University of Chicago, suggested two additional potential biomarkers: “A high number of mutations and inflammation of the tumor as measured by a gene expression signature may be useful additional markers, particularly if used in conjunction with PD-L1 expression,” he said.

head and neck cancer,” Dr. Seiwert said. Pembrolizumab is the first anti–programmed cell death protein 1 (PD-1) therapy to be approved by the U.S. Food and Drug Administration. It is approved in advanced melanoma and is now being studied in other solid tumors. Recurrent/metastatic head and neck cancer has a poor prognosis, associated with a median overall survival of 10 to 13 months in the first-line setting and 6 months in previously treated patients, which represent the majority of patients in KEYNOTE-012. The current standard of care is platinum-based doublet chemotherapy with or without cetuximab. Second-line options are methotrexate,

Pembrolizumab in Head and Neck Cancer ■■ A 132-patient expansion-cohort study found that pembrolizumab achieved responses in 24.8% of patients with recurrent/metastatic head and neck cancer. ■■ Responses were achieved in both HPV-positive and HPV-negative cancers. ■■ Duration of response was impressive in those who responded.

ery 3 weeks) for 24 months or until disease progression or intolerable toxicity. About 59% had been previously treated with two or more therapies for recurrent or metastatic head and neck cancer. Tumor shrinkage was reported in 56%. The overall objective response rate was 24.8%: 27.2% in HPV-negative patients and 20.6% in HPV-positive patients.

tients had any adverse events, but were mostly mild: 15% had mild, low grade (grade 1/2) side effects included hypothyroidism (9.1%), decreased appetite (7.6%), and rash (7.6%). Serious side effects (grade 3/4) were reported in fewer than 10% of patients. Few patients experienced serious immunerelated adverse events, which included pneumonitis and colitis (one patient).

Looking Ahead

We have high hopes that immunotherapy will change the way we treat head and neck cancer. —Tanguy Y. Seiwert, MD

taxanes, and cetuximab. These therapies have downsides: Chemotherapy is associated with significant side effects, and only 10% to 13% of patients respond to singleagent cetuximab.

Study Details This expansion cohort enrolled 132 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, irrespective of PD-L1 or HPV status. All patients received fixed-dose pembrolizumab (infusion of 200 mg ev“Just as buying more tickets in the lottery increases your chance of winning, having more mutations makes it more likely for the tumor to be recognized by the immune system.”

Promising Results “Nivolumab is an anti–PD-1 immunotherapy that takes the brakes off of the immune system and allows it to attack the tumor,” said press conference moderator Lynn Schuchter, MD, ASCO expert and Chief of Hematology/Oncology at Penn Medicine, Philadelphia. “These results in a phase III lung cancer trial show improvement with im-

About 25% of patients had stable disease, for a disease control rate of about 50%, which Dr. Seiwert called “very promising” as many patients with prolonged stable disease may ultimately also benefit from immunotherapy, Dr. Seiwert said. The duration of response in responders was excellent, he continued; 86% of responding patients remained in response at the time of his presentation. “Pembrolizumab was well tolerated, better than with chemotherapy or radiation,” Dr. Seiwert said. About 60% of pamunotherapy compared with standard treatment and are promising,” she added. Safety results were reassuring, Dr. Schuchter commented. “Toxicities can be immune-related, and immunotherapies have unique toxicities,” she continued. “In this study, the immune-related adverse events were less severe than those seen with chemotherapy.” n Disclosure: Dr. Paz-Ares has received honoraria from Roche/Genentech, Lilly, Pfizer, BoehringerIngelheim, Clovis Oncology, Bristol-Myers Squibb, and Merck, Sharp & Dohme. Dr. Seiwert has received honoraria from Amgen, Merck, Jounce Therapeutics, and Novartis. Dr. Schuchter reported no potential conflicts of interest.

Dr. Seiwert noted that longer followup is needed to assess survival. “Studies of other immunotherapies have shown that patients who have disease stabilization or even experience disease progression initially on these therapies may ultimately derive significant benefit that can translate to longer survival,” he said. Furthermore, it may be possible to predict who is most likely to benefit from pembrolizumab using PD-L1 as a biomarker, Dr. Seiwart noted. Analysis of PD-L1 status and response is ongoing. Dr. Seiwert is the lead author of another study presented at the meeting, suggesting that an interferon-gamma expression signature is another promising biomarker that might predict the benefit of pembrolizumab in PD-L1–positive head and neck cancer, with high accuracy including a 95% negative preditive, continued on page 5

References 1. Paz-Ares K, Horn L, Borghaei H, et al: Phase III randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract LBA109. Presented May 30, 2015. 2. Spigel DR, Reckamp KL, Rizvi NA, et al: A phase III study (CheckMate 017) of nivolumab (NIVO; anti-programmed death-1 [PD-1]) versus docetaxel (DOC) in previously treated advanced or metastatic squamous cell non-small cell lung cancer. 2015 ASCO Annual Meeting. Abstract 8009. Presented May 31, 2015.

ASCOPost.com | JUNE 10, 2015

PAGE 5

ASCO Annual Meeting Plenary Report

Whole-Brain Radiation: Risks Outweigh Benefits for Limited Brain Metastases By Alice Goodman

ew data from a phase III A lliance trial weighs in on a longstanding debate in the treatment of brain metastases: Should whole-brain radiation therapy be added to stereotactic radiosurgery? The study found that although wholebrain radiation therapy improved local tumor control in patients with one to three See page 13 brain metastases, but it exacerbated cognitive decline and did not improve overall survival.1 “Adjuvant whole-brain radiation therapy improved control of brain metastases but had no impact on survival. We saw decline in cognitive function with wholebrain radiation therapy, and quality of life was worse. We recommend treating initially with stereotactic radiosurgery and reserving whole-brain radiation therapy until the time of symptom progression,” said senior study author Jan C. Buckner, MD, of Mayo Clinic, Rochester.

‘Which Is Worse: The Disease or the Treatment?’ Dr. Buckner spoke about the trial at a press conference during the 2015 ASCO Annual Meeting, and Paul Brown, MD,

of The University of Texas MD Anderson Cancer Center, Houston, presented the data at the Plenary Session. In the United States alone, up to 400,000 cancer patients are diagnosed with brain metastases each year. Although stereotactic radiosurgery is effective initial treatment, there is a high rate of recurrence at treated sites, and additional lesions develop after stereotactic radiosurgery. Studies have shown that the addition of

References 1. Seiwert T, Haddad RI, Gupta S, et al: Antitumor activity and safety of pembrolizumab in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). 2015 ASCO Annual Meeting. Abstract LBA6008. Presented June 1, 2015. 2. Seiwert T, Burtness B, Weiss J, et al: Inflamed-phenotype gene expression signatures to predict benefit from the anti-PD-1 antibody pembrolizumab in PD-L1+ head and neck cancer patients. 2015 ASCO Annual Meeting. Abstract 6017. Presented May 30, 2015.

The federally funded prospective randomized phase III trial was initiated 10

—Jan C. Buckner, MD

whole-brain radiation therapy to stereotactic radiosurgery can reduce the number of patients with recurrence in treated sites and the number of new metastases. “New metastases have negative effects on cognitive function and may require additional therapy, so wholebrain radiation therapy is attractive. But on the other side, whole-brain radiation

years ago and enrolled 213 patients at 34 institutions with one to three brain metastases stratified according to age, control of extracranial disease, number of brain metastases, and institution. Patients were randomized to receive stereotactic radiosurgery or whole-brain radiation therapy plus stereotactic radiosurgery. Baseline characteristics were well

Paul Brown, MD

distributed between the two arms. Seventy percent had primary lung cancer, and 50% had only one brain metastasis. At a median follow-up of 7 months, whole-brain radiation therapy significantly decreased disease progression in the brain (P < .0001) yet had no impact on survival. For the primary endpoint of cognitive function at 3 months, significantly greater decline was observed in the whole-brain radiation therapy group: 91.7% of patients who received wholebrain radiation therapy exhibited cognitive deterioration vs 63.5% of the stereotactic radiosurgery group (P = .0007), as measured by a battery of cognitive and neuropsychiatric tests. Cognitive domains affected were immediate recall, memory, and verbal communication. Quality-of-life measurement scores were significantly worse with wholecontinued on page 9

EXPERT POINT OF VIEW

continued from page 4

Disclosure: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc. Dr. Seiwert reported receiving honoraria from Bayer/ Onyx, Merck, and Novartis and research funding via his institution from Boehringer Ingelheim and Genentech/Roche. For full disclosures of the study authors visit abstract.asco.org.

Study Details

We recommend [treating initially] with stereotactic radiosurgery and reserving whole-brain radiation therapy until the time of symptom progression.

Pembrolizumab and 40% positive predictive value, however additional validation is needed.2 Pembrolizumab is currently being compared with standard treatment in two ongoing phase III studies in patients with recurrent/metastatic head and neck cancer. n

therapy carries risks. The question has been which is worse: the disease or the treatment,” Dr. Buckner continued. “A clear understanding of the risks of whole-brain radiation therapy is essential in making treatment decisions,” Dr. Brown noted at the Plenary Session.

“P

embrolizumab [Keytruda] has a more favorable side-effect profile than cytotoxic chemotherapy and cetuximab [Erbitux]. This is particularly important for recurrent/metastatic head and neck cancer patients who have been so beaten up by their disease, the

General Hospital and Harvard Medical School, Boston. “The 25% overall response rate is life altering for these patients, who have been through the ringer with surgery, radiotherapy, and chemotherapy directed to the head and neck,” she continued.

Chemotherapy dampens the immune response, and if we can boost that response up front, it may have the potential to cure patients. —Lori J. Wirth, MD

treatment for their disease, and their comorbidities,” explained Lori J. Wirth, MD, Medical Director of the Head and Neck Oncology Program, Center for Head and Neck Cancers, Massachusetts

Dr. Wirth is impressed that the drug works on both human papillomavirus (HPV)-positive and HPV-negative squamous cell head and neck cancers. “We previously assumed that head and

neck cancers would not respond to immunotherapy. There is an emerging story about immunotherapy in oncology, showing that our assumption was wrong. This study is one more proof that our older assumptions were off base, and it is an example of when it is good to be proven wrong,” she said. The encouraging results in recurrent/metastastic squamous cell head and neck cancers suggest that bringing pembrolizumab upfront as part of first-line therapy may lead to improved outcomes. In the future, combination therapies that include chemotherapy, radiation, and immunotherapy will be studied, she said. “Chemotherapy dampens the immune response, and if we can boost that response up front, it may have the potential to cure patients,” Dr. Wirth commented. n Disclosure: Dr. Wirth reported no potential conflicts of interest.

When faced with overactive signaling . . .

Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Important Safety Information Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi

Severe neutropenia (ANC <0.5 X 109/L) was generally reversible by withholding Jakafi until recovery Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk-benefit determination Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment

Inhibit the JAK pathway* in polycythemia vera not controlled with hydroxyurea 1-3

Jakafi® (ruxolitinib) is the first and only FDA-approved treatment for patients who have had an inadequate response to or are intolerant of hydroxyurea3 Jakafi demonstrated superior results in a phase 3 trial vs best available therapy3,4†

Primary Response at Week 323,4 80

* Ruxolitinib, a kinase inhibitor, inhibits JAK1 and JAK2 (Janus-associated kinases 1 and 2), which mediate the signaling of cytokines and growth factors important for hematopoiesis and immune function.3 A randomized, open-label, active-controlled phase 3 trial comparing Jakafi with best available therapy (BAT) in 222 patients. Best available therapy included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%). Patients had been diagnosed with polycythemia vera for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy, and exhibited splenomegaly. The primary end point was the proportion of subjects achieving a response at week 32, with response defined as having achieved both hematocrit (Hct) control (the absence of phlebotomy eligibility beginning at the week 8 visit and continuing through week 32) and spleen volume reduction (a ≥35% reduction from baseline in spleen volume at week 32). Phlebotomy eligibility was defined as Hct >45% that is ≥3 percentage points higher than baseline or Hct >48% (lower value).3,4

P < 0.0001

Jakafi (n = 110) BAT (n = 112)

(n = 66)

38%

21%

20 0

Individual Components of Primary End Point

60%

Patients (%)

†

Composite Primary End Point

(n = 23)

1%b

(n = 22)

(n = 1)

Hct Control + Spleen Volume Reduction

95% CI, 14%-30%

When discontinuing Jakafi, myeloproliferative neoplasmrelated symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi‐organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation Non‐melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations The three most frequent non-hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy

20%

(n = 42)

(n = 1)

Hct Control Without Phlebotomy

≥35% Spleen Volume Reduction

95% CI, 0%-5%

Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed

Please see Brief Summary of Full Prescribing Information for Jakafi on the following page. References: 1. Rampal R et al. Blood. 2014;123(22):e123-e133. 2. Keohane C et al. Biologics. 2013;7:189-198. 3. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation. 4. Vannucchi AM et al. N Engl J Med. 2015;372(5):426-435.

Review the clinical trial data at

www.jakafidata.com

Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in ≥ 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Jakafi (N=110) BRIEF SUMMARY: For Full Prescribing Information, see package insert. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding Jakafi until recovery [see Adverse Reactions (6.1)]. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions (6.1)]. Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)] • Risk of Infection [see Warnings and Precautions (5.2)] • Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3)] • Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]. 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. Clinical Trials Experience in Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebo-controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi (N=155) Adverse Reactions

Adverse Events

All Gradesa (%)

Grade 3-4 (%)

All Grades (%)

Headache

Abdominal Painb

Diarrhea

Dizzinessc

Fatigue

Pruritus

Dyspnead

Muscle Spasms

Nasopharyngitis

Constipation

Cough

Edemae

Arthralgia

Asthenia

Epistaxis

Herpes Zosterf

Nausea

a b c d e f

Laboratory Parameter

Grade 3 (%)

Grade 4 (%)

All Grades (%)

Anemia

Thrombocytopenia

Placebo (N=151)

Neutropenia

Hypercholesterolemia

Elevated ALT

Elevated AST

Hypertriglyceridemia

Grade 4 (%)

Bruisingb

Dizzinessc

Headache

Urinary Tract Infectionsd

Weight Gaine

Flatulence

Herpes Zosterf

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present includes weight increased, abnormal weight gain includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya Jakafi (N=155) Laboratory Parameter

All Gradesb (%)

Grade 3 (%)

Placebo (N=151) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Thrombocytopenia

Anemia

Neutropenia

a b

Grade 4 (%)

Chemistry

Grade 3 (%)

Hematology

All Grades (%)

Best Available Therapy (N=111)

All Gradesb (%)

Grade 4 (%)

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes abdominal pain, abdominal pain lower, and abdominal pain upper includes dizziness and vertigo includes dyspnea and dyspnea exertional includes edema and peripheral edema includes herpes zoster and post-herpetic neuralgia

Jakafi (N=110)

Grade 3 (%)

Grade 3-4 (%)

Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with Jakafi were: Weight gain, hypertension, and urinary tract infections Clinically relevant laboratory abnormalities are shown in Table 4. Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatmenta

All Gradesa (%)

Best Available Therapy (N=111)

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi.

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics (12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 52% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment [see Dosage and Administration (2.4) in Full Prescribing Information]. OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib. Jakafi is a registered trademark of Incyte. All rights reserved. U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013 © 2011-2014 Incyte Corporation. All rights reserved. Issued: December 2014 RUX-1428a

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ASCO Annual Meeting Plenary: Checkmate 067 continued from page 1

utility of PD-L1 expression for selecting patients for nivolumab monotherapy, to me, is still unconvincing,” he said.

CheckMate 067 Details CheckMate 067 randomly assigned 945 treatment-naive patients with advanced or metastatic melanoma 1:1:1 to (1) nivolumab (1 mg/kg every 2 weeks) plus ipilimumab (3 mg/kg ev-

sion or unacceptable toxicity. Patients were stratified by PD-L1 status (≥ 5% expression was considered positive), BRAF mutation status, and M stage. The study’s coprimary endpoint was progression-free survival for nivolumab alone, and for nivolumab/ipilimumab, vs ipilimumab. Results for overall survival will not be reported until after 22 months of follow-up. “Nivolumab alone and nivolumab plus ipilimumab significantly improved

PD-L1 expression is not a binary discriminator of absolute benefit, but this trial is a first effort to try to introduce a precision aspect to immunotherapy. —Jedd Wolchok, MD, PhD

Table 1: Key Outcome Comparisons in CheckMate 067 Endpoint

Nivolumab plus ipilimumab

Nivolumab

Ipilimumab

Total population Median PFS

11.5 mo

6.9 mo

2.9 mo

HR vs ipilimumab

0.42 (P < .00001)

0.57 (P < .00001)

—

HR vs nivolumab

0.74*

—

PD-L1 expression ≥ 5% Median PFS

14.0 mo

3.9 mo

HR vs ipilimumab

0.40

—

PD-L1 expression < 5% Median PFS

11.2 mo

5.3 mo

2.8 mo

HR vs ipilimumab

0.42

0.60

—

*Exploratory analysis. HR = hazard ratio; PFS = progression-free survival.

ery 3 weeks for four doses), followed by nivolumumab (3 mg/kg every 2 weeks), (2) nivolumab (3 mg/kg every 2 weeks) plus placebo, or (3) ipilimumab (3 mg/kg every 3 weeks for four doses) plus placebo, until disease progres-

progression-free survival and objective response rates vs ipilimumab alone in patients with previously untreated melanoma,” Dr. Wolchok announced (Table 1). “Nivolumab plus ipilimumab re-

sulted in numerically longer progression-free survival and a higher response rate, but in patients whose tumors had at least 5% PD-L1 expression, both nivolumab alone and nivolumab/ipilimumab resulted in a similar prolongation in progression-free survival [14 months],” he reported.

Whole-Brain Radiotherapy

brain metastases amenable to stereotactic radiosurgery,” Dr. Brown stated. More acute radiation-induced side effects were seen in the whole-brain radiation therapy arm at 6 weeks, but there was no difference in radiation necrosis between the two arms. The investigators also tested a smaller group of long-term survivors at 12 months who completed at least one

cognitive test. These survivors represented about one-sixth of the original study population. Cognitive function remained worse in the whole-brain radiation therapy arm and was statistically inferior for recognition, with a strong trend toward worse word association compared with stereotactic radiosurgery. “This shows that over time, patients treated with whole-brain radiation

continued from page 5

brain radiation therapy, showing clinically and statistically significant decrements for functional well-being and quality of life, Dr. Brown noted. “As initial treatment, we recommend stereotactic radiosurgery alone and close monitoring to better preserve cognitive function in patients with newly diagnosed

Key Data

therapy continued to have worse cognitive function for up to 12 months,” Dr. Brown said. n

Steven O’Day, MD, speaking at a press briefing as an ASCO expert in melanoma, commented, “Right now, in PD-L1–positive patients, we can be fairly reassured that their progression-free survival will be very similar” whether they receive a sincontinued on page 11

Disclosure: Drs. Buckner and Brown reported no potential conflicts of interest.

Reference 1. Brown PD, Asher AL, Ballman KV, et al: NCCTG N0574 (Alliance). 2015 ASCO Annual Meeting. Abstract LBA4. Presented May 31, 2015.

EXPERT POINT OF VIEW

ormal discussant, Andrew B. Lassman, MD, of the Department of Neurology at Herbert Irving Comprehensive Cancer Center and Columbia University Medical Center in New York, congratulated Dr. Brown and his

Andrew B. Lassman, MD

coauthors for undertaking and completing a “herculean task” that took 10 years. To illustrate the scope of affected patients, about 25% of all cancer patients develop brain metastasis. “More patients are diagnosed with brain me-

tastasis than with breast, lung, or prostate cancer. Treatment for these patients represents an unmet clinical need,” Dr. Lassman noted. Dr. Lassman said that another interpretation of the results is that whole-brain radiation therapy does improve survival in appropriate patients. “Survival was not the primary endpoint of the Alliance trial, and the needed subgroup analyses have not yet been conducted to evaluate the issue of survival effectively. If you defer whole-brain radiation therapy, it leads to more recurrences, so it should be used in selected patients,” he added. “It is reasonable to conclude that whole-brain radiation therapy leads to improved survival if brain metastases are the life-limiting site of disease such as with stable extracranial disease,” he stated. “With progressive extracranial disease, there is no difference in survival with whole-brain radiation therapy

plus stereotactic radiosurgery. In the appropriate context, such as those with controlled or absent systemic disease, whole-brain radiotherapy can influence survival.… However, it is unrealistic to expect a difference in survival with whole-brain radiation therapy if patients are not appropriately selected.”

Cognitive Findings Differ From Other Studies This is the largest trial to date studying neurocognitive effects with such a detailed battery of tests, he continued. The authors found a 12-month persistent worsening of cognitive function after whole-brain radiotherapy. “This is discordant with other studies. This finding should be interpreted with caution. The 12-month data represent a post-hoc analysis with only 34 patients, and the numbers are too small to draw this conclusion defini-

tively,” Dr. Lassman stated. “The metastatic sites in the brain determine the neurologic effect. The difference of locations of metastasis in other trials could partially explain the discordant results,” he added. “Both whole-brain radiation therapy and stereotactic radiosurgery are bad for the brain. We need alternative approaches,” Dr. Lassman continued. Use of memantine along with whole-brain radiation therapy might be helpful, and avoiding the hippocampus as part of whole brain-radiotherapy may also reduce cognitive effects. Upcoming randomized trials by NRG Oncology will further evaluate hippocampal-sparing whole-brain radiotherapy and memantine for patients with or at risk for brain metastases. n Disclosure: See the online version of this article at ASCOPost.com for Dr. Lassman’s disclosure information.

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ASCO Annual Meeting Gastrointestinal Cancer

Mismatch Repair Deficiency continued from page 1

cers associated with Lynch syndrome. Several other tumor types demonstrate mismatch repair deficiency, a mechanism of DNA repair. Approximately 4% of colorectal cancer that has spread may be mismatch–repair deficient.

Lynn Schuchter, MD

“Mutations have been shown to encode proteins that can be recognized and targeted by the immune system. The average tumor has dozens of somatic mutations, but tumors deficient in mismatch repair proteins harbor hundreds to thousands of mutations, as a result of dysfunctional DNA repair,” Dr. Le explained.

A high mutational load in a tumor increases the probability of recognition by the immune system. This scenario formed the rationale for the study of immune blockade with PD-1 inhibitors. In the study, mismatch repair–deficient tumors carried an average of 1,782 mutations, compared with 73 mutations in mismatch repair–proficient tumors. Lynn Schuchter, MD, an ASCO expert who moderated a press briefing where the results were first presented, commented on this number. “More than 1,700 mutations—that’s like putting a red flag on the cancer cell and saying to the immune system, ‘Here I am,’” she said. In the study, higher numbers of mutations were linked to better responses to pembrolizumab, the investigators reported.

Study Details The study included three groups of patients: metastatic colorectal cancer patients with mismatch repair–proficient tumors (n = 25), a similar group with mismatch repair–deficient tumors (n = 25), and metastatic patients with other

Predicting Response to PD-1 Inhibitor in Colorectal Cancer ■■ Colorectal cancer patients whose tumors demonstrate mismatch repair deficiency responded robustly to the PD-1 inhibitor pembrolizumab. ■■ Immune-related responses were seen in 62% of patients with mismatch repair–deficient tumors, vs 0% with mismatch repair–proficient tumors; 60% of patients with noncolorectal mismatch repair–deficient tumors also responded. ■■ Tumors with high mutational loads are more likely to be recognized by the immune system. ■■ Mismatch repair status is easily determined with an available commercial assay and could serve as a means of selecting colorectal cancer patients for anti–PD-1 therapy.

types of tumors that were mismatch repair–deficient (n = 21). A majority of patients had shown disease progression after at least two lines of treatment. For the Annual Meeting presentation, Dr. Le reported on 13 mismatch repair–deficient colorectal cancer patients as well as 25 mismatch repair–proficient and 10 mismatch repair–deficient non– colorectal cancer patients. The primary endpoint of immunerelated response rate strongly favored the mismatch repair–deficient cohort, of

EXPERT POINT OF VIEW

eil Howard Segal, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, who discussed the study at the 2015 ASCO Annual Meeting, emphasized that pembrolizumab (Keytruda) exerted a “clear benefit in patients with mismatch repair de-

mismatch repair and response, Dr. Segal commented that such tumors and their release of antigens constitute “essentially a gold mine” for the immune system and therapies that modulate it. He further noted that minimum thresholds for mutational

Early analysis demonstrates compelling efficacy of pembrolizumab in this rare, but immunologically important, subset of colorectal cancer characterized by microsatellite instability and hypermutation. —Neil Howard Segal, MD, PhD

ficiency,” based on the “very impressive response rate of 62% vs 0%,” the primary endpoint, as well as the encouraging progression-free survival. “This endpoint will likely continue to be met once accrual has been completed and the statistical outcome has been determined,” he predicted. He added that although progression-free survival in the mismatch repair–proficient cohort seems “short,” it is similar to what some other studies have shown. Referring to Dr. Le’s discussion of mutational burden and its role in

burden, as they relate to response to anti–PD-1 agents, have been established for melanoma (> 100 mutations) and for non–small cell lung cancer (> 178). “This study demonstrates that this principle may also apply in colorectal cancer: high mutational burden (at least in microsatellite-high tumors) correlates with improved response rate, progression-free survival, and overall survival,” he said. “However, can we learn something from this about conventional, stable

colorectal cancer?” he questioned. “Conventional” colorectal cancer accounts for at least 95% of colorectal tumors, he pointed out, and in this study, 0% of such tumors responded to pembrolizumab. Dr. Segal believes there are “factors beyond mutational burden that impair colorectal cancer” and that “immunepromoting strategies need to be studied in addition to blockade of the PD-1 pathway,” such as immune agonists, antigen-release strategies, and possibly vaccination with neo-epitopes. Dr. Segal concluded, “Early analysis from the current study demonstrates compelling efficacy of pembrolizumab in this rare, but immunologically important, subset of colorectal cancer characterized by microsatellite instability and hypermutation. There is potential for change in clinical practice in the treatment of metastatic microsatellitehigh colorectal cancer after progression on standard therapy.” “These data support initiating a front-line randomized study in metastatic microsatellite-high disease,” he concluded, adding, “There is no further role for PD-1 blockade alone in conventional colorectal cancer: factors beyond mutational burden are important.” n Dislosure: Dr. Segal has received research funding from Merck.

whom 62% responded, vs 0% with mismatch repair–proficient tumors; 60% of patients with noncolorectal mismatch repair–deficient tumors also responded. The disease control rate (stable disease ≥ 12 weeks) was 92%, 16%, and 70%, respectively, Dr. Le reported. “On the waterfall plot, you can see that virtually all the mismatch repair–deficient target tumors showed response,” she said. “These responses were durable in a treatment-refractory population, and many are ongoing for more than 1 year.”

Survival Data Among colorectal cancer patients, median progression-free survival was significantly increased in the mismatch repair–deficient cohort—it has not been reached for this group—but was limited to 2.3 months in the mismatch repair– proficient cohort (P < .0001). She noted that this is similar to the median progression-free survival (1.7 months) in the placebo arm of the CORRECT trial of regorafenib (Stivarga).2 “Overall survival is also very promising in the mismatch repair–deficient cohort,” Dr. Le reported, observing that median overall survival has not been reached, at a median follow-up of about 7 months. She emphasized that mismatch repair status is easily determined with a commercially available test and is already commonly used in colorectal cancer management. n

Disclosure: Drs. Le and Schuchter reported no potential conflicts of interest.

References 1. Le DT, Uram JN, Wang H, et al: PD-1 blockade in tumors with mismatch repair deficiency. 2015 ASCO Annual Meeting. Abstract LBA100. Presented May 30, 2015. 2. Grothey A, Van Cutsem E, Sobrero A, et al: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebocontrolled phase 3 trial. Lancet 381:303-312, 2012.

ASCOPost.com | JUNE 10, 2015

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ASCO Annual Meeting Plenary: Checkmate 067 continued from page 9

gle-agent anti–PD-1 agent or a combined immunotherapy. Deaths were reduced by 43% to 58% with the PD-1 inhibitor on board,

Steven O’Day, MD

and in a descriptive analysis, the combination reduced deaths by 26% over nivolumab monotherapy. Objective response rates in the intent-to-treat population were 57.6% for the combination, 43.7% with nivolu mab alone, and 19.0% for ipilimumab alone; for both nivolumab-containing arms, these differences were statistically significant vs ipilimumab (P < .0001). Complete responses were observed in

11.5%, 8.9%, and 2.2%, respectively. “Characteristic of any immunotherapy,” he said, the duration of response in all three arms was not yet reached at a minimum follow-up of 9 months. The median change in tumor burden was −51.9% with the combination, −34.5% with nivolumab alone, and +5.9% with ipilimumab alone.

■■ The phase III CheckMate 067 trial showed that the combination of nivolumab plus ipilimumab almost doubled median progression-free survival vs nivolumab alone (11.5 vs 6.9 months). Median progression-free survival was 2.9 months for ipilimumab alone.

Toxicity Well Managed

■■ Response rates were highest with the combination.

Dr. Wolchok emphasized that the combination proved to be relatively well tolerated, as physicians were able to manage the common immune-related toxicities. Grade 3/4 treatment-related adverse events, which were consistent with previous reports, occurred in 55% of the combination arm, 16.3% of the nivolumab arm, and 27.3% of the ipilimumab arm. Most adverse events were “managed and resolved with established safety guidelines,” he noted. “We had no drug-related deaths in the combination arm. This is a very important point, because the trial was conducted in 137 sites globally. Safety guidelines were put into place so that

Nivolumab/Ipilimumab in Melanoma

■■ In patients with PD-L1 expression ≥ 5%, median progression-free survival was 14 months in patients receiving nivolumab alone or nivolumab plus ipilimumab. ■■ The safety profile was consistent with previous experience with these immunotherapies, and there were no treatment-related deaths.

physicians in a variety of venues were able to handle the side effects,” he said. Treatment-related discontinuations were seen in 36.4% of the combination arm, but two-thirds of patients with immune-related adverse events developed responses, half of which occurred after the treatment was stopped. “Based upon the available evidence,” Dr. Wolchok concluded, “the combination represents a means to improve outcomes vs nivolumab alone, particularly for patients whose tumors have less than 5% PD-L1 expression.” n

Disclosures: For full disclosures of Drs. Wolchok, Atkins, and O’Day, see the online version of this article at ASCOPost.com.

Reference 1. Wolchok JD, Chiarion-Sileni V, Gonzales R, et al: Efficacy and safety results from a phase III trial of nivolumab alone or combined with ipilimumab versus ipilimumab alone in treatment-naive patients with advanced melanoma (CheckMate 067). 2015 ASCO Annual Meeting. Abstract LBA1. Presented May 31, 2015.

EXPERT POINT OF VIEW

ichael B. Atkins, MD, Deputy Director, Lombardi Cancer Center of Georgetown University, Washington, DC, discussed CheckMate 067 at the Plenary Session. Pending overall survival data, he concluded, “Nivolumab and nivolumab plus ipilimumab are superior to ipilimumab. These treatments (along with pembrolizumab) are a new standard for advanced melanoma therapy.” “The principal take-home message is that, in my opinion, ipilimumab can no longer be considered a standard first-line immunotherapy for patients with advanced melanoma,” Dr. Atkins said. “This clearly has important implications for the field and for our patients.” He also noted that the combination was more effective than nivolu mab alone, based on the exploratory analysis showing a 26% reduction in progression and higher overall response rate, but he maintained that biomarker-based selection of patients for single-agent vs combination therapy “is not ready for prime time.”

Many Questions Remain Discussing toxicity, Dr. Atkins’ slide read, “Toxicity was severe,” as 55% of the combination arm experienced

grade 3/4 adverse events; however, the occurrence of adverse events did not appear to impact efficacy, he pointed out. “There seems to be a margin of safety. If one stops treatment and initiates immunomodulatory drugs when

how nivolumab compares to pembrolizumab. From the available data on the two anti–PD-1 agents, in Dr. Atkins’ opinion, “there is no clearcut distinction in therapeutic index” between the agents. Therefore,

My view is that nivolumab plus ipilimumab should be the preferred treatment for patients who need a response and who are perceived as being able to tolerate the combination regimen. —Michael B. Atkins, MD

significant immune-related adverse events appear, toxicity can be controlled without eliminating efficacy,” he observed. Dr. Atkins cautioned that while the results are “resoundingly” positive for the combination and for nivolumab alone vs ipilimumab, many questions remain. “A new combination immunotherapy platform has been established on which to explore…. Much work remains to be done,” he said. One question on the minds of many researchers and clinicians is

he believes, lacking a head-to-head comparison, treatment decisions will likely be based on other factors, such as dosing schedule, clinical experience, marketing, cost, and predictability of biomarkers. Utility of PD-L1 as a biomarker, in fact, is a sticking point, in Dr. Atkins’ opinion. He noted that only 27% of CheckMate 067 patients were positive by the trial’s assay, while 80% of patients in the KEYNOTE-006 trial of pembrolizumab were PD-L1– positive by Merck’s assay. “In fact, in

CheckMate 067, the biomarker failed to identify roughly two-thirds of the nivolumab monotherapy responders,” he indicated.

Biomarker Refinement Taking these and other observations into consideration, he maintained, “PD-L1 expression is a weak biomarker,” at least at this point. “Biomarker refinement and standardization are needed for clinical decision-making.” Finally, Dr. Atkins said it is too early to judge the true efficacy of this regimen. “It behooves us to wait for critical survival data,” he said, before concluding the combination is the winner. Meanwhile, he suggested, “especially if overall survival follows the tumor response data, my view is that nivolu mab plus ipilimumab should be the preferred treatment for patients who need a response and are perceived as being able to tolerate the combination regimen. Nivolu mab alone and pembrolizumab alone are acceptable treatment alternatives, irrespective of PD-L1 status, where toxicity is a concern for the patient.” n Disclosure: Dr. Atkins reported no potential conflicts of interest.

The ASCO Post | JUNE 10, 2015

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ASCO Annual Meeting Genitourinary Oncology

Intensified Therapy Improves Survival in Wilms Tumor Patients With Rare Genetic Abnormality By Alice Goodman

ata from two phase III studies led by the Children’s Oncology Group show that augmenting or intensifying therapy for children with highrisk Wilms tumor improved relapse-free survival. These children are deemed to be at high risk due to a specific chromosomal abnormality that confers worse prognosis: loss of heterozygosity for chromosomes 1p and 16q. “Intensification of therapy upfront is not advisable for all patients with Wilms tumor. We have identified a biomarker for high-risk patients at diagnosis [loss of heterozygosity for chromosomes 1p and 16q], and in these patients, intensification of therapy improves outcomes,” said lead author David B. Dix, MD, of British Columbia Children’s Hospital in Vancouver, Canada, at a press briefing held in advance of the ASCO A nnual Meeting, where the new data was presented.1 “We are encouraged that augmentation of therapy can overcome a known adverse biomarker.” Wilms tumor is a rare form of kidney cancer that typically occurs in children under the age of 5 years. About 500 new cases are diagnosed each year in North America. Children with favorable-histology Wilms tumor account for about

We have identified a biomarker for high-risk patients at diagnosis [loss of heterozygosity for chromosomes 1p and 16q], and in these patients, intensification of therapy improves outcomes. —David B. Dix, MD

75% of childhood kidney cancers, and only about 5% of these patients harbor loss of heterozygosity for 1p and 16q.

Study Details The AREN0532 and AREN0533 trials enrolled 1,134 patients, 35 with favorable-histology stage I/II Wilms tumor and loss of heterozygosity for 1p and 16q and 52 who had stage III/IV favorable-histology stage I/II Wilms tumor and loss of heterozygosity for 1p and 16q. These two groups of patients were treated differently according to stage. The augmented regimens were as follows: Stage I/II patients received vincristine, dactinomycin, and doxorubicin (Regimen DD4A), while stage III/

IV patients received those three drugs alternating with four cycles of cyclophosphamide/etoposide and radiotherapy (Regimen M). Previous studies showed that stage I/II patients with loss of heterozygosity treated with standard therapy (vincristine/dactinomycin) had a 4-year eventfree survival rate of 74.9%, and stage IIII/IV patients with loss of heterozy-

gosity treated with standard therapy (those two drugs plus doxorubicin and radiotherapy) had a 4-year event-free survival rate of 65.9%. Median follow-up was 3.6 years. By augmenting the regimens and targeting them to patients with high-risk Wilms tumor (favorable histology but loss of heterozygosity for 1p and 16q), 4-year event-free survival was boosted from 74.9% to 83.9% in stage I/II patients and from 65.9% to 91.5% in stage III/ IV patients. “These studies suggest that augmentation of therapy markedly improves outcomes for patients with advanced disease and this abnormality. Due to smaller numbers in the study sample, the benefit [of augmentation therapy] is less clear for those with lower-stage disease but suggests improved outcome,” he commented.

New Data in Wilms Tumor ■■ Loss of heterozygosity at chromosomes 1p and 16q is a biomarker for poor prognosis in patients with favorable histology Wilms tumor. ■■ Two phase III studies found that Wilms tumor patients who harbor this abnormality had improved 4-year event-free survival when therapy was intensified/augmented.

EXPERT POINT OF VIEW

ommenting on the AREN0532/ AREN0533 data, Alison M. Friedmann, MD, of the Department of Hematology/Oncology at Mas-

highly successful risk-adapted treatment approach of the previous National Wilms Tumor Study Group [NWTS] trials. Previous trials were

The study is a beautiful demonstration of the utility of correlative biology studies that allow for the identification of genetic and molecular features of tumors, which can help us identify cohorts of patients who may not do well with standard therapy and who may benefit from intensification of treatment. —Alison M. Friedmann, MD

sachusetts General Hospital, Boston, said that this is an important study. “This continues to build on the

limited to the use of tumor stage and histology [presence or absence and degree of anaplasia] to stratify pa-

tients, but careful biology studies conducted on patients enrolled in NWTS-5 identified a small subset of patients with a genetic feature in their tumor cells that had a significant adverse impact on event-free survival,” she explained. The present study, conducted by the Children’s Oncology Group, tested for this abnormality prospectively in tumor tissue obtained at the time of diagnosis, identifying it in 7.7% of the patients enrolled (87 of the total 1,134).

Important Research “Intensifying therapy for this handful of patients improved their event-free survival, though it is anticipated that the additional therapy will introduce a risk of reproductive dysfunction for the advanced-stage patients that they would otherwise not have had, which is more likely to

be an issue for male survivors than females,” Dr. Friedmann continued. “The study is a beautiful demonstration of the utility of correlative biology studies that allow for the identification of genetic and molecular features of tumors, which can help us identify cohorts of patients who may not do well with standard therapy and who may benefit from intensification of treatment. This type of research is important even in diseases like Wilms tumor, which have an excellent prognosis overall, and the findings provide a strong rationale for the planned national effort—Project: Every Child—which will procure tumor samples for a huge biorepository linked to clinical data, allowing us to continue to improve the outcomes in childhood cancer,” she concluded. n Disclosure: Dr. Friedmann reported no potential conflicts of interest.

ASCOPost.com | JUNE 10, 2015

PAGE 13

ASCO Annual Meeting Adverse Events The treatment was well tolerated overall, and toxicities were manageable, Dr. Dix said. In earlier-stage patients, augmented therapy did not lead to a significant increase in adverse events over the short term. In later-stage patients, myelosuppression was the most common severe adverse event associated with the augmented regimen, reported in 60% of patients. Regimen M used to treat laterstage patients is associated with a risk of reduced fertility, but according to the authors, this regimen spares some patients from having to undergo intensive relapse therapy. The authors recommend that oncologists have a clear discussion outlining risks and benefits of augmented therapy for higher-risk patients with loss of heterozygosity. Testing for loss of heterozygosity (for 1p and 16q) is considered the standard of care and is performed at the Children’s Oncology Group Biopathology Center and several other centers, Dr. Dix said.

She added, “It would not be possible to do this study without federally funded research. The goal of this study is to use genetic testing to escalate therapy in high-risk patients and de-escalate it in low-risk patients.” n Julie M. Vose, MD

Disclosure: The National Institutes of Health funded this study. For full disclosures of the study authors, visit meetinglibrary.asco.org.

Reference 1. Dix DB, Fernandez CV, Chi Y-Y, et al: Augmentation of therapy for favorable histology Wilms tumor combined with loss of heterozygosity of chromosomes 1p and 16q: A report from the Children’s Oncology Group studies AREN0532 and AREN0533. 2015 ASCO Annual Meeting. Abstract 10009. Presented June 1, 2015.

It’s what’s inside that counts.

Poor-Prognosis Patients Commenting on these findings, ASCO President-Elect Julie M. Vose, MD, said, “It’s very encouraging that we’re making progress even for kids with a rare, high-risk form of this disease. The ability to easily identify a small subset of patients with a poorer prognosis means these children can receive treatment that’s right for them, while decreasing side effects for lowerrisk patients. And that means a better shot at surviving their cancer.”

The molecular alterations that lead to cancer are unique to each patient. At Foundation Medicine, our approach tests for all clinically relevant alterations driving a patient’s cancer.

Federally Funded Cancer Research ASCO has created a badge to raise awareness of the importance of federally funded biomedical research that improves the lives of people worldwide. Among all of the presentations at ASCO’s Annual Meeting, many were the result of federally funded research. To call attention to the value of federal funds, The ASCO Post has printed this badge alongside reports on data resulting from federally funded research and presented at the 2015 ASCO Annual Meeting.

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1. Frampton GM, Fichtenholtz A, Otto GA, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023-1031. ©2015 Foundation Medicine, Inc. Foundation Medicine® and FoundationOne® are registered trademarks.

The ASCO Post | JUNE 10, 2015

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American Society of Breast Surgeons Annual Meeting Breast Cancer

Cost Analysis of Bilateral Prophylactic Mastectomy By Caroline Helwick

ilateral prophylactic mastectomy may ease cancer-related anxiety for patients at high risk of breast cancer, but it does very little to contain the costs. A study presented at the American Society of Breast Surgeons 16th Annual Meeting found that bilateral prophylactic mastectomy was not cost-effective unless the patient has a lifetime breast

screening and prevention in high-risk women, in terms of life-years or qualityadjusted life-years gained, which represent a year of life in perfect health. It showed that annual screening mammography is significantly more costeffective than bilateral prophylactic mastectomy in managing the care of most women at high risk for breast can-

Our model suggests that [bilateral prophylactic mastectomy] should primarily be considered in women with a substantial risk of breast cancer. —Brandy Edwards, MD

cancer risk of about 50%.1 The typical woman’s lifetime risk is 12%, although factors such as family history, certain benign breast conditions, and hormone use can elevate this risk. “Cost-effectiveness analysis is an increasingly important tool to aid in clinical decision-making, particularly in today’s age of health-care reform,” said Brandy Edwards, MD, a general surgery resident at the University of Virginia, Charlottesville, who led the study. “Previous studies have made the economic case for prophylactic procedures in women with BRCA mutations or contralateral mastectomies for patients with cancer in the other breast. This is the first study to demonstrate that a woman without breast cancer or known genetic mutation must have substantial risk to costjustify prophylactic surgery.”

Study Details The study was an overview of costeffectiveness studies that examined

cer. Women with a known BRCA gene mutation, which carries an exceptionally high risk, as well as women with multiple concomitant risk factors are a notable exception. The study relied on a Markov model, which simulates effects that change over time. Model parameters included costs, sensitivity, and specificity of screening modalities, as well as mortality rates. Incremental cost-effectiveness ratios were calculated and interpreted with respect to willingness-to-pay thresholds—typically $50,000 and $100,000. The study assumed a 90% breast cancer risk reduc-

tion with bilateral prophylactic mastectomy. It focused on patients beginning at age 30 and assumed that full lifetime risk would be met at age 80. “Based on information in published literature, we also adjusted the model to account for expected patient preferences for [bilateral prophylactic mastectomy] compared to screening,” noted Dr. Edwards. Even in this subset, the numbers showed that bilateral prophylactic mastectomy should primarily be considered only in women with a very high risk. When accounting for these patient preferences, an approximate 50% lifetime risk still emerged as the point where bilateral prophylactic mastectomy would be considered a cost-effective alternative to screening, she reported. The study also found that screening with a combination of mammography and magnetic resonance imaging (based on Medicare reimbursement rates) was never more cost-effective than bilateral prophylactic mastectomy at any risk level and that the additional survival benefit associated with combined screening is very small, if any, when compared to mammography screening alone.

Lifetime Risk Must Be Substantial The key numbers from the analysis—for the cost-effectiveness of bilat-

Cost-Effectiveness of Bilateral Prophylactic Mastectomy ■■ Bilateral prophylactic mastectomy is not cost-effective unless a woman has a lifetime risk of approximately 50% or more. ■■ Combined mammography and magnetic resonance imaging was never more cost-effective than bilateral prophylactic mastectomy at any risk level; combined imaging provides only a very small survival benefit, if any, over mammography alone.

eral prophylactic mastectomy—were as follows: • At a willingness-to-pay threshold of $50,000, in unadjusted life-years gained, the lifetime risk must be at least 43%; in quality-adjusted lifeyears, the risk must be at least 57%. • At a willingness-to-pay threshold of $100,000, in unadjusted life-years gained, the lifetime risk must be at least 26%; in quality-adjusted lifeyears, the risk must be at least 51%. “Our model suggests that [bilateral prophylactic mastectomy] should primarily be considered in women with a substantial risk of breast cancer,” Dr. Edwards concluded. However, while cost-effectiveness studies are a valuable tool for comparing interventions, she said the results should not be the sole criterion for deciding whether or not a certain treatment should be used or covered by health insurance. “At the end of the day, this is a highly personal decision that must be made on a patient-by-patient basis,” she said. “Clearly there is a need for additional affordable screening technologies for women at high risk for breast cancer,” Dr. Edwards added. “While prophylactic mastectomy is appropriate for some women, it can carry steep costs, both economically and in quality-of-life, because prophylactic surgery isn’t without risk.” n

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

Reference 1. Edwards BL, Hu Y, Stukenborg GJ, et al: Cost-effectiveness of bilateral prophylactic mastectomy in patients at high risk for breast cancer without known BRCA mutation. American Society of Breast Surgeons Annual Meeting. Presented April 30, 2015.

Don’t Miss These Important Reports in This Issue of The ASCO Post Judy Salerno, MD, on First National Breast Cancer Subtype Data see page 44

Jeffrey S. Weber, MD, PhD, on Nivolumab in Advanced Melanoma After Anti–CTLA-4 Treatment see page 52

Visit The ASCO Post online at ASCOPost.com

Douglas R. Lowy, MD, on His New Role at the NCI see page 56

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ASCOPost.com | JUNE 10, 2015

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American Society of Breast Surgeons Annual Meeting Breast Cancer

Nipple-Sparing Mastectomy Shown to Be Oncologically Safe By Caroline Helwick

astectomies that preserve the nipple and an envelope of breast skin are as safe as more radical operations for qualifying early-stage breast cancer patients, according to a metaanalysis and systemic literature review

tween 2004 and 2015 involving 5,393 patients, of whom 2,013 received nipple-sparing mastectomy. Some studies compared nipple-sparing mastectomy with skin-sparing mastectomy and modified radical mastectomy, whereas

Nipple-sparing mastectomy was found to be at least as safe as more radical surgeries, judged on both overall survival and disease-free survival. —Lucy De La Cruz, MD

presented at the American Society of Breast Surgeons 16th Annual Meeting.1 Data from the Surveillance, Epidemiology, and End Results (SEER) registry have shown that the rate of nipple-sparing mastectomy has increased 202% since 2005, but “oncological safety has been a concern, due to the potential for residual glandular breast tissue to harbor future cancer,” said lead author Lucy De La Cruz, MD, of the University of Miami, Florida. The incidence of occult malignancy in the nipple-areolar complex ranges from 0% to 53%, with an average of 11.5%, she said. Generally, however, studies have suggested that nipplesparing mastectomy is as safe and effective in preventing cancer recurrence as more radical procedures, Dr. De La Cruz indicated.

Study Details Dr. De La Cruz and colleagues evaluated the safety and efficacy of nipplesparing mastectomy by conducting a systematic literature review and metaanalysis of 19 studies published be-

others were single-arm nipple-sparing mastectomy studies. Studies followed patients ranging from 10 to 156 months.

Comparison of Surgical Techniques In the comparison-arm studies, 29.9% of women underwent nipplesparing mastectomy, 15% had skinsparing mastectomy, and 55.1% had modified radical mastectomy. In the 19 studies combined, overall survival was 96% for nipple-sparing mastectomy, and the disease-free survival rate was 93.6%. The rate of nipple-areolar recurrence was 1.2% overall with nipplesparing mastectomy. Compared with other surgical techniques, overall survival was found to be 2.5% greater among the nipple-sparing mastectomy cohorts, and disease-free survival was 4.4% greater, both statistically significant. When we looked at local recurrence, there was no difference between the groups. “Nipple-sparing mastectomy was found to be at least as safe as more radical surgeries, judged on both overall

Nipple-Sparing Mastectomy ■■ A meta-analysis and systematic literature review of 19 studies showed nipple-sparing mastectomy to be at least as oncologically safe as more radical surgery. ■■ With nipple-sparing mastectomy, overall survival was 96%, disease-free survival was 93.6%, and the rate of nipple-areolar recurrence was 1.2%.

survival and disease-free survival,” Dr. De La Cruz reported. They also compared nipple-sparing mastectomy outcomes between women having nipple-sparing mastectomy for therapeutic mastectomy alone and for either therapeutic or prophylactic purposes (ie, combined group). In this comparison, overall survival was 93.0% for the therapeutic nipple-sparing mastectomy group vs 99.0% for the combined group (P = .006); disease-free survival was 84.2% vs 96.2% (P = .012); and nipple-areolar recurrence was 2.6% vs 0.4% (P = .001). The better results in the combined group were not surprising, since many of these women did not have cancer, she pointed out. “Our conclusion is that nipple-

sparing mastectomy is oncologically safe in carefully selected women with early-stage breast cancer,” Dr. De La Cruz said, “but our data need validation from other sources, including the use of prospective data registries, most notably the Nipple-Sparing Mastectomy Registry.” n Disclosure: Dr. De La Cruz reported no potential conflicts of interest.

Reference 1. De La Cruz LM, Blankenship S, Tappy, E et al: Overall survival, disease-free survival, and nipple-areolar recurrence in the setting of nipple-sparing mastectomy: A meta-analysis. 2015 American Society of Breast Surgeons Annual Meeting. Presented April 30, 2015.

EXPERT POINT OF VIEW

ulie A. Margenthaler, MD, of Siteman Cancer Center, St. Louis, who moderated a press briefing at the American Society of Breast Surgeons 16th Annual Meeting, commented on these findings and fielded some questions about the procedure. Dr. Margenthaler indicated that although nipple-sparing mastectomy is gaining ground, it probably constitutes only about 5% of mastectomies nationwide. Among surgeons specifically trained to do it, nipple-sparing mastectomy represents at least 20% of mastectomies among their eligible patients, she estimated.

Many surgeons are developing the skill, but it’s technically more challenging. You need a very small incision and have limited visibility. —Julie A. Margenthaler, MD

“Many surgeons are developing the skill, but it’s technically more challenging. You need a very small incision and have limited visibility,” explained Dr. Margenthaler. She indicated the procedure might cost no more than standard skin-sparing mastectomy with reconstruction, since implants can be placed during the nipple-sparing mastectomy, making it a one-stage operation. Women with the tumor location no closer than 2 cm from the nipple are eligible for the procedure. Women with large breasts are often not the best candidates, as cosmesis tends to be worse in these patients. Preserving the nipple usually does not preserve its sensation, she added. n Disclosure: Dr. Margenthaler reported no potential conflicts of interest.

DISCOVERING HOW FAR THERAPY CAN GO IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®. The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA®. Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly. Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification. Second Primary Malignancies - Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).

IMBRUVICA® (ibrutinib) is the ﬁrst and only FDA-approved therapy for use in patients with Waldenström’s macroglobulinemia (WM) IMBRUVICA® is approved for use in 4 indications IMBRUVICA® is indicated for the treatment of patients with Mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Chronic lymphocytic leukemia with 17p deletion. Waldenström’s macroglobulinemia (WM).

Tumor Lysis Syndrome - Tumor lysis syndrome has been reported with IMBRUVICA® therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden).

DRUG INTERACTIONS

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

ADVERSE REACTIONS The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash. Seven percent of patients receiving IMBRUVICA® discontinued treatment due to adverse events.

CYP3A Inhibitors - Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.

SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA® dose. Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit

www.IMBRUVICA.com

Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICA® (ibrutinib) capsules

INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in Full Prescribing Information]. Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in Full Prescribing Information]. Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in Full Prescribing Information]. Waldenström’s Macroglobulinemia: IMBRUVICA is indicated for the treatment of patients with Waldenström’s macroglobulinemia (WM) [see Clinical Studies (14.3) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in Full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. [See Adverse Reactions]. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly. Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in Full Prescribing Information]. Second Primary Malignancies: Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11 %). Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Cytopenias [see Warnings and Precautions] • Atrial Fibrillation [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience: Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis Fatigue Peripheral edema Pyrexia Asthenia

All Grades (%) 51 31 25 24 23 17 11 34 14 14 14 13 41 35 18 14

Grade 3 or 4 (%) 5 0 0 5 0 1 0 0 3 7 5 1 5 3 1 3

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) (continued) System Organ Class

Preferred Term

Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

All Grades (%)

Grade 3 or 4 (%)

30 25 11 37 14 11 27 19 11 21 12 14 13

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

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. Approximately five percent of patients receiving IMBRUVICA in Study 1 and Study 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 All Grades (%)

Grade 3 or 4 (%)

Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection Fatigue Pyrexia Peripheral edema Asthenia Chills Bruising Rash Petechiae Cough Oropharyngeal pain Dyspnea Musculoskeletal pain Arthralgia Muscle spasms Dizziness Headache Peripheral neuropathy Decreased appetite

63 23 21 21 19 15 13 48 21 17 10 10 31 25 23 13 13 54 27 17 19 15 10 27 23 19 21 19 10 17

4 2 2 0 2 0 0 2 6 6 8 0 4 2 0 4 0 2 0 0 0 0 0 6 0 2 0 2 0 2

Second malignancies*

10*

Laceration

Anxiety Insomnia Hypertension

10 10 17

0 0 8

System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders Metabolism and nutrition disorders Neoplasms benign, malignant, unspecified Injury, poisoning and procedural complications Psychiatric disorders Vascular disorders

Preferred Term

*One patient death due to histiocytic sarcoma.

IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenström’s Macroglobulinemia (N=63) (continued)

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) 71 10 54 27 44 0

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2. Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Vomiting General disorders and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue disorders Rash* Petechiae Bruising* Musculoskeletal and connective tissue disorders Musculoskeletal Pain* Arthralgia Nervous system disorders Headache Dizziness Injury, poisoning and procedural complications Contusion Eye disorders Vision blurred

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%)

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%)

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

28 17

2 1

18 7

1 0

14 11

1 0

6 5

0 0

Subjects with multiple events for a given ADR term are counted once only for each ADR term. The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%) 51 23 52 5 36 0

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%) 57 26 45 10 21 0

* Based on laboratory measurements per IWCLL criteria Waldenström’s Macroglobulinemia The data described below reflect exposure to IMBRUVICA in an open label clinical trial that included 63 patients with previously treated WM. The most commonly occurring adverse reactions in the WM trial (≥ 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue. Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients. Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 reflect exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial. Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenström’s Macroglobulinemia (N=63) System Organ Class Gastrointestinal disorders Skin and subcutaneous tissue disorders

Preferred Term Diarrhea Nausea Stomatitis* Gastroesophageal reflux disease Rash* Bruising* Pruritus

All Grades (%) 37 21 16 13 22 16 11

Grade 3 or 4 (%) 0 0 0 0 0 0 0

System Organ Class

Preferred Term Fatigue

All Grades (%) 21

Grade 3 or 4 (%) 0

General disorders and administrative site conditions Musculoskeletal and connective tissue disorders Infections and infestations

Muscle spasms Arthropathy

21 13

0 0

Respiratory, thoracic and mediastinal disorders Nervous system disorders Neoplasms benign, malignant, and unspecified (including cysts and polyps)

Upper respiratory tract infection Sinusitis Pneumonia* Skin infection* Epistaxis Cough

19 19 14 14 19 13

0 0 6 2 0 0

Dizziness Headache Skin cancer*

14 13 11

0 0 0

The system organ class and individual ADR terms are sorted in descending frequency order. * Includes multiple ADR terms. Table 8: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with WM (N=63)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=63) All Grades Grade 3 or 4 (%) (%) 43 13 44 19 13 8

* Based on laboratory measurements. Postmarketing Experience: The following adverse reactions have been identified during postapproval use of IMBRUVICA. 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. Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in Full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in Full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in Full Prescribing Information]. Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), and infections (pneumonia and urinary tract infection) occurred more frequently among elderly patients.

IMBRUVICA® (ibrutinib) capsules Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Hepatic Impairment: Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The safety of IMBRUVICA has not been evaluated in patients with hepatic impairment. Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. Plasmapheresis: Management of hyperviscosity in patients with WM may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions]. • Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. • Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions]. • Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in Full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in Full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration. Active ingredient made in China. Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics, Inc. © Pharmacyclics, Inc. 2015 © Janssen Biotech, Inc. 2015 PRC-00787

PAGE 22

The ASCO Post | JUNE 10, 2015

AUA Scientific Meeting Genitourinary Oncology

New Studies Call for Smarter Approach to Prostate Cancer Screening

rostate cancer is one of the most common cancers in American men, yet controversy over the utilization and frequency of prostate-specific antigen (PSA) screening methods remains, due to the overdiagnosis and overtreatment of men with low-grade, less-aggressive forms of the disease. At the 110th Annual Scientific Meeting of the American Urological Association (AUA), several studies examined new approaches to smarter prostate cancer screening methods.

Using genotypes of four genetic variants associated with serum PSA levels, researchers studied how genetic correction of PSA levels in men with known low-risk prostate cancer resulted in PSA results below biopsy thresholds. Results from the study showed that in the surgical cohort, genetic correction of serum PSA levels was associated with

Long-Term Risk Directly Related to Baseline PSA Level New research from Kara Choate, MD, and colleagues of the University of Texas Health Science Center at San Antonio suggests that, for men with low baseline PSA levels (0.1–0.9 ng/ mL), repeated prostate cancer screening on an annual basis was not required and could be conducted once every 10 years.1 According to the researchers, this approach has the potential to reduce the cost of screening dramatically as well as significantly reduce the detection of low-grade, potentially inconsequential prostate cancer. Researchers evaluated men with no history of prostate cancer over an average of 7.4 years to determine whether baseline PSA levels could predict intermediate-term risk of prostate cancer. Of the 2,923 men studied, 302 were diagnosed with prostate cancer during follow-up. Men with lower baseline PSA levels (0.1–0.9 ng/mL) had a greatly reduced risk (2%–5%) of being diagnosed with prostate cancer after 10 years, and 90% of those cancers were low-risk cancers. By comparison, men with higher PSA levels (2.3–9.9 ng/ mL) had a 10% to 36% risk of cancer detection, reaching a 36% risk of cancer after 10 years.

Genetic Correction of PSA Levels May Reduce Unnecessary Biopsies Understanding a man’s genetic risk for prostate cancer could potentially reduce the number of biopsies and diagnoses of low-grade, low-risk prostate cancer, according to investigators in a Northwestern University–led study. James Kearns, MD, presented the study.

James Kearns, MD

a significantly decreased percentage of men meeting biopsy thresholds of ≥ 2.5 ng/ mL and ≥ 4.0 ng/mL. Similar analyses in the active surveillance cohort demonstrated that genetic correction of these four PSA genetic variants could potentially reduce the number of biopsies and prostate cancer diagnoses by 39% and 40%, respectively. By correcting for the effects of these variants on PSA levels, it may be possible to create a personalized PSA cutoff to identify more accurately individuals for whom biopsy is recommended.

New Biomarker Index Detects Aggressive Prostate Cancer The Prostate Health Index (PHI) demonstrated better specificity than total PSA or percent-free PSA and could be a useful tool to decrease unnecessary prostate biopsies, according to Claire De La Calle, MD, and colleagues of Emory University School of Medicine, University of Michigan Medical School, Weill Cornell Medical College, and Johns Hopkins University School of Medicine.3 The study applied the PHI, a new formula that combines three well-known

Claire De La Calle, MD

ASCOPost.com | JUNE 10, 2015

PAGE 23

AUA Scientific Meeting biomarkers (total PSA, percent-free PSA, and proPSA) to discern aggressive prostate cancer from slow-growing cancer or no cancer in men who had not previously had biopsies. Based on PHI

(PLCO), Michael Liss, MD, and colleagues of the University of Texas Health Science Center at San Antonio, Wake Forest School of Medicine, University of California at San Diego

Although more research is needed, these data show promise in new techniques to minimize unnecessary biopsies and more accurately identify high-risk patients. —Scott Eggener, MD

cut points and corresponding specificities that were calculated at three fixed sensitivities (95%, 90%, and 80%), results from the study showed that up to 41% of unnecessary biopsies could be avoided using PHI.

Prostate Genetic Score Stratifies Baseline Prostate Cancer Risk New research evaluates the genetic risk for prostate cancer as a means of improving PSA screening methods for high-risk patients.4 Using data collected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

School of Medicine, and Fudan University in Shanghai evaluated and aggregated genomic data from 2,244 patients with no cancer, nonaggressive cancer, or aggressive prostate cancer. Results showed that using the prostate genetic risk score may help to better identify an individual’s prostate cancer risk as well as identify patients who may benefit from screening. “These studies demonstrate progress toward more targeted approaches to prostate cancer screening and further our evolution from a ‘one-size-fits-all’ approach,” said Scott Eggener, MD,

AUA Spokesperson and Associate Professor of Surgery for Urologic Oncology at the University of Chicago Medicine. “Although more research is needed, these data show promise in new techniques to minimize unnecessary biopsies and more accurately identify high-risk patients.” n

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

References 1. Choate K, Gelfond J, Ankerst D, et al: Long-term risk of prostate cancer is directly related to baseline PSA. 2015 American Urological Association Annual Scientific Meeting. Abstract MP77-09. Presented May 19, 2015. 2. Kearns J, Helfand B, Roehl K, et al: Genetic correction of PSA can reduce the

Update on Prostate Cancer Screening ■■ Men with a low baseline PSA level had a greatly reduced risk of being diagnosed with prostate cancer after 10 years. ■■ Correcting for four PSA genetic variants prior to prostate cancer biopsy could significantly reduce the number of prostate cancer diagnoses. ■■ Up to 41% of unnecessary biopsies could be avoided using the Prostate Health Index. ■■ The prostate genetic risk score may help to better identify an individual’s prostate cancer risk, when compared with PSA screening.

Visit ASCOPost.com for Interviews Filmed Live During the 2015 ASCO Annual Meeting The ASCO Post presents these and other important discussions: ■■

■■ ■■

Whole-Brain Radiation and Radiosurgery in Patients With Brain Metastases Issues of Value in Melanoma Treatment PALOMA3 Study on Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer Global Oncology: Cancer Care in Resource-Challenged Areas Ibrutinib, Bendamustine, and Rituximab in Previously Treated CLL/SLL

Visit The ASCO Post online at ASCOPost.com

number of men diagnosed with potentially insignificant prostate cancer: Results from a surgical and active surveillance cohort. 2015 American Urological Association Annual Scientific Meeting. Abstract PD38-07. Presented May 18, 2015. 3. De La Calle C, Patil D, Wei J, et al: Multicenter evaluation of the Prostate Health Index (PHI) for detection of aggressive prostate cancer in biopsy-naive men. 2015 American Urological Association Annual Scientific Meeting. Abstract PD46-02. Presented May 18, 2015. 4. Liss M, Xu J, Chen H, et al: The Prostate Genetic Score (PGS) stratifies baseline risk of prostate cancer and improves PSA performance in the PLCO trial. 2015 American Urological Association Annual Scientific Meeting. Abstract PD44-01. Presented May 18, 2015.

The ASCO Post | JUNE 10, 2015

PAGE 24

AUA Scientific Meeting Genitourinary Oncology

Studies Evaluate Effectiveness of Active Surveillance in Prostate Cancer Patients

ctive surveillance has become a viable option for many men with low-risk prostate cancer who choose not to undergo active treatment such as surgery or radiotherapy. Four studies evaluating the effectiveness, trends, and other considerations for active surveillance in managing prostate cancer were presented during the 110th Annual Scientific Meeting of the American Urological Association (AUA).

cer has the most favorable results. These men have clinical stage T1c with a Gleason score ≤ 6. Patients with very lowrisk prostate cancer have a PSA density less than 0.15 ng/mL/g. Upon biopsy, these patients have no more than two cores with cancer, and the positive cores have no more than 50% cancer. Among 808 men identified on ac-

Long-Term Follow-up for Favorable-Risk Prostate Cancer Jeffrey Tosoian, MD, and colleagues of Johns Hopkins University School of Medicine in Baltimore found that active surveillance appears to be a safer management strategy for men with “favorable-risk” prostate cancer.1 Favorable-risk patients are defined as patients with a Gleason score ≤ 6 and a prostate-specific antigen (PSA) level ≤ 10 ng/mL. A long-term study evaluated data from 1,298 men diagnosed since 1995 for primary outcomes, in-

Ridwan Alam, MD

tive surveillance (557 with very low-risk disease and 251 with low-risk disease), researchers found similar reclassification rates within the first 2 years. After this period, however, men in the low-risk group were twice as likely to be diagnosed with progressing disease (Gleason score > 6) than those in the very low-risk group. For both groups, the risk of lifetime reclassification beyond 2 years decreased by 30% and 35%, respectively, after each nonreclassifying biopsy.

Active Surveillance Rates in Community Urology Practices Jeffrey Tosoian, MD

cluding overall survival, cancer-specific survival, and metastasis-free survival. At 10- and 15-year follow-up, overall survival was 93.2% and 68.7%, cancerspecific survival was 99.9% and 99.9%, and metastasis-free survival was 99.4% and 99.4%, respectively. These data suggest that for men with an extended life expectancy of more than 15 years, active surveillance may be the safest management strategy for men with very low-risk disease.

When Can Patients Stop Worrying? A new study conducted by Ridwan Alam, MD, and colleagues of Johns Hopkins University School of Medicine suggests that men on active surveillance for low-risk prostate cancer can expect the likelihood of disease reclassification to decline with each additional stable biopsy after 2 years.2 Low-risk prostate cancer can be defined as category T1 or T2a. The subcategory of very low-risk prostate can-

Across the country, the adoption of active surveillance as a treatment option for men with low-risk prostate cancer is on the rise, according to new research by Jeremy Shelton, MD, and colleagues of the University of California, Los Angeles; Bethesda North Hospital; Providence Little Company of Mary Medical Center Torrance; and Carolina Urologic Research Center.3 Of the 1,401 men identified in the study as meeting study inclusion criteria, the average age was 63.6 years.

Active surveillance should be encouraged for men with low-risk prostate cancer that can delay or avoid the need for treatment. —Stacy Loeb, MD

Additionally, based on data from community-based urology practices in California, Colorado, Indiana, North Carolina, Ohio, Oregon, and South Carolina, 17.3% had very low-, 36.1% had low-, and 42.7% had intermediate-risk prostate cancer. Across all risk groups, the primary therapy choice was active surveillance (70.2% of men with very low, 39.2% of men with low, and 7.7% of

Jeremy Shelton, MD

men with intermediate risk of disease progression). Risk level, age, and urology practice predicted the choice of active surveillance, whereas race did not.

Patterns of Care for Men Undergoing Active Surveillance Despite a global increase in active surveillance as a treatment strategy for men with low-risk prostate cancer, there is no consensus on the protocol to use when following men during surveillance, and practice patterns vary widely, according to a retrospective study by Stacy Loeb, MD, and colleagues of

Active Surveillance in Prostate Cancer ■■ Active surveillance may be the safest management strategy for men with very low-risk prostate cancer and an extended life expectancy of more than 15 years. ■■ Men on active surveillance with low-risk prostate cancer can expect the likelihood of disease reclassification to decline with each additional stable biopsy after 2 years. ■■ Active surveillance was the primary therapy choice for 1,401 men with prostate cancer from 7 states across all risk groups. ■■ Although most men on active surveillance receive at least one PSA test per year, rates of imaging and biopsies have declined over time, as has the number of patients adhering to active surveillance protocols.

New York University (NYU).4 Reviewing records for 5,192 men from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, researchers found that although most men receive at least one PSA test per year, rates of imaging and biopsies declined over time, as did the number of patients adhering to active surveillance protocols. Younger men and those diagnosed in more recent years had a higher frequency of surveillance biopsies. “Active surveillance should be encouraged for men with low-risk prostate cancer that can delay or avoid the need for treatment,” said Dr. Loeb, who is Assistant Professor in the Department of Urology, Population Health and Laura & Isaac Perlmutter Cancer Center, New York University, and who moderated a press conference on these studies. “However, the surveillance is meant to be an active process, so men on active surveillance should continue to follow up with their doctor regularly.” n

Disclosure: Dr. Loeb is on the advisory board of and receives honorarium for lecture from Bayer.

References 1. Tosoian J, Mamawala M, Epstein J, et al: A prospective, longitudinal active surveillance program for favorable-risk prostate cancer. 2015 AUA Annual Scientific Meeting. Abstract PD6-04. Presented May 15, 2015. 2. Alam R, Ballentine Carter H, Landis P, et al: Active surveillance: When can patients stop worrying? 2015 AUA Annual Scientific Meeting. Abstract MP42-04. Presented May 17, 2015. 3. Shelton J, Buffington P, Koo A, Shore, N: Contemporary active surveillance rates for newly diagnosed prostate cancer patients in community urology practices. 2015 AUA Annual Scientific Meeting. Abstract MP4-03. Presented May 15, 2015. 4. Loeb S, Walter D, Dewitt S, et al: Patterns of care for men with prostate cancer undergoing active surveillance as initial management. 2015 AUA Annual Scientific Meeting. Abstract PD34-11. Presented May 18, 2015.

MPDL3280A (an engineered anti-PDL1 antibody)

CURRENTLY ENROLLING

Clinical trials in various tumor types for MPDL3280A (an engineered anti-PDL1 antibody) Trials for MPDL3280A,* an investigational anti-PDL1 antibody, are currently recruiting patients in various tumor types: • Bladder • Kidney • Melanoma — NCT02302807

• Colorectal — NCT02291289

• Hematologic malignancies — NCT02220842

— NCT01656642

— NCT01984242

• Lung

• Solid tumors

— NCT02366143 — NCT02367781 — NCT02367794 — NCT02013219

— NCT02323191 — NCT02304393 — NCT01633970 — NCT02174172 — NCT01375842

For more information about the MPDL3280A clinical trial program Call: Genentech Trial Information Support Line: 1-888-662-6728 (US only) Visit: ClinicalTrials.gov or antiPDL1ClinicalTrials.com/hcp

Email: global.rochegenentechtrials@roche.com

*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 trials and should not be construed as a recommendation for use of any product for unapproved purposes.

The ASCO Post | JUNE 10, 2015

PAGE 26

AACR Annual Meeting Breast Cancer

Anti–PD-L1 Agent Shows Activity in Early Study of Triple-Negative Breast Cancer By Alice Goodman

n investigational immunotherapy called MPDL3280A showed encouraging and durable clinical activity in heavily pretreated patients with metastatic triple-negative breast cancer, in an early study presented at the 2015 Annual Meeting of the American Association of Cancer Research (AACR).1 Responses were seen in patients who were PD-L1–positive, suggesting that PD-L1 (programmed death ligand 1) may turn out to be a biomarker for response. The durable responses seen in this first-in-human study are not typically seen with chemotherapy in this population. “This anti–PD-L1 agent has promising clinical activity in triple-nega-

of 19%, and three of four responses are ongoing,” she said.

An Unmet Need New treatment for metastatic triple-negative breast cancer is an unmet need. Triple-negative breast cancer carries a poor prognosis compared with other types of breast cancer. Chemotherapy is currently the standard approach, and no targeted therapy is currently approved for triple-negative breast cancer in the United States, although bevacizumab (Avastin) is approved for this indication in more than 80 countries worldwide. An anti–PD-L1 approach is attractive for triple-negative breast cancer,

EXPERT POINT OF VIEW

“T

hese results are promising. The fact that there were two patients with a complete response caught my eye. This is very exciting in metastatic triple-negative breast cancer. These were heavily pretreated patients; 85% had more than four lines of prior therapy,” said Aditya Bardia, MD, a breast medical oncologist at Massachusetts General Hospital, Harvard Medical School, Boston.

The fact that there were two patients with a complete response caught my eye. This is very exciting in metastatic triplenegative breast cancer. —Aditya Bardia, MD

This anti–PD-L1 agent [MPDL3280A] has promising clinical activity in triplenegative breast cancer, and these findings support further study in this cancer subtype. —Leisha Emens, MD

tive breast cancer, and these findings support further study in this cancer subtype. The company [Genentech] is preparing to launch a global phase III trial of MPDL3280A in combination with nab-paclitaxel [Abraxane] as first-line therapy for metastatic triple-negative breast cancer,” said lead author Leisha Emens, MD, of Johns Hopkins Sidney Kimmel Cancer Center in Baltimore. “Immunotherapy is creating a lot of excitement, because many of the responses we see are prolonged. The latest analysis of our data showed a 24week progression-free survival rate of 27%, with an objective response rate

because this type of cancer is highly mutagenic and produces neoantigens that induce an immune response. Triple-negative breast cancer is characterized by an increased number of tumorinfiltrating lymphocytes, which can also facilitate an immune response. Furthermore, triple-negative breast cancer is associated with high levels of PD-L1 expression compared with other types of breast cancer. MPDL3280A is an engineered anti–PD-L1 antibody that interferes with the binding of PD-L1 to PD-1 and B7, which is thought to restore antitumor T-cell activity and enhance T-cell priming.

Immunotherapy for Triple-Negative Breast Cancer ■■ Triple-negative breast cancer may be added to the growing list of cancers that appear to respond to investigational immunotherapy approaches. ■■ A phase I study suggests that the anti–PD-L1 agent MPDL3280A has activity in triple-negative breast cancer. ■■ This agent will be studied further in triple-negative breast cancer. ■■ The safety of this agent needs to be better characterized. ■■ Biomarkers are needed to identify patients who will and won’t respond to this approach.

Dr. Bardia added, we need to be mindful of three things. First, while there is no doubt immunotherapy is promising, one should note the study is small (less than 100 patients), single-arm, and MPDL3280A cannot be considered the standard of care yet. Also, while PD-L1 is a potential biomarker, we need other biomarkers that can help predict the likelihood of response and help more breast cancer patients get the “home-run.” Second, up to 55% of patients had adverse events, including some patients with grade 3 and 4 toxicity, and risk of autoimmune conditions is real. We need more data to characterize the efficacy and safety of this drug. Third, there are other anti– PD-L1 and anti–PD-1 immunotherapy agents under development, and it is not clear whether MPDL3280A will be better than these agents and what the best combination and sequence strategy should be. Some of these issues are being investigated in clinical trials and the results are eagerly awaited. n Disclosure: Dr. Bardia reported no potential conflicts of interest.

Study Findings The phase I trial Dr. Emens reported at the AACR meeting included a variety of cancer types, analysis included 54 patients total, with any level of PD-L1 expression. All 54 patients were evaluable for safety, and 69% of these patients had PD-L1–positive (IHC 2/3) disease by the proprietary assay. Twenty-one of the 54 patients were evaluable for efficacy, all of whom were PD-L1–positive (IHC 2/3). MPDL3280A was generally well tolerated. The most common treatment-related adverse events included fatigue, nausea, fever, decreased appetite, and asthenia. Eleven percent of patients had grade 3 treatment-related adverse events. Two deaths occurred, and the causes are currently being — investigated. The overall response rate was 19%, and 24-week progression-free survival

was 27%. There were two complete responses and two partial responses; three of four responses are ongoing. The median duration of response has not yet been reached (range, 18–56 weeks). The median duration of survival follow-up is 40 weeks (range, 2+ to 85+ weeks). Of the 21 PD-L1–positive patients, 3 experienced pseudoprogression, and all 3 eventually had tumor shrinkage. Dr. Emens explained that pseudoprogression occurs with anti– PD-L1 treatment, a phenomenon that other investigators have reported. This means that in patients with observable tumor shrinkage of target lesions who are doing well clinically on an anti– PD-L1 agent, new lesions can emerge after treatment, but they eventually respond. “The phenomenon of pseudoprocontinued on page 27

ASCOPost.com | JUNE 10, 2015

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JCO Spotlight Gynecologic Oncology

Long-Term Survival Advantage Seen With Intraperitoneal vs Intravenous Chemotherapy in Advanced Ovarian Cancer By Matthew Stenger

n an analysis of Gynecologic Oncology Group (GOG) studies reported in the Journal of Clinical Oncology, Devansu Tewari, MD, of Kaiser Permanente Irvine Medical Center, and colleagues found that intraperitoneal chemotherapy was associated with a survival advantage compared with intravenous chemotherapy over long-term follow-up in women with advanced ovarian cancer.1 The findings of long-term benefit may raise issues regarding wider incorporation of intraperitoneal treatment into clinical practice in this setting.

Study Details The retrospective analysis involved data from 876 patients in the phase III GOG studies 114 (N = 462) and 172 (N = 414), both of which randomly assigned patients to intraperitoneal (combined n = 440) or intravenous (combined n = 436) chemotherapy. All patients had stage III epithelial ovarian or peritoneal carcinoma with no residual disease more than 1 cm in diameter after surgery. In GOG 114, patients were randomly assigned to receive either intravenous paclitaxel at 135 mg/m2 followed by intravenous cisplatin at 75 mg/m2 for six courses or intravenous carboplatin for two courses followed by intravenous paclitaxel at 135 mg/m2 on day 1 and intraperitoneal cisplatin at 100 mg/m2 on day 8 for six courses. Intravenous cisplatin was substituted for intraperitoneal cisplatin in patients

with catheter-related problems. In GOG 172, patients received 135 mg/m2 of intravenous paclitaxel followed by either 75 mg/m2 of intravenous cisplatin on day 2 or 100 mg/m2 of intraperitoneal cisplatin on day 2 and 60 mg/m2 of intraperitoneal paclitaxel on day 8 for six cycles. Substitution

—Devansu Tewari, MD, and colleagues

with intravenous carboplatin was permitted if administration of intraperitoneal cisplatin was prevented by toxicity or catheter-related problems. Patients in the intraperitoneal and intravenous groups were generally balanced for baseline characteristics. Overall, patients had a median age of 47 years (55% aged ≥ 55 years); 90% were white; GOG performance status was 0 for 44% and 1 for 48%; tumor grade was 1 in 11%, 2 in 38%, and 3 in 50%; histology was serous in 72% and endometrioid in 9%; and 64% had gross residual disease. Overall, 94 patients in the intraperitoneal group (21%) crossed over to intravenous treatment.

■■ Intraperitoneal therapy was associated with significantly prolonged overall survival. ■■ Overall survival increased with increasing number of intraperitoneal cycles completed.

continued from page 26

gression is new for clinicians to manage. If there is evidence of new lesions on a scan and a patient is doing well clinically, continue to treat [with anti– PD-L1] and re-evaluate. We need to work with physicians, patients, and payers to educate them about how to manage this,” she noted. “This is another powerful indication of immune checkpoint

Median follow-up was 10.7 years. Median progression-free survival was 25 months in the intraperitoneal group vs 20 months in the intravenous group (P = .019). Median overall survival with intraperitoneal therapy was 61.8 months (95% confidence interval [CI]

The ability to better select patients who are more likely to complete [intraperitoneal] therapy with better outcomes and less toxicity warrants further investigation as we move toward individualizing therapies.

Chemotherapy Administration Methods in Ovarian Cancer

Anti–PD-L1 Agent

Improved Overall Survival

inhibitor strategies for diseases for which we don’t have many effective therapies,” said Louis M. Weiner, MD, who moderated a press conference at the AACR meeting where these data were discussed. “Triple-negative breast cancer has a worse prognosis than other subtypes and is a disease that gives cancer a bad name.” Dr. Weiner is Director of the Lombardi Comprehensive Cancer Center at Georgetown University

= 55.5–69.5 months) vs 51.4 months (95% CI = 46.0–58.2 months) for intravenous therapy (P = .042). After adjustment for age, performance status, cell type, tumor grade, and residual disease, hazard ratios (HRs) were 0.79 (P = .003) for progression and 0.77 (P = .002) for death among those receiving intraperitoneal therapy. Overall, there was a significant association of reduced risk of death with each cycle of intraperitoneal treatment completed (adjusted HR = 0.88, P < .001, for each cycle).

Subgroup Analysis and Predictive Factors In subgroup analysis, intraperitoneal treatment was associated with significantly improved overall survival among patients with gross residual (≥ 1 cm) disease vs no visible disease (adjusted HR = 0.75, P = .006), with this improvement observed in the context of the significantly increased risk of

mortality associated with gross residual disease (adjusted HR = 1.89, P < .001). Factors significantly associated with poorer overall survival included clear/mucinous vs serous histology (adjusted HR = 2.79, P < .001), gross residual vs no visible disease (adjusted HR = 1.89, P < .001), and fewer cycles of intraperitoneal chemotherapy with crossover to intravenous therapy (adjusted HR = 1.43, P = .041). Overall, only 50% of patients completed the protocol-stipulated six cycles of intraperitoneal treatment. Younger patients were more likely to complete intraperitoneal regimens, with the probability of completion decreasing by 5% with each additional year of age (odds ratio = 0.95, P < .001). Other demographic and clinicopathologic factors, including performance status, were not predictive of completing intraperitoneal therapy. The investigators concluded: “The advantage of [intraperitoneal] over intravenous chemotherapy extends beyond 10 years. [Intraperitoneal] therapy enhanced survival of those with gross residual disease. Survival improved with increasing number of [intraperitoneal] cycles.” They noted: The long-term survival benefits described in this report may encourage more clinicians to adopt [intraperitoneal] chemotherapy in the community. In addition, [intraperitoneal] therapy may be implemented as a quality measure at institutions with the expertise and support teams necessary to administer [intraperitoneal] treatment. Clinicians should support patients through the [intraperitoneal] regimen, particularly if there are continued on page 28

breast cancer are exciting,” Dr. Weiner stated. n

Disclosure: Dr. Emens reported no potential conflicts of interest. Dr. Weiner is an advisor to Jounce Therapeutics and Celldex Therapeutics.

Louis M. Weiner, MD

Medical Center in Washington, DC. “The implications for triple-negative

Reference 1. Emens LA, Braiteh FS, Cassier P, et al: Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer. 2015 AACR Annual Meeting. Abstract 2859. Presented April 20, 2015.

The ASCO Post | JUNE 10, 2015

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Perspective

What Is the Future of Intraperitoneal Treatment in Advanced Ovarian Cancer? By Robert L. Coleman, MD

n analysis of Gynecologic Oncology Group (GOG) studies recently reported in the Journal of Clinical Oncology by Tewari and colleagues and reviewed in this issue of The ASCO Post showed a survival benefit of intraperitoneal chemotherapy vs intravenous chemotherapy over long-term follow-up in women with advanced ovarian cancer.1 The findings add to the ongoing conversation on the fate of intraperitoneal treatment in this setting.

A ‘Trifecta’ of Sorts The publication of GOG-172 in 2006 completed an intraperitoneal chemotherapy “trifecta” of sorts in demonstrating its utility as primary adjuvant therapy in women with advanced-stage ovarian cancer.2-4 Although at the time of its publication, there had been eight prospective clinical trials of intraperitoneal therapy, the three from GOG/ Southwest Oncology Group (SWOG) represented the largest, with the strongest treatment effects.5 Concomitant with this latter trial’s publication came a National Cancer Institute (NCI) clinical announcement on January 4, 2006, stating that intraperitoneal therapy was “encouraged…after surgery, for women with advanced ovarian cancer.” However, long before this landmark publication and rare NCI media release, presentations and debates at national and international conferences discussing the implications of each of these three studies (GOG-104/SWOG8501, GOG-114, and GOG-172) had already tainted the touted benefit as bittersweet, citing excessive toxicity of the regimen, poorer patient-reported outcomes, catheter complications, and physician and patient inconvenience among the oncology community.6,7 Dr. Coleman is Professor and Deputy Chair, Ann Rife Cox Professor in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston.

Intraperitoneal Chemotherapy continued from page 27

no significant or excessive toxicities. Lastly, the ability to better select patients who are more likely to complete [intraperitoneal] therapy with better outcomes and less toxicity warrants

It was noteworthy, and in some respects affirming, that the NCI announcement did not endorse a specific intraperitoneal regimen, despite heralding the results of GOG-172. This is likely due to the unique designs, endpoints, and findings of the three trials, not the least of which was that each evaluated a different intraperitoneal experimental arm. Since GOG-114 and GOG-172 compared intraperitoneal therapy with a common intravenous regimen (24-hour paclitaxel on day 1 followed by cisplatin on day 2) in a relatively contemporary ovarian cancer population, Tewari and colleagues combined the data sets and performed a long-term follow-up analysis. As expected in this setting, the

GOG-172, only 58%, 71%, and 42% of intraperitoneal patients, respectively, received all six cycles of intended therapy via that route. Although these data were/are alarming for any modality in front-line therapy, they grossly underestimated the difficulty of extrapolation to a broader medical community, particularly those outside the experienced investigators, nurses, and support staff of the cooperative group sites. Thus, it is not surprising that many clinicians considering intraperitoneal therapy as a practice standard never embraced the data and that some brave enough to try experienced significant challenges—particularly in adoption of GOG-172’s multiday/weekly strategy.

Continuous interrogation into the biology of ovarian cancer and its microenvironment may hold new avenues of clinical investigation for intraperitoneal treatment. —Robert L. Coleman, MD

combined analysis (now with 10-year follow-up) of two individually “positive” trials was a “positive” evaluation—notably, there was an impressive 23% adjusted reduced risk of death for patients treated with intraperitoneal vs intravenous therapy. This amounted to an approximate 10.4-month survival advantage at the median between the two modalities of delivery. Few trials before or since have documented this kind of impact among this patient cohort. Progression-free survival was similarly and consistently “positive” in this analysis. However, one of the acknowledged difficulties with intraperitoneal therapy is inconsistent delivery success throughout the intent-to-treat interval after surgery. In GOG-104, GOG-114, and

further investigation as we move toward individualizing therapies.

John K. Chan, MD, of California Pacific/Palo Alto Medical Foundation/ Sutter Research Institute, San Francisco, is the corresponding author for the

Criticisms Temper Clinical Adoption One of the many criticisms of the “trifecta” was choice of the control arm in each of the studies. GOG-104, published the same year as GOG-111, which introduced paclitaxel in the frontline setting to poorer-prognosis patients, lacked this new agent. GOG-114 and GOG-172 used 24-hour infusion of paclitaxel and cisplatin (day 2). However, data from GOG-158, featuring paclitaxel (3-hour infusion) with carboplatin (area under the curve = 7.5) compared with the same intravenous control arm used in GOG-172, were already known and a community standard. In addition, cross-trial evaluation (albeit statistically invalid) of the control arm in GOG-172 vs the experimental

Journal of Clinical Oncology article. n Disclosure: The study was supported by National Cancer Institute grants, a Gynecologic Oncology Group Young Investigator Award, and the John A. Kerner Denise & Prentis Cobb Hale Research Award. For full disclosures of the study authors, visit jco.ascopubs.org.

arm in GOG-158 implied “underperformance” of GOG-172’s control arm. Furthermore, at the time of GOG-172’s publication, intense interest was focused on bevacizumab (Avastin), which was serving in experimental arms of new GOG and international front-line phase III trials.8,9 This, along with an extremely provocative dose-dense, dose-intense intravenous paclitaxel phase III study by the Japanese GOG demonstrating similar efficacy results on overall survival, tempered clinical adoption of intraperitoneal therapy.10

New Light on Its Potential Nevertheless, a series of reports like the current article by Tewari et al have cast new light on the potential for intraperitoneal therapy. First is the significant improvement in surgical standards for primary cytoreduction. At the time of initial reports on intraperitoneal therapy, the rate of complete surgical cytoreduction (R0) was 10% to 25%; R0 rates have now doubled, largely due to more aggressive surgery and advanced surgical training, globally, of gynecologic oncologists.11 Several reports, including the Tewari et al analysis, have suggested that the R0 cohort represents the subgroup most likely to benefit from intraperitoneal therapy. Second, improvements in supportive care and alterations in the dosing/infusion schedules of the agents have dramatically improved the proportion of patients completing all six cycles of intended intraperitoneal chemotherapy.12 Although it remains a risk that alterations in dosing/schedule could impact survival efficacy, this may be countered by the ability to complete all therapy via intraperitoneal administration. Third, understanding genomic alterations in the tumor may further clarify who should be given intraperitoneal therapy. Recently, an analysis of somatic loss of BRCA1 in patients participating in GOG-172 demonstrated a profound effect on overall survival.13 In this analysis of 393 patients (94% of GOG-172 par-

Reference 1. Tewari D, Java JJ, Salani R, et al: Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer. J Clin Oncol 33:1460-1466, 2015.

ASCOPost.com | JUNE 10, 2015

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Perspective

ticipants), somatic loss of BRCA1 was observed in 48%. Among this cohort, the median overall survival for intraperitoneal vs intravenous therapy was 84 vs 47 months (P = .0002), amounting to a 33% reduction in the hazard for death. There was no difference between intraperitoneal and intravenous therapy among patients with normal expression of BRCA1. Finally, histology may be important, as patients with serous cancer, the most prevalent subtype, appeared to benefit from intraperitoneal therapy, but only if six cycles could be administered.

Looking Ahead The future of intraperitoneal therapy will likely undergo another transition, as the results of the GOG-252 (clinicaltrials.gov, NCT00951496), iPocc (NCT01506856), and NCICOV21 (NCT00993655) trials become available. In GOG-252, two different intraperitoneal infusion strategies are being evaluated in combination with bevacizumab against a contemporary control arm (paclitaxel, carboplatin, bevacizumab followed by bevacizumab maintenance). The Japanese iPocc trial is comparing the same dose-dense, doseintense paclitaxel intravenous arm as in its previous trial vs intraperitoneal carboplatin (same intravenous and intraperitoneal doses) but is allowing both optimal and suboptimal surgical cytoreduction patients to participate. NCIC-OV21 is focusing exclusively on the neoadjuvant chemotherapy population, administering intravenous or one of two intraperitoneal regimens following interval debulking surgery planned after three to four induction cycles of intravenous platinum-based therapy. Although each of these trials has the potential to solidify and/or broaden the potential audience for intraperitoneal therapy, they may also define it as a relic of early ovarian cancer clinical therapy. Nevertheless, continuous interrogation into the biology of ovarian cancer and its microenvironment may hold new avenues of clinical investigation for intraperitoneal treatment. n

Disclosure: See online version on ASCOPost.com for Dr. Coleman’s disclosure information.

References 1. Tewari D, Java JJ, Salani R, et al: Longterm survival advantage and prognostic factors associated with intraperitoneal che-

motherapy treatment in advanced ovarian cancer. J Clin Oncol 33:1460-1466, 2015. 2. Alberts DS, Liu PY, Hannigan EV, et al: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335:1950-1955, 1996. 3. Markman M, Bundy BN, Alberts DS, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma. J Clin Oncol 19:1001-1007, 2001. 4. Armstrong DK, Bundy B, Wenzel L, et al: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354:34-43, 2006. 5. Hess LM, Benham-Hutchins M, Herzog TJ, et al: A meta-analysis of the efficacy of intraperitoneal cisplatin for the front-line treatment of ovarian cancer. Int J Gynecol Cancer 17:561-570, 2007. 6. McGuire WP: Intraperitoneal therapy for ovarian cancer. J Clin Oncol 19:921923, 2001. 7. Alberts DS, Markman M, Armstrong D, et al: Intraperitoneal therapy for stage III ovarian cancer. J Clin Oncol 20:3944-3946, 2002. 8. Burger RA, Brady MF, Bookman MA, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473-2483, 2011. 9. Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:2484-2496, 2011. 10. Katsumata N, Yasuda M, Takahashi F, et al: Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer. Lancet 374:1331-1338, 2009. 11. Chi DS, Eisenhauer EL, Lang J, et al: What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol 103:559-564, 2006. 12. Skaznik-Wikiel ME, Lesnock JL, McBee WC, et al: Intraperitoneal chemotherapy for recurrent epithelial ovarian cancer is feasible with high completion rates, low complications, and acceptable patient outcomes. Int J Gynecol Cancer 22:232-237, 2012. 13. 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 108:1231-1237, 2013.

2015 ASPIRE Breast Cancer Research Awards Program Pfizer is proud to announce the Advancing Science through Pfizer – Investigator Research Exchange (ASPIRE) Breast Cancer Research Awards, a competitive, peerreviewed grants program sponsored by Pfizer for investigators in the United States

Call for Research Proposals For complete information on the scope of research, please visit ASPIRE website at www.aspireresearch.org Mission The mission of the ASPIRE Awards is to support clinical research of a Pfizer compound in advanced breast cancer through a competitive grants program to advance knowledge in the treatment and disease management of advanced breast cancer. Awards 2015 ASPIRE Breast Cancer Research Awards program intends to fund three to six clinical studies within scope, for a total of approximately 3 million US dollars. It is open to US investigators. Selection of research proposals will be performed by an independent external review panel of breast cancer experts.

Submissions are due September 8, 2015

www.aspireresearch.org

The ASCO Post | JUNE 10, 2015

PAGE 30

Journal Spotlight Thoracic Oncology

Outcomes of the CUSTOM ‘Basket’ Trial of Molecular Profiling and Targeted Therapy in Advanced Thoracic Malignancies By Matthew Stenger

n the phase II CUSTOM trial reported in the Journal of Clinical Oncology, Ariel Lopez-Chavez, MD, Anish Thomas, MD, and colleagues performed molecular profiling of tumors in patients with advanced non– small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or thymic malignancies and assigned those in any of five actionable mutation groups to matched targeted therapy.1 Enrollment and molecular profiling were rapid, but sufficient numbers of evaluable patients could not be enrolled into most treatment groups due to the low frequency of target mutations. CUSTOM was designed as a “ basket” trial—a novel type of investigation based on the hypothesis that a molecular marker can predict response to a targeted therapy independent of tumor histology. The study may be the first completed basket clinical trial to evaluate targeted agents against specific molecular aberrations simultaneously across different histologic subtypes of disease.

Giuseppe Giaccone, MD, PhD

Giuseppe Giaccone, MD, PhD, of Georgetown University and National Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article. Dr. Lopez-Chavez, of Oregon Health and Science University, and Dr. Thomas, of the National Cancer Institute, contributed equally to the article.

Study Details In the study, 647 patients with advanced thoracic malignancy underwent molecular profiling for oncogenic drivers. The population consisted of 481 pa-

tients with NSCLC (74%), 68 (10.5%) with SCLC, and 98 (15.2%) with thymic malignancy. Enrollment required only 20 months (February 2011 to December 2012). Molecular profiling was successful in 569 (88%). Patients were assigned to standardof-care therapies or one of five biomarker-matched treatment groups: erlotinib for EGFR mutations; the MEK inhibitor selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; the AKT inhibitor MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib (Tykerb) for ERBB2 mutation or amplification; and sunitinib for KIT or PDGFRA mutation or amplification. It had been planned to generate up to 15 treatment groups by dividing the 5 biomarker-matched groups according to tumor type (NSCLC, SCLC, thymic malignancy). The primary endpoint of each treatment group was a response rate of 40%. Among those with successful profiling, the prespecified mutations were found in 257, with 23 having multiple abnormalities; 313 were wild-type or unknown for the mutations of interest. Of the patients with mutations, 212 were considered screen failures and not enrolled in targeted treatment groups. Previous use of erlotinib and the early closure of the selumetinib arm accounted for 68% of all screen failures. A total of 602 patients received standardof-care therapy or were enrolled in other clinical trials and were followed until death.

Frequency of Mutations and Response to Treatment Completion of accrual to 13 of the proposed 15 treatment groups was considered unfeasible due to low frequencies of target mutations overall or among SCLC and thymic malignancy subgroups. EGFR mutations were detected in 88 (22.1%) of 398 patients with NSCLC, 1 (2%) of 51 patients with SCLC, and 1 (1.1%) of 92 patients with thymic malignancy. A total of 16 evaluable patients were allocated to

Innovative ‘Basket’ Trial ■■ The trial design allowed rapid enrollment and molecular profiling. ■■ The design was not feasible for evaluation of targeted therapy for rare mutations.

erlotinib treatment, consisting of 15 with NSCLC and 1 with thymic malignancy. Response was observed in 9 (60%) of 15 with NSCLC, with no response seen in the patient with thymic malignancy. KRAS mutations were detected in 91 (24.9%) of 366 patients with

of 38 with SCLC, and 4 (4.7%) of 85 patients with thymic malignancy. PDGFRA mutations were found in 1 (1.2%) of 85 patients with thymic malignancy and in none of 103 NSCLC patients or 23 SCLC patients. PDGFRA amplifications were found in 5 (12.8%) of 39 NSCLC patients and in none of 3

[A]lthough it was feasible to enroll a large number of patients and perform molecular profiling analyses at a high success rate in an innovative basket trial, the CUSTOM design seems to be unfeasible in its current form given the rarity of the selected genetic abnormalities in the populations under study. —Ariel Lopez-Chavez, MD (top), Anish Thomas, MD (bottom), and colleagues

NSCLC and 2 (4.1%) of 49 with SCLC. In nine evaluable patients with NSCLC, response was observed in one patient (11%). No response was seen in one evaluable patient with SCLC. ERBB2 mutation was detected in 8 (2.8%) of 284 patients with NSCLC and none of 40 patients with SCLC or 85 with thymic malignancy. Of seven evaluable patients who received lapatinib, consisting of six with NSCLC and one with SCLC, none had objective response. PIK3CA mutations were found in 11 (3.9%) of 285 patients with NSCLC, 4 (8.5%) of 47 with SCLC, and 2 (2.4%) of 85 patients with thymic malignancy. PIK3CA amplification was found in 2 (11.1%) of 18 patients with NSCLC. Mutations in AKT1 were found in 1 (0.4%) of 283 NSCLC patients and 1 (2.2%) of 45 with SCLC. PTEN mutations were found in 8 (4.4%) of 181 patients with NSCLC and 2 (9.5%) of 21 with SCLC. Among seven evaluable patients, consisting of four with NSCLC, two with SCLC, and one with thymic malignancy, no responses to MK2206 were observed. KIT mutations were found in none of 269 patients with NSCLC, 1 (2.6%)

SCLC patients or 7 thymic malignancy patients. Among three evaluable patients, consisting of two with NSCLC and one with thymic malignancy, no responses to sunitinib were observed. Among other genetic abnormalities, rearrangements in ALK were found in 29 (8.7%) of 335 patients with NSCLC and in none of 19 SCLC patients or 86 with thymic malignancy.

Survival in NSCLC by Molecular Group Survival differences according to molecularly defined subgroups were observed among patients with NSCLC: patients with EGFR mutations had a median survival of 3.51 years, followed by 2.94 years in those with ALK rearrangements, 2.3 years in those with KRAS mutations, 2.17 years in those with other genetic abnormalities, and 1.85 years in those with no actionable mutation. The investigators concluded: “This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.” They noted: “[A]lthough it was feasible to enroll a large number of patients continued on page 31

ASCOPost.com | JUNE 10, 2015

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Perspective

The Basket Trial: An Evolving Clinical Trial Design By Amanda J. Redig, MD, PhD, and Pasi A. Jänne, MD, PhD

he recently published results of the CUSTOM (Molecular Profiling and Targeted Therapies in Advanced Thoracic Malignancies) trial, reviewed in this issue of The ASCO Post, describe a basket trial focused on identifying molecular biomarkers in advanced non–small cell lung cancer (NSCLC), small cell lung cancer, and thymic malignancies, followed by evaluation of five targeted therapies in patients grouped by molecular markers and tumor histology.1,2 The five targeted therapies included erlotinib (Tarceva; EGFR mutations); the MEK inhibitor selumetinib (KRAS, HRAS, NRAS, or BRAF mutations); MK2206, an AKT inhibitor (PIK3CA, AKT1, PTEN mutations); lapatinib (Tykerb; HER2 mutations); and sunitinib (Sutent; KIT, PDGFRA mutations). The initial study goal was to evaluate each treatment in each of 3 histology subtypes, for a total of 15 study arms. However, as the authors noted in the final publication, they were only able to complete accrual for 2 of the 15 available arms (erlotinib in NSCLC and selumetinib in NSCLC). Basket trials are an emerging form of clinical trial design and represent a novel way of combining traditional clinical trial methodology with emerging data from the genomic era of medicine. Historically, oncology patients have been treated with a primary focus on a tumor’s tissue of origin and histopathology: This categorization is reflected in the clinical classification of modern oncology, with separate departments, journals, and academic meetings focused on the biology and treatment strategies for a group of cancers defined by anatomic location. However, advances in Dr. Redig is a Clinical Fellow in Medicine at Dana-Farber Cancer Institute, Boston, Massachusetts. Dr. Jänne is Professor of Medicine, Harvard Medical School, DanaFarber Cancer Institute.

CUSTOM ‘Basket’ Trial continued from page 30

and perform molecular profiling analyses at a high success rate in an innovative basket trial, the CUSTOM design seems to be unfeasible in its current form given the rarity of the selected genetic abnormalities in the populations under study.

The molecular alterations that define a tumor may be as relevant, if not more so, than the histopathology that would historically have been used to classify a tumor and direct therapeutic options. —Amanda J. Redig, MD, PhD (top), and Pasi A. Jänne, MD, PhD (bottom)

both technology and molecular biology have begun to challenge the elements of this paradigm.

From Histopathology to Molecular Alterations Some 15 years after the first reports of groundbreaking efficacy in matching a targeted therapy to a defining molecular alteration in the context of the bcr-abl driver of chronic myeloid leukemia,3 the number of targetable molecular alterations and targeted therapies has expanded dramatically. In this setting, the molecular alterations that define a tumor may be as relevant, if not more so, than the histopathology that would historically have been used to classify a tumor and direct therapeutic options. In some cases, two tumors from different anatomic locations may share more in common with each other—based upon genetic vulnerabilities to targeted therapies—than either tumor does to paired tumors from the same tissue of origin but lacking the shared driver mutation. As next-generation sequencing has become more and more integrated into research practices and clinical decision-making within oncology— New basket trial designs should consider including a larger number of institutions and an adaptive design to successfully conduct such studies.” n Disclosure: The study was supported by the Cancer Therapy Evaluation Program at the National Cancer Institute under a collaborative research and development

particularly within thoracic oncology, as seen in CUSTOM—a logical next step in the emerging clinical trial design is to pair targeted therapies with a targetable mutation, irrespective of cancer diagnosis. In CUSTOM, targeted therapies and actionable mutations were identified prospectively, but socalled basket trials may also function in reverse, with initial use of a targeted therapy in an unselected population and use of next-generation sequencing in patients who respond to identify putative genetic biomarkers for further prospective analysis. Perhaps most central, a basket trial approach represents a hypothesis-driven mechanism of combining precision medicine with clinical trial design, a strategy that may be of particular relevance for mutations that are not uncommon within cancer globally but may be prohibitively rare for study within a single disease center. In recognition of the value of a basket trial approach, in 2015, the National Cancer Institute will launch the NCIMATCH trial (Molecular Analysis for Therapy Choice), with plans to screen up to 3,000 patients with enrollment of at least 1,000 individuals to a targeted agreement with the study drug manufacturers AstraZeneca (selumetinib), Genentech/OSI Pharmaceuticals (erlotinib), GlaxoSmithKline (lapatinib), and Merck (MK2206). Funding for the companion research study Personalized Cancer Medicine Registry was provided by Novartis. For full disclosures of the study authors, visit jco.ascopubs.org.

drug combination, independent of tumor histology.4 Similarly the NCIIMPACT trial (Molecular ProfilingBased Assignment of Cancer Therapy) will randomize patients with a known mutation in a specific genetic pathway to either pathway-driven targeted therapies or a treatment not known to be pathway-specific (ClinicalTrials.gov identifier NCT01827384).

Strengths and Challenges Results of the CUSTOM trial reveal key strengths of the basket trial design as well as some challenges. It is notable that a basket trial strategy can be used not only to validate a clinical target but also to identify a favorable response to targeted therapy in a small number of patients. However, at the same time, CUSTOM was unable to complete accrual to 13 of 15 planned study arms, and one of the arms that did complete accrual (selumetinib in NSCLC) did not achieve its primary endpoint. As with any clinical trial approach, rigorous evaluation of preclinical data when designing a basket study will continue to be of central importance. Notably, the one arm of CUSTOM that did complete accrual and reach its primary endpoint was using a therapeutic agent (erlotinib) for which clear evidence of clinical efficacy (in EGFRmutant NSCLC) was already apparent. In addition, some studies suggest that inhibition of MAPK signaling in tumors with KRAS mutations may depend upon the genomic landscape of the tumor, specifically the presence or absence of key tumor suppressors.5 Furthermore, previously published studies demonstrate efficacy for combined MEK inhibition and chemotherapy, not the MEK inhibition as monotherapy used in CUSTOM.6 Moving forward, basket trials will continue to provide a valuable way to link the emerging genomic landscape of precision medicine with the continued on page 36

Reference 1. Lopez-Chavez A, Thomas A, Rajan A, et al: Molecular profiling and targeted therapy for advanced thoracic malignancies: A biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol 33:1000-1007, 2015.

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM). REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials NOW FOR NEWLY DIAGNOSED MULTIPLE MYELOMA

SHAPE PROGRESSION-FREE SURVIVAL WITH CONTINUOUS TREATMENT Continuous REVLIMID + dex until progression showed a PFS and OS benefit in patients with newly diagnosed multiple myeloma vs MPT

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. • Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. REVLIMID is available only through a restricted distribution program called the REVLIMID REMS® program (formerly known as the “RevAssist® program”). HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia. • For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. VENOUS AND ARTERIAL THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving REVLIMID with dexamethasone. Anti-thrombotic prophylaxis is recommended.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®. Please see additional Important Safety Information and Brief Summary, including Boxed WARNINGS, on the following pages. Learn more at www.REVLIMID.com

Median Progression-Free Survival (PFS) Rd Continuous (n=535) 25.5 mo (95% CI 20.7, 29.4) Rd18 (n=541) 20.7 mo (95% CI 19.4, 22.0) MPT (n=547) 21.2 mo (95% CI 19.3, 23.2)

100

Survival Probability (%)

80 Rd Continuous vs MPT Rd Continuous vs Rd18 Rd18 vs MPT

Logrank P value (2-sided) HR (95% CI) 0.72 (0.61, 0.85) P<0.0001 0.70 (0.60, 0.82) 1.03 (0.89, 1.20)

Planned duration of treatment in the Rd18 40 and MPT arms was 18 months 20

Progression-Free Survival (Years) •535 PFS Rd Continuous Rd18 541 MPT MM-020 547 Study design: The

Events: (52.0%), (64.3%), MPT=334/547 400Rd Continuous=278/535 319 265 218 Rd18=348/541 168 105 55 19 (61.1%)2 391 380 (FIRST)

319 265 167 304 244 compared REVLIMID170+

108 116 low-dose

56 30 58 28 (Rd) dexamethasone

7 2 6 1 Continuous until

0 0 0 progression,

trial fixed-cycle MPT, and fixed-cycle Rd18. MM-020 was a Phase 3, randomized, multicenter, open-label, 3-arm study enrolling 1623 newly diagnosed Number of Subjects at mg Risk patients who did not receive a stem cell transplant (SCT). REVLIMID was given 25 once daily orally on Days 1 to 21 of 28-day cycles, PFS Events: Rd Continuous=278/535 (52.0%), Rd18=348/541 (64.3%), MPT=334/547 (61.1%) ≤75 years and 20 mg for patients and dex was dosed once daily orally on Days 1, 8, 15, and 22 of each 28-day cycle (40 mg for patients >75 years). The primary endpoint in the trial was progression-free survival (PFS), as the time from randomization to the first documentation of disease progression as determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd Continuous and MPT arms.

58.9 months median overall survival (OS) with Rd Continuous until progression in an interim analysis, compared with 48.5 months with MPT (HR 0.75 [95% CI 0.62, 0.90]) and 56.7 months with Rd18 (HR 0.91 [95% CI 0.75, 1.09]) • At median follow-up of 45.5 months, only 78% of prespecified events had occurred (697/896 of the final OS events) • OS is defined as the time from randomization to death from any cause ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75% Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, StevensJohnson syndrome, toxic epidermal necrolysis) to lenalidomide

Treatment is a science. Patient care is your art.

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM) REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS® program (formerly known as the “RevAssist®” program). Information about the REVLIMID REMS® program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in offspring of female monkeys who received drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID REVLIMID REMS® Program Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS® program (formerly known as the “RevAssist®” program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS®

program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436 Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and PE (3.7%) occurred in patients with MM after at least one prior therapy, treated with REVLIMID/dex compared to placebo/dex (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In NDMM study, in which nearly all patients received antithrombotic prophylaxis, DVT (3.6%) and PE (3.8%) were reported in the Rd continuous arm. Myocardial infarction (MI, 1.7%) and stroke (CVA, 2.3%) are increased in patients with MM after at least 1 prior therapy who were treated with REVLIMID/dex therapy compared with placebo/dex (0.6%, and 0.9%) in clinical trials. In NDMM study, MI (including acute) was reported (2.3%) in the Rd Continuous arm. Frequency of serious adverse reactions of CVA was (0.8%) in the Rd Continuous arm. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events occurred in patients with refractory and relapsed MM who were treated with REVLIMID/dex compared to 8.3% thrombosis in the placebo/dex group. Median time to first thrombosis event was 2.8 months. In NDMM study, which nearly all patients received antithrombotic prophylaxis, overall frequency of thrombotic events was 17.4% in combined Rd Continuous and Rd18 arms. Median time to first thrombosis event was 4.37 months. Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision. See Boxed WARNINGS Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41] consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID

WARNINGS AND PRECAUTIONS (continued) treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials Second Primary Malignancies: In clinical trials in patients with MM receiving REVLIMID, an increase of invasive second primary malignancies (SPM) notably AML and MDS have been observed. The increase of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (5.3%) or immediately following high dose intravenous melphalan and ASCT (up to 5.2%). The frequency of AML and MDS cases in the REVLIMID/dex arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received REVLIMID in the post-ASCT setting. Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and risk of second primary malignancies when considering treatment Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID in combination with dex. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken Tumor Flare Reaction: Tumor flare reaction (TFR) has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash.

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are autologous stem cell transplant (ASCT) candidates, referral to a transplant center should occur early in treatment to optimize timing of the stem cell collection ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75%

Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous • After at least one prior therapy most adverse reactions and Grade 3 or 4 adverse reactions were more frequent in MM patients who received the combination of REVLIMID/dex compared to placebo/dex. Grade 3 or 4 adverse reactions included neutropenia 33.4% vs 3.4%, febrile neutropenia 2.3% vs 0%, DVT 8.2% vs 3.4% and PE 4% vs 0.9% respectively Adverse reactions reported in ≥15% of MM patients (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%) DRUG INTERACTIONS Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436 Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother Pediatric Use: Safety and effectiveness in patients below the age of 18 have not been established Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the following pages.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®.

The ASCO Post | JUNE 10, 2015

PAGE 36

Perspective

Amanda J. Redig, MD, PhD Pasi A. Jänne, MD, PhD continued from page 31

emerging toolbox of targeted therapeutic strategies. As next-generation sequencing technology and drug development strategies continue to de-

velop, basket trials will likely become more nuanced, with randomization to trial arms driven by the presence or absence of modifying mutations in addition to a known driver mutation. However, established standards of clinical trial design will continue to apply in

References 1. Lopez-Chavez A, Thomas A, Rajan A, et al: Molecular profiling and targeted therapy for advanced thoracic malignancies: A biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol 33:1000-1007, 2015.

the genomic era. As with any other approach to translational medicine, the success of the basket trial strategy is linked to both scientific preclinical development and rigorous trial design. n Disclosure: Dr. Redig reported no potential conflicts of interest. T:7”

REVLIMID [lenalidomide] capsules, for oral use

Table 1: Dose Adjustments for Hematologic Toxicities for MM

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

Platelet counts

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2). Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)].

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM). 1.4 Limitations of Use: REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)]. 2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed. 2.1 Multiple Myeloma Multiple Myeloma The recommended starting dose of REVLIMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients > 75 years old, the starting dose of dexamethasone may be reduced. Treatment should be continued until disease progression or unacceptable toxicity. In patients who are not eligible for autologous stem cell transplantation (ASCT), treatment should continue until disease progression or unacceptable toxicity. For patients who are ASCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a REVLIMID-containing therapy [see Warnings and Precautions (5.11)]. Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID.

When Platelets

Recommended Course

Fall to <30,000/mcL

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Return to ≥30,000/mcL For each subsequent drop <30,000/mcL Return to ≥30,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Absolute Neutrophil counts (ANC) Neutropenia in MM When Neutrophils

Recommended Course

Fall to <1000/mcL Return to ≥1,000/mcL and neutropenia is the only toxicity

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at 25 mg daily or initial starting dose

Return to ≥1,000/mcL and if other toxicity

Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

For each subsequent drop <1,000/mcL Return to ≥1,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Other Toxicities in MM For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MM: [See Dosage and Administration (2.4)]. 2.4 Starting Dose for Renal Impairment in MM Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. The recommendations for initial starting doses for patients with MM are as follows: Table 3: Starting Dose Adjustments for Patients with Renal Impairment in MM Category

Renal Function (Cockcroft-Gault)

Dose in MM

Moderate Renal Impairment

CLcr 30-50 mL/min

10 mg Every 24 hours

Severe Renal Impairment

CLcr < 30 mL/min (not requiring dialysis)

15 mg Every 48 hours

End Stage Renal Disease

CLcr < 30 mL/min (requiring dialysis)

5 mg Once daily. On dialysis days, administer the dose following dialysis.

Moderate renal impairment for MM: Consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity. After initiation of REVLIMID therapy, subsequent REVLIMID dose increase or decrease is based on individual patient treatment tolerance, as described elsewhere [See Dosage and Administration (2.1-2.3)]. 4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)].

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Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions (5.4)].

Thrombocytopenia in MM

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Perspective

2. Redig AJ, Jänne PA: Basket trials and the evolution of clinical trial design in an era of genomic medicine. J Clin Oncol 33:975-977, 2015. 3. Druker BJ, Sawyers CL, Kantarjian H, et al: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the

blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038-1042, 2001. 4. National Cancer Institute: Molecular analysis for therapy choice (NCI-MATCH). Available at http://

d ea i n f o. n c i . n i h . go v / a d v i s o r y / ncab/164_1213/Conley.pdf. Accessed April 13, 2015. 5. Chen Z, Cheng K, Walton Z, et al: A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature

483:613-617, 2012. 6. Jänne PA, Shaw AT, Pereira JR, et al: Selumetinib plus docetaxel for KRAS-mutant advanced nonsmall-cell lung cancer: A randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14:38-47, 2013.

T:7”

4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.8)].

5.2 REVLIMID REMS™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements. Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking REVLIMID should have their complete blood counts assessed periodically as described below [see Dosage and Administration (2.1, 2.2, 2.3)]. Patients taking REVLIMID in combination with dexamethasone for MM should have their complete blood counts (CBC) assessed every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every

Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days) [see Boxed Warning and Dosage and Administration (2.2)]. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. 5.4 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) [see Boxed Warning and Adverse Reactions (6.1)]. Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction (including acute) was reported as a serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse Reactions (6.1)]. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed multiple myeloma who were treated with REVLIMID and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months. In the NDMM study in which nearly all patients received antithrombotic prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The median time to first thrombosis event was 4.37 months in the combined Rd Continuous and Rd18 Arms. Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving REVLIMID [see Drug Interactions (7.2)]. 5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

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5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID.

28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see Dosage and Administration (2.1)].

The ASCO Post | JUNE 10, 2015

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Announcements

Eduardo M. Sotomayor, MD, Named Director of GW Cancer Center

he George Washington University (GW) School of Medicine and Health Sciences (SMHS), the GW University Hospital, and the GW Medical Faculty Associates announced the appointment of Eduardo M. Sotomayor, MD, as the inaugural Director of the GW

Cancer Center (GWCC). He will also serve as a Professor of Medicine. These roles will become effective July 2015. Dr. Sotomayor will serve as Chief Academic and Clinical Leader with responsibility and authority over all aspects of the GWCC. One of Dr.

S otomayor’s top goals will be to develop a roadmap to efficiently deliver personalized medicine at the point of care, and, in the near future, position the GWCC to join the Oncology Research Information Exchange Network, T:7” a unique research partnership of North

5.6 Second Primary Malignancies In clinical trials in patients with multiple myeloma receiving REVLIMID an increase of invasive second primary malignancies notably AML and MDS have been observed. The increase of cases of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (frequency of 5.3%) or immediately following high dose intravenous melphalan and ASCT (frequency of up to 5.2%). The frequency of AML and MDS cases in the REVLIMID / dexamethasone arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received lenalidomide in the post-ASCT setting. Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID. 5.7 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. 5.8 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions.

5.9 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 5.10 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 5.11 Impaired Stem Cell Mobilization A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are ASCT candidates, referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a REVLIMID-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered.

6 ADVERSE REACTIONS The following adverse reactions are described in detail in other sections of the prescribing information: • Embryo-Fetal Toxicity [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Venous and arterial thromboembolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] • Second Primary Malignancies [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Allergic Reactions [see Warnings and Precautions (5.8)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.9)] • Tumor Flare Reactions [see Warnings and Precautions (5.10)] • Impaired Stem Cell Mobilization [see Warnings and Precautions (5.11)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1 Clinical Trials Experience Specific Populations Newly Diagnosed Multiple Myeloma: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7). In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18. In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID were infection events (3.4%). In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous. Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms. Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms* Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541) General disorders and administration site conditions Fatigue%

173 (32.5) 177 (32.8) 154 (28.5) 39 (7.3)

46 (8.5)

31 (5.7)

Asthenia

150 (28.2) 123 (22.8) 124 (22.9) 41 (7.7)

33 (6.1)

32 (5.9)

Pyrexiac

114 (21.4) 102 (18.9) 76 (14.0) 13 (2.4)

7 (1.3)

< 1%

18 (3.3)

8 (1.5)

Non-cardiac chest pain f

29 (5.5)

31 (5.7)

18 (3.3)

<1%

Gastrointestinal disorders Diarrhea

242 (45.5) 208 (38.5) 89 (16.5) 21 (3.9)

Abdominal pain%f 109 (20.5) 78 (14.4) 60 (11.1) Dyspepsia f

57 (10.7)

28 (5.2)

36 (6.7)

7 (1.3)

9 (1.7)

< 1%

<1%

< 1%

0 (0.0) (continued)

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REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.

American cancer centers who collaborate and share information to offer patients novel targeted treatments. “I am proud to welcome Dr. Sotomayor as a member of the Department of Medicine who will advance the clinical, educational, and research mission

ASCOPost.com | JUNE 10, 2015

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Announcements

of the department,” said Alan Wasserman, MD, Chair of the Department of Medicine and President of the GW Medical Faculty Associates. Prior to joining the GWCC, he served as the Scientific Director of the DeBartolo Family Personalized Medicine Institute at Moffitt Cancer Center. He was also SusanT:7”and John Sykes En-

Eduardo M. Sotomayor, MD

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms* All Adverse Reactionsa

dowed Chair of Hematologic Malignancies and Chair of the Department of Malignant Hematology at the Moffitt Cancer Center and Research Institute. In addition, he was Professor in the Department of Oncologic Sciences and the Department of Pathology and Cell Biology at the University of South Florida College of Medicine.

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms*

Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541)

Musculoskeletal and connective tissue disorders

Psychiatric disorders

Back painc

170 ( 32) 145 (26.9) 116 (21.4)

37 (7)

34 (6.3)

28 (5.2)

Muscle spasms f

109 (20.5) 102 (18.9) 61 (11.3)

< 1%

Arthralgia f

101 (19.0) 71 (13.1) 66 (12.2)

9 (1.7)

8 (1.5)

Bone pain f

87 (16.4) 77 (14.3) 62 (11.5) 16 (3.0)

15 (2.8)

14 (2.6)

Pain in extremity f 79 (14.8) 66 (12.2) 61 (11.3)

8 (1.5)

7 (1.3)

Musculoskeletal pain f

67 (12.6) 59 (10.9)

36 (6.7)

< 1%

Musculoskeletal chest pain f

60 (11.3)

51 (9.4)

39 (7.2)

6 (1.1)

< 1%

Muscular weakness f

43 (8.1)

35 (6.5)

29 (5.4)

< 1%

8 (1.5)

< 1%

40 (7.5)

19 (3.5)

10 (1.8)

< 1%

90 (16.9) 59 (10.9)

43 (7.9)

9 (1.7)

6 (1.1)

3 (0.6)

33 (6.1)

0 (0.0)

Neck pain

Infections and infestations Bronchitisc Nasopharyngitis f Urinary tract infection f

80 (15)

54 (10)

76 (14.3) 63 (11.7)

41 (7.6)

8 (1.5)

< 1%

Upper respiratory tract infectionc% f

69 (13.0)

Pneumoniac@

93 (17.5) 87 (16.1) 56 (10.4) 60 (11.3) 57 (10.5) 41 (7.6)

53 (9.8)

31 (5.7)

< 1%

8 (1.5)

< 1%

Respiratory tract infection%

35 (6.6)

25 (4.6)

21 ( 3.9)

7 ( 1.3)

4 ( 0.7)

1 ( 0.2)

Influenza f

33 (6.2)

23 (4.3)

15 (2.8)

< 1%

0 (0.0)

Gastroenteritis f

32 (6.0)

17 (3.1)

13 (2.4)

0 (0.0)

< 1%

29 (5.5)

14 (2.6)

16 (3.0)

10 (1.9)

3 (0.6)

Rhinitis f

29 ( 5.5)

24 ( 4.4) 14 ( 2.6)

0 (0.0)

Cellulitisc

< 5%

8 (1.5)

3 ( 0.6)

2 ( 0.4)

Sepsisc@

33 (6.2)

26-(4.8)

18 (3.3)

26 (4.9)

20 (3.7)

13 (2.4)

Nervous system disorders Headache f

75 (14.1)

52 (9.6)

56 (10.4)

< 1%

Dysgeusia f

39 (7.3)

45 (8.3)

22 (4.1)

< 1%

0 (0.0)

< 1%

Blood and lymphatic system disordersd Anemia

233 (43.8) 193 (35.7) 229 (42.3) 97 (18.2) 85 (15.7) 102 (18.9)

Neutropenia

186 (35.0) 178 (33) 328 (60.6) 148 (27.8) 143 (26.5) 243 (44.9)

Thrombocytopenia 104 (19.5) 100 (18.5) 135 (25.0) 44 (8.3)

43 (8.0)

60 (11.1)

Febrile neutropenia

7 (1.3)

17 (3.1)

15 (2.8)

6 (1.1)

16 (3.0)

14 (2.6)

Pancytopenia

5 (0.9)

6 (1.1)

7 (1.3)

1 (0.2)

3 (0.6)

5 (0.9)

Respiratory, thoracic and mediastinal disorders Cough f

121 (22.7) 94 (17.4) 68 (12.6)

Dyspneac,e

117 (22.0) 89 (16.5) 113 (20.9) 30 (5.6)

< 1%

22 (4.1)

18 (3.3)

Epistaxis f

32 (6.0)

31 (5.7)

17 (3.1)

< 1%

0 (0.0)

Oropharyngeal pain f

30 (5.6)

22 (4.1)

14 (2.6)

0 (0.0)

Dyspnea exertional e

27 (5.1)

29 (5.4)

< 5%

6 (1.1)

2 (0.4)

0 (0.0)

Metabolism and nutrition disorders Decreased appetite

123 (23.1) 115 (21.3) 72 (13.3) 14 (2.6)

7 (1.3)

5 (0.9)

Hypokalemia%

91 ( 17.1) 62 (11.5)

20 (3.7)

11 (2.0)

38 ( 7)

35 (6.6)

Hyperglycemia

62 (11.7)

52 (9.6)

19 (3.5)

28 (5.3)

23 (4.3)

9 (1.7)

Hypocalcemia

57 (10.7) 56 (10.4)

31 (5.7)

23 (4.3)

19 (3.5)

8 (1.5)

Dehydration%

25 ( 4.7)

29 ( 5.4)

17 ( 3.1)

8 (1.5)

13 (2.4)

9 (1.7)

Gout e

< 5%

8 (1.5)

0 (0.0)

Diabetes mellitus% e

< 5%

8 (1.5)

4 (0.7)

2 (0.4)

Hypophosphatemia e

< 5%

7 (1.3)

3 (0.6)

1 (0.2)

Hyponatremia% e

< 5%

7 (1.3)

13 (2.4)

6 (1.1)

139 (26.1) 151 (28.0) 105 (19.4) 39 (7.3)

38 (7.0)

33 (6.1)

Skin and subcutaneous tissue disorders Rash Pruritus f

47 (8.8)

49 (9.1)

24 (4.4)

< 1%

< 1% (continued)

Insomnia

147 (27.6) 127 (23.5) 53 (9.8)

4 (0.8)

6 (1.1)

0 (0.0)

Depression

58 (10.9)

46 (8.5)

30 (5.5)

10 (1.9)

4 (0.7)

1 (0.2)

Deep vein thrombosisc%

55 (10.3)

39 (7.2)

22 (4.1)

30 (5.6)

20 (3.7)

15 (2.8)

Hypotensionc%

51 (9.6)

35 (6.5)

36 (6.7)

11 (2.1)

8 (1.5)

6 (1.1)

Vascular disorders

Injury, Poisoning, and Procedural Complications Fall f

43 (8.1)

25 (4.6)

< 1%

6 (1.1)

Contusion f

33 (6.2)

24 (4.4)

15 (2.8)

< 1%

0 (0.0)

73 (13.7)

31 (5.7)

5 (0.9)

31 (5.8)

14 (2.6)

3 (0.6)

< 5%

7 (1.3)

0 (0.0)

48 (8.9)

11 (2.1)

4 (0.7)

Eye disorders Cataract Cataract subcapsular e Investigations Weight decreased 72 (13.5) 78 (14.4) Cardiac disorders Atrial fibrillationc Myocardial infarction (including acute)c ,e

37 (7.0)

25 (4.6)

13 (2.4)

9 (1.7)

6 (1.1)

< 5%

10 (1.9)

3 (0.6)

5 (0.9)

54 (10.0)

37 (6.8)

28 (5.3)

33 (6.1)

29 (5.4)

Renal and Urinary disorders Renal failure (including acute)c@,f 49 (9.2)

Neoplasms benign, malignant and unspecified (Incl cysts and polyps) Squamous cell carcinomac e

< 5%

8 (1.5)

4 (0.7)

0 (0.0)

Basal cell carcinomac e,f

< 5%

< 1%

0 (0.0)

Note: System organ classes (SOC) and preferred terms (PTs) reflect coding of adverse reactions using MedDRA. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable SOC/PT. a All treatment-emergent adverse reactions in at least 5.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 2.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders SOC were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) *PTs for combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalised, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis

After At Least One Prior Therapy for MM Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients). In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or Cosmos Communications

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Lower respiratory tract infection

“I am humbled and thrilled with my selection as the inaugural director of the GW Cancer Center,” said Dr. Sotomayor. Dr. Sotomayor is widely recognized in the field of lymphoma research and treatment. His primary area of research is immunobiology and immunotherapy of B-cell malignancies. n

The ASCO Post | JUNE 10, 2015

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Announcements

Large Urology Group Practice Association Appoints President-Elect

eal Shore, MD, FACS, of Atlantic Urology Clinics, LLC, was recently appointed President-Elect of the Large Urology Group Practice Association (LUGPA). “I am honored to be appointed to this prestigious position within [the As-

sociation] and look forward to furthering the organization’s goal, ensuring that quality urologic care is available for all patients,” said Dr. Shore. An expert in systemic therapies for patients with advanced urologic cancers, Dr. Shore serves as the National

Urology Research Director for 21st Century Oncology. In this role, he has taught continuing medical education courses with the American Urological Association (AUA), serving as Codirector for five courses through the AssociaT:7” tion’s Office of Education.

Extensive Background Having an extensive clinical research and patient care background, Dr. Shore has held many positions leading to his role as President-Elect of the LUGPA. He is currently on the board of the Society of Urologic Oncology, Urology

without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.

Tables 5, 6, and 7 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.

Metabolism and nutrition disorders Anorexia Hypokalemia Hypocalcemia Appetite Decreased Dehydration Hypomagnesemia Investigations Weight Decreased Eye disorders Blurred vision Vascular disorders Deep vein thrombosis% Hypertension Hypotension

55 (15.6) 48 (13.6) 31 (8.8) 24 (6.8) 23 (6.5) 24 (6.8)

34 (9.7) 21 (6.0) 10 (2.9) 14 (4.0) 15 (4.3) 10 (2.9)

69 (19.5)

52 (14.9)

61 (17.3)

40 (11.4)

33 (9.3) 28 (7.9) 25 (7.1)

15 (4.3) 20 (5.7) 15 (4.3)

Table 6: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups System Organ Class/ Preferred Term REVLIMID/Dex# Placebo/Dex# (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia% 118 (33.4) 12 (3.4) Thrombocytopenia@ 43 (12.2) 22 (6.3) Anemia@ 35 (9.9) 20 (5.7) Leukopenia 14 (4.0) 1 (0.3) Lymphopenia 10 (2.8) 4 (1.1) Febrile Neutropenia% 8 (2.3) 0 (0.0) General disorders and administration site conditions Fatigue 23 (6.5) 17 (4.9) Vascular disorders Deep vein thrombosis% 29 (8.2) 12 (3.4) Infections and infestations Pneumonia@ 30 (8.5) 19 (5.4) Urinary Tract Infection 5 (1.4) 1 (0.3) Metabolism and nutrition disorders Hypokalemia 17 (4.8) 5 (1.4) Hypocalcemia 13 (3.7) 6 (1.7) Hypophosphatemia 9 (2.5) 0 (0.0) Respiratory, thoracic and mediastinal disorders Pulmonary embolism@ 14 (4.0) 3 (0.9) Respiratory Distress@ 4 (1.1) 0 (0.0) Musculoskeletal and connective tissue disorders Muscle weakness 20 (5.7) 10 (2.9) Gastrointestinal disorders Diarrhea@ 11 (3.1) 4 (1.1) Constipation 7 (2.0) 1 (0.3) Nausea@ 6 (1.7) 2 (0.6) Cardiac disorders Atrial fibrillation@ 13 (3.7) 4 (1.1) Tachycardia 6 (1.7) 1 (0.3) Cardiac Failure Congestive@ 5 (1.4) 1 (0.3) Nervous System disorders Syncope 10 (2.8) 3 (0.9) Dizziness 7 (2.0) 3 (0.9) (continued)

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Table 5: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex* Placebo/Dex * (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia % 149 (42.2) 22 (6.3) Anemia@ 111 (31.4) 83 (23.7) Thrombocytopenia@ 76 (21.5) 37 (10.6) Leukopenia 28 (7.9) 4 (1.1) Lymphopenia 19 (5.4) 5 (1.4) General disorders and administration site conditions Fatigue 155 (43.9) 146 (41.7) Pyrexia 97 (27.5) 82 (23.4) Peripheral edema 93 (26.3) 74 (21.1) Chest Pain 29 ( 8.2) 20 (5.7) Lethargy 24 ( 6.8) 8 (2.3) Gastrointestinal disorders Constipation 143 (40.5) 74 (21.1) Diarrhea@ 136 (38.5) 96 (27.4) Nausea@ 92 (26.1) 75 (21.4) Vomiting@ 43 (12.2) 33 (9.4) Abdominal Pain@ 35 (9.9) 22 (6.3) Dry Mouth 25 (7.1) 13 (3.7) Musculoskeletal and connective tissue disorders Muscle cramp 118 (33.4) 74 (21.1) Back pain 91 (25.8) 65 (18.6) Bone Pain 48 (13.6) 39 (11.1) Pain in Limb 42 (11.9) 32 (9.1) Nervous system disorders Dizziness 82 (23.2) 59 (16.9) Tremor 75 (21.2) 26 (7.4) Dysgeusia 54 (15.3) 34 (9.7) Hypoaesthesia 36 (10.2) 25 (7.1) Neuropathyª 23 (6.5) 13 (3.7) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 83 (23.5) 60 (17.1) Nasopharyngitis 62 (17.6) 31 (8.9) Pharyngitis 48 (13.6) 33 (9.4) Bronchitis 40 (11.3) 30 (8.6) Infectionsb and infestations Upper respiratory tract infection 87 (24.6) 55 (15.7) Pneumonia@ 48 (13.6) 29 (8.3) Urinary Tract Infection 30 (8.5) 19 (5.4) Sinusitis 26 (7.4) 16 (4.6) Skin and subcutaneous system disorders Rashc 75 (21.2) 33 (9.4) Sweating Increased 35 (9.9) 25 (7.1) Dry Skin 33 (9.3) 14 (4.0) Pruritus 27 (7.6) 18 (5.1) (continued)

ASCOPost.com | JUNE 10, 2015

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Announcements

Neal Shore, MD, FACS

Times, and Carolina Urologic Research Center, among other urology boards and associations. Dr. Shore received both his bachelor’s degree in public policy sciences and his medical degree from Duke University. He completed his residency at The New York Hospital, Cornell Medical Center T:7” in general surgery,

Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)] Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious

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adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively). Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/ dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively. Other Adverse Reactions: After At Least One Prior Therapy for MM In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported: Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia Cardiac disorders: bradycardia, myocardial infarction, angina pectoris Endocrine disorders: hirsutism Eye disorders: blindness, ocular hypertension Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia General disorders and administration site conditions: malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Nervous system disorders: cerebral ischemia Psychiatric disorders: mood swings, hallucination, loss of libido Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: cough, hoarseness Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation 6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/ cholestatic hepatitis and transient abnormal liver laboratory tests. 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 [see Warnings and Precautions Section (5.7 to 5.10)]. Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended. 7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions. 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID [see Warnings and Precautions (5.4)].

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Table 7: Serious Adverse Reactions Reported in ≥1% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex& Placebo/Dex& (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Febrile Neutropenia% 6 (1.7) 0 (0.0) Vascular disorders Deep vein thrombosis% 26 (7.4) 11 (3.1) Infections and infestations Pneumonia@ 33 (9.3) 21 (6.0) Respiratory, thoracic, and mediastinal disorders Pulmonary embolism@ 13 (3.7) 3 (0.9) Cardiac disorders Atrial fibrillation@ 11 (3.1) 2 (0.6) Cardiac Failure Congestive@ 5 (1.4) 0 (0.0) Nervous system disorders Cerebrovascular accident@ 7 (2.0) 3 (0.9) Gastrointestinal disorders Diarrhea @ 6 (1.7) 2 (0.6) Musculoskeletal and connective tissue disorders Bone Pain 4 (1.1) 0 (0.0) For Tables 5, 6 and 7 above: @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.

where he also served as Chief Resident of Urology. Dr. Shore was a founding board member of the Association in 2008 and was appointed Secretary of the organization in 2014. He will serve as PresidentElect for 2015 and in 2016 will succeed current President Gary M. Kirsh, MD, of The Urology Group in Cincinnati. n

The ASCO Post | JUNE 10, 2015

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Announcements

Institute of Medicine to Become National Academy of Medicine

t its 152nd Annual Meeting on April 28, 2015, the membership of the National Academy of Sciences voted to change the name of the Institute of Medicine to the National Academy of Medicine. The newly named National Academy of Medicine will

continue to be an honorific society and will inherit the more than 1,900 current elected members and foreign associates of the Institute of Medicine. The National Academy of Medicine will join the National Academy of Sciences and National Academy of Engineering

in advising the nation on matters of science, technology, and health. The vote amends the National Academy of Sciences’ constitution to change the name of the Institute of Medicine to the National Academy of Medicine, effective July 1, 2015.T:7” This change is part

7.3 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1).]

NDMM: Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521 /1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all treatment arms, the frequency in most of the AE categories (eg, all AEs, grade 3/4 AEs, serious AEs) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. Grade 3 or 4 AEs in the General Disorders and Administration Site Conditions SOC were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment arms. Grade 3 or 4 TEAEs in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) SOCs were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. For other SOCs (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was a less consistent trend for increased frequency of grade 3/4 AEs in older vs younger subjects across all treatment arms Serious AEs were generally reported at a higher frequency in the older subjects than in the younger subjects across all treatment arms. REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. 8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation.

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Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. 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 adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 91 years of age. After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients.

of a broader internal reorganization to more effectively integrate the work of the National Academies of Sciences, Engineering, and Medicine. Reports and studies on health and medicine will continue uninterrupted as activities of the Institute of Medicine, which will

ASCOPost.com | JUNE 10, 2015

PAGE 43

Announcements

become one of the six program units operating under the direction of the integrated academies.

More Integrated Approach “The establishment of the National Academy of Medicine is a significant milestone in our history,” said National Academy of Sciences President Ralph

J. Cicerone, PhD. “It is an acknowledgment of the importance of medicine and related health sciences to today’s global research enterprise. It will also better align us to take a more integrated, multidisciplinary approach to our work, reflecting how science is best done today.” T:7” engineering, and “Today, science,

Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)]. 8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route. 10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients with MM, MDS, or MCL. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with lenalidomide have not been conducted. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindications (4.1)]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy. • Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. • Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

• All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Physician agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product. Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)]. Venous and Arterial Thromboembolism Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Boxed Warnings and Warning and Precautions (5.4)]. Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)]. Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID [see Warnings and Precautions (5.6)]. Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.7)]. Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens-Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.8)]. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.9)]. Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.10)]. Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water. Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed. Manufactured for:

Celgene Corporation Summit, NJ 07901

REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. Pat. www.celgene.com/therapies ©2005-2015 Celgene Corporation, All Rights Reserved. REV_MM_HCP_BS_v020 02_2015

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The Einstein Memorial Sculpture (copyright Robert Berks, 1978) at the National Academy of Sciences, Washington, DC. Photograph by Alex Jamison, courtesy of National Academy of Sciences.

tackling today’s grand challenges.” “This is indeed a momentous occasion,” said Institute of Medicine President Victor J. Dzau, MD, who will be the first President of the National Academy of Medicine. “This change recognizes the important achievements of medical and health researchers, clinicians, and policymakers in improving health and medicine both nationally and globally. We look forward to expanding our work together with the other academies, and I am confident that this development will enhance our ability to provide evidencebased advice aimed at improving the lives of people everywhere.” The National Academy of Sciences is a private, nonprofit institution that was established under a congressional charter signed by President Abraham Lincoln in 1863. It recognizes achievement in science by election to membership, and—with the National Academy of Engineering, Institute of Medicine, and National Research Council—provides science, technology, and health policy advice to the federal government and other organizations. n T:10”

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

medicine share many common areas of interest in the pursuit of discoveries, advancing knowledge, and solving problems of people and society,” added National Academy of Engineering President C. Daniel Mote Jr, PhD. “Having three national academies under one roof shows the ongoing collaboration among the people who are

NCI’s Commitment to Supporting the Best Science See page 56 in this issue of The ASCO Post for a conversation with D ouglas R. Lowy, MD, Acting Director of the National Cancer Institute. Dr. Lowy succeeds Harold Varmus, MD, who left NCI in March to join the faculty of Weill Cornell Medical College in New York.

The ASCO Post | JUNE 10, 2015

PAGE 44

Issues in Oncology Breast Cancer

First National Data on Breast Cancer Subtypes Mark New Era in Biomarker Epidemiology By Caroline McNeil

his year’s Report to the Nation on the Status of Cancer contains the first national combined data set on the incidence of four major breast cancer subtypes by race/ethnicity, poverty level, geography, and other factors. The findings show that “there are unique racial/ ethnic-specific incidence patterns for breast cancer subtypes, likely because of both biologic and social risk factors, including variation in mammography use,”

The subtype findings are expected to help researchers more accurately stratify breast cancer by clinically relevant degrees of risk and will help patients understand their risk and the link between biomarker status and risk. “It is an important first step, really a step forward,” said Judy Salerno, MD, the CEO of Susan G. Komen for the Cure, which has launched a major effort to address breast cancer disparities.

The SEER program will continue to develop reporting of cancers by these more clinically meaningful categories starting in the coming year. —Lynne Penberthy, MD

the authors concluded. Coauthored each year by the North American Association of Central Cancer Registries, the National Cancer Institute (NCI), the American Cancer Society, and the Centers for Disease Control and Prevention, the report also documents a continuing decline in mortality and incidence for most cancers. It was published online in the Journal of the National Cancer Institute.1 While the subtype findings generally confirmed those of smaller studies, this first gathering of nationwide data on molecular subtypes of a specific cancer is an important landmark, experts say. Covering over 90% of the U.S. population in 42 states and the District of Columbia, it is a first for the surveillance community.

Presentation Precedent “It sets a precedent for the presentation of cancer surveillance data according to important clinical subcategories,” said Lynne Penberthy, MD, Associate Director of the NCI’s Surveillance Research Program. “The SEER program will continue to develop reporting of cancers by these more clinically meaningful categories starting in the coming year,” she said.

“More is needed—to help patients understand therapy options and how they may differ by subtype and to develop a better focus on outcomes by subtype.” Komen is now holding a series of Disparities Roundtables in urban areas around the country. It also funds disparity research and scholarships for young researchers in the field. “This is a national priority,” she said, “and we need to shine a light on it.”

blacks also had the highest rates of distant-stage disease at diagnosis. While the data suggest differences in access to care, said Dr. Penberthy, they don’t explain all the disparities among racial and ethnic groups. For instance, among all those with the triple-negative subtype, non-Hispanic black women had the most poorly differentiated or undifferentiated tumor cells. “This suggests something else may be going on,” she said. The other two subtypes are luminal B (positive for both HR and HER2) and HER2-enriched (negative for HR and positive for HER2). There was little ethnic/racial variation in incidence for these two subtypes.

Streamlined Data Collection Planning is already underway to collect similar data on other cancer subtypes. In lung cancer, a pilot study is now gathering data on the EGFR and ALK markers, Dr. Penberthy said. A bump in lung cancer incidence is expected as more people begin using spiral computed tomography screening, recently approved for Medicare reimbursement. Work is also in progress to improve and streamline the collection process, an effort that NCI’s Surveillance, Epidemiology, and End Results (SEER) program launched several years ago.

Subtype Findings The new data cover the four major breast cancer subtypes, which are based on HER2 and hormone (estrogen and progesterone) receptor status. Luminal A tumors—those positive for hormone receptors (HR) and negative for HER2—carry the lowest risk. This subtype was most common among all racial/ethnic groups but highest for non-Hispanic whites. It declined with increasing poverty for every group and was generally higher in states with higher rates of mammography screening. The triple-negative subtype (negative for both hormones and for HER2), which has the worst prognosis, was most common among non-Hispanic blacks and younger women. Non-Hispanic

Judy Salerno, MD

One vital part of that process is the flow of information from oncology practices, pathology laboratories, and hospitals to state registries. Though mandated by state laws, there are gaps in the process, Dr. Penberthy said. Some cancers are not treated in hospitals, and smaller oncology practices may not know about the mandate or may not have the re-

sources to do the reporting. To facilitate the process, “we are trying to learn how to automate it and to use natural language processing,” she said. The hope is that natural language processing—also known as “text mining”—will allow information to be automatically extracted from pathology reports and sent directly to state registries. If successful, these new methods and technologies will be made available to all registries and will populate data within the SEER public use files. SEER already has an agreement with Genomic Health, the company that performs the molecular diagnostic assay Oncotype DX for early-stage breast cancer, to have its data on test results sent directly to the SEER registries.

More Treatment Data Another long-term goal of NCI’s is to begin collecting more data on treatment. Current reporting, limited to whether or not the patient received one or multiple chemotherapy agents, is not sufficiently robust to help us understand disparities in outcomes, Dr. Penberthy said. Dr. Salerno noted that more data on the use of oral agents, targeted at specific molecular biomarkers, could be especially important because of their cost and the potential for disparities. “We know there is a significant issue with insurance coverage,” she said. A pilot program at NCI, now being developed, will test ways to capture more data on treatment, including chemotherapy, radiation, and oral agents, directly from oncology practices. “This is a big initiative,” Dr. Penberthy said. “I feel very, very strongly that this is something we have to address. It is a huge challenge…. We have to be inventive.” n

Disclosure: Drs. Penberthy and Salerno reported no potential conflicts of interest.

Reference 1. Kohler BA, Sherman RL, Howlader N, et al: Annual report to the nation on the status of cancer, 1975–2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst 107(6):djv048, 2015.

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PAGE 46

Direct From ASCO

New ASCO Journal to Focus on Cancer in Resource-Constrained Countries

nternationally renowned oncologist David Kerr, MD, DSc, will serve as founding Editor-in-Chief of the new ASCO publication, Journal of Global Oncology ( JGO). JGO will be the first journal focused exclusively on cancer research, treatment, and care delivery in middleand low-resource countries with per capita gross national incomes between $1,000 and $12,000.1 The first issue of JGO is scheduled for publication in the fall. The journal will highlight issues in global oncology in six annual issues. The publication will be online only and open access. More than 60% of new annual cases of cancer occur in Africa, Asia, Central America, and South America, regions that account for 70% of the world’s cancer deaths,2 according to the World Health Organization. “This journal will give a voice to oncologists in resource-constrained countries,” said Dr. Kerr. JGO will likely include articles focusing on different countries, including those in sub-Saharan Africa, India, South America, and Southeast Asia. The publication will shed light on the particular issues each country faces regarding cancer care. “We know that there is significant geographic variation in the types of cancer found in different regions of the world,” said Dr. Kerr. “For example, it has been estimated that half of all the world’s cases of liver cancer can be found in China.”

Work Underway JGO has selected an editorial board and issued the first call for submissions in early spring. The articles will cover epidemiology, health policy, barriers to care,

For additional information about JGO, visit GlobalOncologyJournal.org. n References 1. The World Bank: New country classifications. News post, July 2, 2013. Available at data.worldbank.org/news/new-countryclassifications. Accessed March 10, 2015. 2. World Health Organization: Cancer. Fact sheet, February 2015. who.int/mediacentre/factsheets/fs297/en/. Accessed March 10, 2015.

Together, all of us in the wider cancer community have a tremendous opportunity to make a difference. —David Kerr, MD, DSc

cancer treatment, and palliative care. All articles will go through a peerreview process. The editorial team expects numerous submissions, especially from international contributors.

Highly Experienced Editor-in-Chief Dr. Kerr, currently a Professor of Cancer Medicine at the University of Oxford, has published numerous peerreviewed articles on colorectal cancer. His research encompasses drug development, gene therapy, and general medicine. Among his many honors, Dr. Kerr is an Honorary Consultant Medical Oncologist of Oxford University Hospitals NHS Trust, and an Adjunct Professor of Medicine at Weill Cornell Medical College. He is a Fellow of the Royal College of Physicians, the Academy of Medical Sciences, and the European Academy of Cancer Sciences, as well as an Honorary Fellow of the Royal College of General Practitioners. Dr. Kerr is Past President of the European Society of Medical Oncology, and has served on many medical society international committees and working groups. He is the former Editorin-Chief of Annals of Oncology and has served on the editorial boards of Nature Reviews Clinical Oncology, Japanese Journal of Clinical Oncology, Seminars in Oncology, Molecular Oncology, and Chinese Clinical Oncology. A longtime advocate for addressing cancer in resource-constrained countries, Dr. Kerr was among the first to recognize the need for action in Africa. In 2007, he organized the first African Cancer Reform Convention in London. Shortly thereafter, he cofounded the Africa Oxford Cancer Foundation, an organization dedicated to forging partnerships with African countries to assist with implementing cancer prevention and control programs.

“There’s still plenty of juice in the old lemon yet to tackle a new project of this magnitude and importance,” he said. “Together, all of us in the wider cancer community have a tremendous opportunity to make a difference.”

Volume 29, Issue 15

May 20, 2011

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

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg

Originally printed in ASCO Daily News. © American Society of Clinical Oncology. “New ASCO Journal to Focus on Cancer in Resource-Constrained Countries.” ASCO Daily News 18(1), 2015: 4. All rights reserved.

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

What’s Hot in

JCO

Phase III Study of 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 Complete Regression of Metastatic Cervical Cancer After Treatment With Human Papillomavirus–Targeted Tumor-Infiltrating T Cells by Sanja Stevanović, et al

Sequencing and Combining Systemic Therapies for Pancreatic Neuroendocrine Tumors by Matthew H. Kulke

Phase I/II Study of HSP90 Inhibitor AUY922 and Erlotinib for EGFR-Mutant Lung Cancer With Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by Melissa L. Johnson, et al Phase II Study of Gemcitabine, Carboplatin, and Iniparib as Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation–Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105 by Melinda L. Telli, et al SWOG S0925: A Randomized Phase II Study of Androgen Deprivation Combined With Cixutumumab Versus Androgen Deprivation Alone in Patients With New Metastatic HormoneSensitive Prostate Cancer by Evan Y. Yu, et al

ASCOPost.com | JUNE 10, 2015

PAGE 47

Direct From ASCO

ASCO Launches Electronic Practical Tips for the Oncology Practice, 6th Edition

n mid-May, ASCO launched Practical Tips for the Oncology Practice, 6th Edition, a comprehensive resource providing answers to the most commonly asked questions regarding billing, coding, reimbursements, coverage questions, and regulatory policies that affect the day-to-day practice of oncology. Since its establishment as its own medical specialty in the 1960s, the practice of oncology has expanded and changed substantially. The increasing cost of cancer care, concerns about a workforce shortage, and the increasing number of cancer patients call for oncology practices to operate as efficiently and effectively as possible. Practical Tips for the Oncology Practice is a comprehensive, easy-to-use resource for physician practitioners, office managers, and office staff. With up-to-date guidance, it is a convenient informational aid to office managers or staff who are new to the oncology arena or established

Inform Your Patients About Common Cancer Myths

isinformation is everywhere. Direct your patients to visit www.cancer.net/blog to learn what is science fact and what is science fiction in this blog post on nine common cancer myths. Also, order ASCO Answers Fact Sheet—Myths and Facts About Cancer for your practice at www.cancer.net/estore. Shipping is free, and ASCO members save 20%. n © 2015. American Society of Clinical Oncology. All rights reserved.

managers looking for guidance related to common issues faced by modern oncology practices in an ever-changing healthcare landscape.

What’s New The 6th edition of Practical Tips will

be the first published in electronic format only. Updates from the 5th edition include new information on ICD-10, Medicare quality reporting programs, and safe handling guidelines and requirements. Although one of the main focuses

of Practical Tips is providing information about billing, coding, and Medicare regulations, it also delves into the issues of appeals and collection of overpayments. “Appeals can be difficult, stressful, continued on page 49

NOW JOIN US NOW IN REVEAL Prospective Observational Study of Patients with Polycythemia Vera in US Clinical Practices (NCT02252159) The REVEAL study is a multicenter, non-interventional, non-randomized, prospective, observational study in an adult population (patients ≥18 years old) of men and women who have been diagnosed with clinically overt PV.

Patients with PV N=2000

Study start

SCREENING

START OBSERVATION

Usual Care 36 months

DATA COLLECTION

Key Inclusion Criteria

Key Exclusion Criteria

• Age ≥18 years, diagnosis of polycythemia vera (PV) • Willing and able to provide signed informed consent • Under the supervision of US physician

• • • • •

End of study

END OBSERVATION

Participation in a blinded study Life expectancy <6 months Diagnosis of MF, PPV-MF, PET-MF Diagnosis of acute myelocytic leukemia (AML) Diagnosis of Myelodysplastic Syndrome

To join us as an investigative site in REVEAL:

Incyte REVEAL Study Hotline: 1-855-REVEAL-9

RevealPVStudy.com

Info@RevealPVStudy.com

The ASCO Post | JUNE 10, 2015

PAGE 48

Direct From ASCO

Over 30 Organizations, Including ASCO, Call for FDA to Regulate E-Cigarettes

SCO, together with 30 organizations, have sent a letter to President Obama asking for his leadership in giving the U.S. Food and Drug Administration (FDA) the authority to regulate e-cigarettes and other currently unregulated tobacco products. The 2009 Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) gave the FDA immediate authority over cigarettes, smokeless, and roll-your-own tobacco. It also authorized the Secretary of Health and Human Services (HHS) to deem other tobacco products subject to FDA’s jurisdiction. In 2014, the FDA proposed a rule to extend its authority over all unregulated tobacco products, including e-cigarettes, cigars, hookah tobacco, nicotine gels, and dissolvable nicotine products. In response, ASCO and others requested FDA issue its final rule

by April 25, 2015, 1 year from the date the agency issued the proposed rule. Unfortunately, that deadline was not met. Until the regulation is finalized and implemented, there is no federal oversight of these tobacco products. There are no restrictions in place to protect public health against the risks these products pose, particularly to the health of children. ASCO and the other organizations hope this letter will encourage the Obama administration to take swift action in finalizing and implementing these regulations. In the absence of regulation, the organizations have seen irresponsible marketing of unregulated products such as cigars and electronic cigarettes, often using tactics and sweet flavors that clearly appeal to youth. A recent Centers for Disease Control and Prevention report highlights the dramatic

increase in e-cigarette use by minors. Read the full letter at www.asco.org/ sites/www.asco.org/files/4-28-15_ letter_to_president_obama_re_

ASCO’s Community Research Forum Offers Helpful Tools for Community-Based Research Sites

s part of ASCO’s efforts to support research sites and clinical investigators, ASCO’s Community Research Forum (CRF) was created as a solution-oriented venue for community-based research sites. The Forum and its working groups have developed several tools and resources that aim to help researchers and staff conduct and manage clinical trials, including the ASCO Clinical

Trial Workload Assessment Tool and ASCO Research Program Quality Assessment Tool. Visit the Community Research Forum web page at www.asco.org/practiceresearch/community-research-forum for these tools, additional resources, and to learn more about the Forum. n © 2015. American Society of Clinical Oncology. All rights reserved.

Together, we’re taking it down.

While nearly 1 in 2 people will get cancer in their lifetime, 2 in 3 will survive it.* And that’s a profound testament to the progress you’ve helped forge as we work collectively to make it harder for cancer to survive.

Join The Campaign to Conquer Cancer at conquer.org/progress. #ConquerCancer * CancerProgress.Net. Progress & Timeline. Timeline. Major Milestones Against Cancer. Available at: http://cancerprogress.net/timeline/major-milestones-against-cancer. Accessed April 7, 2015.

ASCOPost.com | JUNE 10, 2015

PAGE 49

Direct From ASCO

New ASCO University® Tumor Genomics Program Helps Cancer Care Providers Increase Their Understanding of Next-Generation Sequencing

nnovation in the field of genomic assessment and characterization has rapidly progressed in recent years. As next-generation sequencing increasingly becomes a standard of care, it is vital for cancer care providers to de-

tions for clinical research and patient care. The Tumor Genomics program was created to complement the ASCO University Cancer Genetics Program, which was released in 2014. “The ASCO University Tumor Ge-

The [Tumor Genomics Program] has been designed to help clinical oncology investigators and practitioners efficiently keep on top of the rapidly changing field of tumor genomic characterization. —Stephen M. Keefe, MD

velop a deeper understanding of its research and clinical applications. For busy clinicians, this can be difficult to keep up with—especially as technology quickly evolves. In response to this need, ASCO University® recently introduced a Tumor Genomics Program to its suite of resources. The program is designed to increase knowledge in the area of tumor genomics, particularly regarding somatic genomic alterations that drive tumor progression and have implica-

nomics Program has been designed to help clinical oncology investigators and practitioners efficiently keep on top of the rapidly changing field of tumor genomic characterization,” said Stephen M. Keefe, MD, of the Hospital of the University of Pennsylvania, Lead Planner and faculty member of the ASCO University Tumor Genomics Program. “Developed by experts in the field, the program’s content covers methods and the laboratory environment, as well as the interpretation and the significance of results.”

Practical Tips for the Oncology Practice

easy-to-understand terms to explain the process and describe what a physician practice’s options are, including explanations of the levels of an appeal and what to expect at each level.”

continued from page 47

and time-consuming situations for oncology practices,” said Allison M. Hirschorn, a coding and reimbursement specialist in the clinical affairs department at ASCO. “Practical Tips for the Oncology Practice uses simple,

New Electronic Format The new electronic format of Practical Tips allows for enhanced search

The Tumor Genomics Program, consisting of six slide-based courses accompanied by audio commentary from expert faculty, provides a comprehensive collection of presentations on a number of important topics regarding genomic methods in cancer. Topics covered include next-generation sequencing technologies, the bioinformatics pipeline, applicability and limitations of results reporting, the laboratory environment, and resources available for use in contextualizing findings and moving forward with results. “Oncology is at an interesting crossroads. On one hand, we are witnessing an explosion of genomic data that could be potentially actionable. On the other hand, there is a dearth of tools to guide an oncologist on how to apply this clinically to help chose the ‘right drug for the right patient,’” said Aditya Bardia, MBBS, MPH, of Massachusetts General Hospital Cancer Center and Harvard Medical School. Dr. Bardia serves as a faculty member of the ASCO Molecular Oncology Tumor Boards, as well as an Associate Editor on the ASCO University Editorial Board. “For example, if a tumor has a mutations in X, Y, and Z, should one choose a drug against X, or Y, or Z? How does

one identify driver from passenger mutations? How does one address the issue of tumor heterogeneity? These are some of the issues that we struggle with on a daily basis, so it is great that ASCO University has created this program to address some of these questions,” said Dr. Bardia.

capabilities and enables users to directly access information listed in the publication’s appendices. Users can access Practical Tips as an eBook from e-readers and mobile devices. Users can also download eBook readers for their computers if they want to access the content of Practical Tips from their desktop computers.

The 6th edition of Practical Tips is $275; however, ASCO members receive a 20% discount of this price. To find out more about Practical Tips, visit www.asco.org/policy-advocacy/ practical-tips-oncology-practice. n

Aditya Bardia, MBBS, MPH

The Tumor Genomics Program may be taken for continuing medical education/continuing education credit. For more information, visit university.asco. org/genomicsprogram. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Increase Your Understanding of NextGeneration Sequencing with New ASCO University® Tumor Genomics Program” connection.asco.org. All rights reserved.

Save the Date Best of ASCO® Boston

Best of ASCO® San Francisco

Best of ASCO® Chicago

July 31–August 1, 2015

August 7–8, 2015

August 28–29, 2015

Renaissance Boston Waterfront Hotel

San Francisco Marriott Marquis

Swissotel Chicago

Boston, Massachusetts

San Francisco, California

Chicago, Illinois

The ASCO Post | JUNE 10, 2015

PAGE 50

Announcements

Merck Chairman and CEO Kenneth C. Frazier Becomes PhRMA Board Chairman PhRMA President John J. Castellani to Retire

enneth C. Frazier, JD, Chairman and CEO of Merck & Co., Inc., was elected Chairman of the Board of the Pharmaceutical Re-

Also elected to the Board were George A. Scangos, PhD, CEO of Biogen, as Chairman-Elect of the PhRMA Board of Directors, and Joaquin

Duato, Worldwide Chairman of Pharmaceuticals at Johnson & Johnson, as Board Treasurer. Dr. Scangos was appointed CEO

of Biogen in June 2010. He joined the company from Exelixis, Inc., where he served as President and CEO since October 1996. From 1987 to 1996,

Kenneth C. Frazier, JD

search and Manufacturers of America (PhRMA). Mr. Frazier formerly held the position of Chairman-Elect and succeeds Ian C. Read, Chairman and CEO of Pfizer, Inc.

New Officers Elected to PhRMA Board “Our member companies have never invested more in researching and developing innovative, targeted new medicines to fight life-threatening diseases. Mr. Frazier’s proven leadership ability and deep experience in the biopharmaceutical industry will be incredible assets for our organization and its member companies,” said current PhRMA President and CEO John J. Castellani, who announced that he will be retiring, effective January 1, 2016. Before becoming Chairman and CEO of Merck in 2011, Mr. Frazier served as President of Merck. He previously served as President of Merck Global Human Health from 2007 to 2010 and as General Counsel, overseeing Merck’s legal and public affairs functions, as well as The Merck Foundation, from 1999 to 2007. In addition to his position with PhRMA, Mr. Frazier sits on the boards of Weill Cornell Medical College and Graduate School of Medical Sciences. He received his bachelor’s degree from Pennsylvania State University, and holds a juris doctorate from Harvard Law School. “Our industry is poised to translate our most promising scientific breakthroughs into meaningful treatments capable of tackling the most urgent and vexing medical challenges of our times,” said Mr. Frazier. “We stand committed to driving progress for patients today and hope for tomorrow.”

Learn more about the unmet needs in EGFRm+ NSCLC at targetEGFR.com

ASCOPost.com | JUNE 10, 2015

PAGE 51

Announcements

Dr. Scangos held various positions at Bayer, Inc, including Senior Vice President of Research and Development and President of Bayer Biotechnology. Before joining Bayer in 1987, he was Professor of Biology at Johns Hopkins University. Dr. Scangos received a bachelor’s degree in biology from Cornell University and a doctorate

from the University of Massachusetts. Mr. Duato became Worldwide Chairman of Pharmaceuticals at Johnson & Johnson in January 2011. Mr. Duato joined Johnson & Johnson in 1989 in Janssen-Cilag Spain, and later became Managing Director of JanssenCilag Italy. He then led Ortho Biotech Europe before relocating to the United

States in 2002, as Vice President for the Ortho Biotech Oncology Franchise. He was named President, Ortho Biotech Products, LP, in 2005. A native of Valencia, Spain, Mr. Duato holds an undergraduate degree in economics and two Master’s degrees—one in business administration and one in international management.

We want to change the face of EGFR-targeted therapy Cutaneous toxicities are caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2 Inhibition of wild-type and mutant EGFR in non–small cell lung cancer (NSCLC)

Cutaneous toxicities can be dose-limiting

Normal, or wild-type, EGFR is highly expressed on epithelial cells in the skin, liver, and gastrointestinal tract.3-5 Current EGFR tyrosine kinase inhibitors (TKIs) target not only the oncogenic mutant forms of EGFR, but also wild-type EGFR, which may lead to cutaneous toxicities including rash, stomatitis, and paronychia.1,2,6-8

The symptoms and psychosocial impact of cutaneous toxicities can negatively affect both patient quality of life and patient compliance.11,12 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.7,8

90% of patients treated with approved EGFR TKIs experience rash7,8

The future of EGFR inhibition

The skin is dependent on wild-type EGFR signaling for normal growth and differentiation.1,9,10 Druginduced inhibition of wild-type EGFR disrupts its normal function and can cause cutaneous inflammation and injury. This accounts for the high incidence of cutaneous toxicities associated with EGFR TKIs.1,9

Strategies that eliminate inhibition of wild-type EGFR may be most effective at mitigating cutaneous toxicities and maintaining optimal dosing.9 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

Clovis Oncology is leading the fight

John J. Castellani Announces Retirement Mr. Castellani will step down as President and CEO of PhRMA after successfully leading the Association since September 2010. “On behalf of the PhRMA Board of Directors, I want to thank Mr. Castellani for his steadfast leadership at PhRMA over the past 5 years,” said Mr.

John J. Castellani

Frazier. “He has been a strong advocate on behalf of the biopharmaceutical research industry, and for the millions of patients we serve all around the world. Under his leadership, PhRMA has worked tirelessly to protect and strengthen an environment that fosters the continued development of new lifesaving therapies and to ensure patients can access the medicines they need to live longer, healthier lives.” Mr. Frazier announced that the search for Mr. Castellani’s successor will begin immediately and will be led by the PhRMA Board’s Nominations and Compensation Committee. n

Contact

The ASCO Post

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

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Harandi A et al. Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. J Clin Oncol. 2009;2009:567486. doi:10.1155/2009/567486. 4. Natarajan A et al. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci U S A. 2007;104(43):17081-17086. 5. Tissue atlas: EGFR. The Human Protein Atlas website. http://www.proteinatlas.org /ENSG00000146648-EGFR/tissue. Accessed February 17, 2015. 6. Antonicelli A et al. EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci. 2013;10(3):320-330. 7. Tarceva [package insert]. Northbrook, IL: Astellas Pharma US Inc; 2014. 8. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 9. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803-812. 10. Melosky B et al. Management of common toxicities in metastatic NSCLC related to anti-lung cancer therapies with EGFR–TKIs. Front Oncol. 2014;4:238. doi:10.3389/fonc.2014.00238. 11. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurs. 2011;15(1):88-96. 12. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci .nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed February 2, 2015.

Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

The ASCO Post | JUNE 10, 2015

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Journal Spotlight Dermatologic Oncology

Nivolumab Increases Response Rate vs Chemotherapy in Advanced Melanoma Progressing After Anti–CTLA-4 Treatment By Matthew Stenger

n a phase III trial (CheckMate 037) reported in The Lancet Oncology, Jeffrey S. Weber, MD, PhD, of the Moffitt Cancer Center, and colleagues found that treatment with the PD-1 (programmed cell death protein 1) inhibitor nivolumab (Opdivo) resulted in a significantly greater response rate vs chemotherapy as second- or later-line treatment in patients with advanced melanoma progressing after anti–CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) treatment.1 Findings in this trial supported the accelerated approval of nivolumab in this setting in December 2014.

Study Details In this open-label trial, 405 patients with unresectable or metastatic melanoma from 90 sites in 14 countries were randomized 2:1 between December 2010 and January 2014 to receive nivolumab (n = 272) or chemotherapy (n = 133). Patients had to have progressed after treatment with ipilimumab (Yervoy) or with ipilimumab and a BRAF inhibitor if they were BRAF V600 mutation-positive. Nivolumab was given at 3 mg/kg IV every 2 weeks. Dose delay but not reduction was permitted in nivolumab patients. Investigator’s choice of chemotherapy consisted of dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 combined with carboplatin area under the curve = 6 every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoints of the trial were objective response and overall survival. In the current report of the first interim analysis, objective response was assessed after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks. Among all randomized patients, the nivolumab and chemotherapy groups were generally balanced for age (median 59 and 62 years), sex (65% and 64% male), Eastern Cooperative Oncology Group performance status, stage M1c disease, stage 4 disease, history of brain metastases, elevated LDH, number of prior systemic treatments, previous

treatment other than ipilimumab, PDL1 (programmed death-ligand 1)–positive status, BRAF-mutant disease, and no benefit from prior ipilimumab.

Objective Response Rate Patients received nivolumab for a median of 5.3 months and chemotherapy for a median of 2.0 months. Confirmed objective response was observed in 38 (31.7%, 95% confidence interval [CI] = 23.5%–40.8%) of the first 120 patients in the nivolumab group (including complete response in 4 patients, 3.3%) vs 5 (10.6%, 95% CI = 3.5%–23.1%) of 47 patients in the chemotherapy group. Median duration of response had not been reached (range = 1.4+ to 10.0+ months) in the nivolumab group and was 3.5 months (range = 1.3+ to 3.5) in the chemotherapy group. Median time to response was 2.1 months (range = 1.6–7.4 months) vs 3.5 months (range = 2.1–6.1 months). At the time of analysis, 33 of 38 nivolumab patients (87%) with response had continuing response with-

BRAF–wild-type patients. Response was observed in 30.0% (12/40) vs 13.3% (2/15) of patients with prior anti–CTLA-4 treatment benefit and in 32.5% (26/80) vs 9.4% (3/32) with no benefit. Response was observed in

Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. —Jeffrey S. Weber, MD, PhD, and colleagues

43.6% (24/55) vs 9.1% (2/22) of patients with PD-L1–positive tumors and in 20.3% (13/64) vs 13.0% (3/23) of those with PD-L1–negative tumors. At the time of the first planned assessment of objective response, 182 patients had been randomized. Among these 182 patients, median progressionfree survival was 4.7 months (95% CI = 2.3–6.5 months) vs 4.2 months (95%

First Interim Analysis of Nivolumab for Advanced Melanoma ■■ Response was observed in 32% of nivolumab patients vs 11% of chemotherapy patients, with a median duration of response not reached in the nivolumab group. ■■ Tumor shrinkage was observed in some patients during continuation of nivolumab after disease progression.

out disease progression on treatment. Nivolumab was continued beyond disease progression in 37 patients (31%), with 10 (8%) exhibiting more than 30% reduction in the sum of the longest diameters of target lesions.

Predefined Subgroups In exploratory subgroup analyses, a higher response rate was observed with nivolumab vs chemotherapy irrespective of BRAF-mutation status or previous anti–CTLA-4 treatment benefit. Response was observed in 23.1% (6/26) vs 9.1% (1/11) of BRAF V600 mutation–positive patients and 34.0% (32/94) vs 11.1% (4/36) of

vs 15%); the most frequent adverse events in the chemotherapy group were nausea (37%), fatigue, and alopecia (27%). Grade 3 or 4 treatment-related adverse events occurred in 9% vs 31%

CI = 2.1–6.3 months; hazard ratio = 0.82, 99.99% CI = 0.32–2.05), and 6-month progression-free survival was 48% (95% CI = 38%–56%) vs 34% (95% CI = 18%–51%).

Adverse Events The reported safety analysis included 268 nivolumab patients and 102 chemotherapy patients who received at least one dose of study treatment at the time of objective response analysis. The most frequent treatment-related adverse events of any grade in the nivolumab group were fatigue (25% vs 34% in the chemotherapy group), pruritus (16% vs 2%), and diarrhea (11%

The Promise of Immune Checkpoint Inhibition See Kim Margolin’s discussion on opposing page.

of patients, with the most common in the nivolumab group being increased lipase (1%), elevated alanine transaminase (1%), fatigue (1%), and anemia (1%). The most common grade 3 or 4 treatment-related adverse events in the chemotherapy group were neutropenia (14%), thrombocytopenia (6%), and anemia (5%). Treatment-related serious adverse events occurred in 5% vs 9% of patients. Adverse events led to discontinuation of treatment in 3% vs 7%. No treatmentrelated deaths were observed. The investigators concluded: Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that have progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. n Disclosure: The study was funded by BristolMyers Squibb. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Weber JS, D’Angelo SP, Minor D, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375-384, 2015.

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Perspective

The Promise of Immune Checkpoint Inhibition: Changing the Therapeutic Landscape for Melanoma and Other Malignancies By Kim A. Margolin, MD

he past 3 years have witnessed transformative changes in the way that solid tumors and hematologic malignancies are approached, in almost every instance now including consideration of some form of immunomodulation in the first- or later-line therapeutic setting. The greatest success has occurred with the advent of immune checkpoint–blocking antibodies, starting with anti–CTLA-4 (cytotoxic T-lymphocyte–associated antigen), which has a relatively low patient benefit rate (about 20% long-term disease control in advanced melanoma) and causes dangerous immune-related toxicities in 10% to 15% of patients. Blockade of the programmed death (PD)-1/PD ligand-1 (PDL1) axis between effector T cells and tumor or other cells in the tumor microenvironment has been very promising in single-agent studies in many malignancies, with combination approaches now being investigated. In melanoma, a lower rate of toxicity and a higher clinical benefit rate have been shown with PD-1 blockade in comparison with cytotoxic therapy, as in the report by Weber et al1 summarized in this issue of The ASCO Post, and ipilimumab (Yervoy), as recently reported by Robert et al.2 Although other new immunotherapies such as unmodified antibodies, immunotoxins, bispecific antibodies, and lesional injection of various immunomodulators have also shown activity—and in some cases have already gained regulatory approval—they are beyond the scope of this commentary but may find an important role in combinations or sequences with immune checkpoint blockade.

PD-1/PD-L1 Blockade vs Cytotoxic Chemotherapy Has PD-1 blockade become the new and nontoxic broad-spectrum anticancer agent, supplanting target-nonspecific cytotoxics Dr. Margolin is Professor of Medicine (Oncology) at Stanford University Medical Center, Stanford, California.

like cyclophosphamide, fluorouracil, anthracyclines, taxanes, and platinum agents? The answer is probably yes

and no—but what isB:7.875 clear is that these in agents are still failing to benefit most T:7.625 in patients with malignancy and may still S:6.625 in

cause unpredictable and dangerous immune-mediated toxicities. continued on page 54

CLINICAL EVIDENCE INDICATES...

THERE ARE DISTINCT WAYS TO HELP MANAGE ADVANCED PROSTATE CANCER * INHIBIT ANDROGEN PRODUCTION

BLOCK THE ANDROGEN RECEPTOR

EACH PLAYS AN IMPORTANT ROLE 1-3 Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Schulze H, Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. J Urol. 1990;144(4):934-941. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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Perspective

Kim A. Margolin, MD continued from page 53

Although such toxicities may be outweighed by the clinical benefit among patients with advanced and sometimes treatment-refractory malignancies, the inevitable exploration of immune checkpoint–blocking antibodies in the adjuvant setting may lead to less favorable therapeutic ratios.3 This could occur if the adjuvant therapy is given to large numbers of patients unselected for the yet-to-be defined predictive factors for benefit, or it could be a result of a requirement for an established tumor microenvironment that has been postulated to be critical for the therapeutic action of PD-1/PD-L1 blockade. Although the therapeutic index of these immunotherapies should never be as unfavorable as for any of the cytotoxics listed above, the identification of biomarkers of maximal benefit is still critical (and the therapeutic index can still be unfavorable for selected immunotherapies such as high-dose interleukin-2). The important concept of immunogenic chemotherapy has been studied extensively in preclinical models, but regimen design based on these interactions has not been widely adopted, and it has not yet been incorporated into studies of immune checkpoint blockade.4

PD-1/PD-L1 Blockade vs Targeted Therapies Is it possible that PD-1/PD-L1 axis blockade will reach a level of target specificity similar to that of imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumor, erlotinib for lung cancer carrying selected epidermal growth factor receptor gene mutations, and vemurafenib (Zelboraf) for melanoma with a BRAF-activating mutation? To this question, the answer is more likely no, since the mechanisms of action and of resistance are dramatically different between the molecular drivers and modifiers of tumor cell biology. So too is the immune system/tumor microenvironment, which involves many different cell types and demonstrates heterogeneity and plasticity over time and the local microenvironment. Interestingly, the overlap of molecularly targeted therapies and immunotherapies has been described for BRAF-mutated melanoma5 and to a lesser extent for combinations with

inhibitors of the mediators of tumor angiogenesis.6

Predictors of Benefit How can the activity of PD-1 axis blockade be predicted in order to select therapy for those patients most likely to benefit? Pretreatment factors are far more valuable than on-therapy or post-therapy correlates, although the latter often provide deep insights into mechanisms of action and acquired resistance. However, on-therapy and post-therapy tissue acquisition is also more challenging due to the likelihood of a lower willingness to undergo biopsy and worsened medical condition among patients with

lieved to be the most important physiologic inducer of PD-L1 expression. Other strategies include altering gene expression with epigenetic agents such as demethylating therapy or histone deacetylase inhibitors or adding hypofractionated radiotherapy, which has immunoenhancing properties via multiple mechanisms.8 Combinations designed to overcome immunosuppressive signals in the tumor microenvironment or enhance cellular cytotoxicity by costimulation of effector T cells are not specific to PD-1 blockade but may provide important additive or synergistic effects. They include agonistic antibodies to the costimulatory mol-

The past 3 years have witnessed transformative changes in the way that solid tumors and hematologic malignancies are approached, in almost every instance now including consideration of some form of immunomodulation in the first- or later-line therapeutic setting. —Kim A. Margolin, MD

disease progression and to a paucity of residual tumor among patients responding well to therapy. To date, only the expression of PDL1 on tumor has been recognized to carry predictive value, but even this parameter is fraught with differences in assay techniques and suboptimal positive and negative predictive values. The co-localization at the invasive tumor margin of CD8 T cells expressing PD-1, cells expressing PDL1, and a restricted T-cell receptor gene clonality among the infiltrating CD8 cells has recently demonstrated a strong association with response of melanoma to pembrolizumab (Keytruda)7; many other factors remain under investigation and are likely to differ among tumor types, stages, and patterns of organ involvement, as well as host germline genetics.

Overcoming Intrinsic and Acquired Resistance One approach to optimize patient benefit may be the enhancement of tumor PD-L1 expression by one of several approaches, including the use of interferon gamma, which is be-

ecules OX40, CD40, and CD137. Blocking negative microenvironmental signals can be achieved with inhibitors of indoleamine dioxygenase or tumor-associated macrophages, as well as the radiotherapy strategies mentioned here. Even combinations with cytokines, including interleukin-2 at lower doses than used as a single agent, are under investigation, in the hope of enhancing patient benefit while maintaining a favorable therapeutic index.

A Bright Future for Immunotherapy Although most of the preclinical basis and clinical results summarized here have been most extensively seen in melanoma and lung cancer—the two diseases in which PD-1–blocking antibodies have regulatory approval—these principles (and the high likelihood of some important differences) will be valuable for the development of regimens for other malignancies. At the time this commentary was written, the clinicaltrials. gov website listed 54 actively recruiting studies with nivolumab (Opdivo)

and 64 with pembrolizumab. The importance of an immune response to cancer has been known for decades and preceded the widespread use of cytotoxic chemotherapy. However, it is only in the past 2 to 3 years that the potent and safe use of immunotherapy has finally achieved promise for melanoma and other malignancies. Patients and their physicians can look forward to a day when the morbidity and mortality of cancer are dramatically reduced by immunotherapy and the optimal use of this modality can be individualized to range from preventive interventions through surgical adjuvant therapy to curative systemic therapy for advanced disease. n

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

References 1. Weber JS, D’Angelo SP, Minor D, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375-384, 2015. 2. Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. April 19, 2015 (early release online). 3. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncol 16:522-530, 2015. 4. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G: The secret ally: Immunostimulation by anticancer drugs. Nat Rev Drug Discov 11:215-233, 2012. 5. Cooper ZA, Reuben A, Amaria RN, Wargo JA: Evidence of synergy with combined BRAF-targeted therapy and immune checkpoint blockade for metastatic melanoma. Oncoimmunology 3:e954956, 2014. 6. Vanneman M, Dranoff G: Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 12:237-251, 2012. 7. Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-571, 2014. 8. Demaria S, Pilones KA, VanpouilleBox C, et al: The optimal partnership of radiation and immunotherapy: From preclinical studies to clinical translation. Radiat Res 182:170-181, 2014.

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Appointments

ASCO Appoints Lidia Schapira, MD, FASCO, Editor in Chief of Patient Information Website, Cancer.Net

SCO appointed Lidia Schapira, MD, FASCO, a medical oncologist at Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School, the new Editor in Chief of its award-winning patient information website, Cancer.Net.

new ideas for the website that will meet the evolving needs of patients and their loved ones over time. “Dr. Schapira is a known champion for strengthening the doctor-patient re-

lationship, in particular, through patient education,” said ASCO President Peter Paul Yu, MD, FACP, FASCO. “EnsurB:7.875 in ing that people are well informed and T:7.625 in have access to accurate information they S:6.625 in

can trust is fundamental, and her expertise in understanding the complete needs of a patient is sure to result in continued enhancements to the tremendous resource that is Cancer.Net.” n

IN ADVANCED PROSTATE CANCER…

DO YOUR PATIENTS HAVE

Lidia Schapira, MD, FASCO

Dr. Schapira assumed this role at the 2015 ASCO Annual Meeting in Chicago on June 1, 2015, and will serve a 3-year term. She served as the website’s Associate Editor of Psychosocial Oncology for more than 10 years. In her new role, she will lead the Cancer.Net Editorial Board, composed of more than 150 medical, surgical, radiation, and pediatric oncologists, physician assistants, oncology nurses, social workers, and patient advocates. She succeeds Robert S. Miller, MD, FACP, FASCO, who was named Medical Director for ASCO’s Institute for Quality in December.

MORE ANDROGEN THAN YOU CAN CATCH WITH ANDROGEN RECEPTOR BLOCKADE?

Committed to Educating Patients “I have focused much of my career on improving the overall experience of patients living with cancer and truly believe in the value of Cancer.Net as a resource that not only helps patients better understand their diagnosis, but also encourages them to engage in meaningful, ongoing conversations with their physicians, as well as other members of the professional team,” said Dr. Schapira. “I feel privileged to be part of this committed and talented editorial board and look forward to continued work with my esteemed colleagues in this new capacity.” Dr. Schapira’s passion for refining oncology communication, in a way that considers and cares for the whole person rather than just the disease, was the catalyst for enhancing the Coping and Emotions section on Cancer.Net. She has guided the expansion of oncologistapproved content that addresses topics like caregiving, managing emotions, and communicating with loved ones. She remains committed to exploring

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

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Director’s Corner Future of Oncology

Fulfilling NCI’s Commitment to Supporting the Best Science A Conversation With Douglas R. Lowy, MD By Jo Cavallo tute, the ramifications of budgetary cuts, and his outlook for cancer research advances over the next 5 years.

Greatest Need and Greatest Opportunity

Douglas R. Lowy, MD

n April 1, 2015, Douglas R. Lowy, MD, became Acting Director of the National Cancer Institute (NCI), succeeding Harold Varmus, MD, who left NCI to join the faculty of Weill Cornell Medical College in New York. (See “The Next Step in a Storied Career,” in the May 25, 2015 issue of The ASCO Post.) Dr. Lowy, who had been serving as Deputy Director of the Institute under Dr. Varmus, is a long-time NCI intramural researcher, with a particular focus on the basic and translational aspects of human papillomavirus (HPV) infection and on cancer genes, especially the DLC1 tumor suppressor gene, a RhoGTPase–activating protein, which is downregulated in many cancers. Last fall, Dr. Lowy and John T. Schiller, PhD, Deputy Chief of the Laboratory of Cellular Oncology at the NCI, were recognized for their basic research on papillomaviruses, which led to the development of the HPV vaccine, with the National Medal of Technology and Innovation. Their work in papillomaviruses, which began in the 1980s, has resulted in three U.S. Food and Drug Administration (FDA)-approved vaccines for HPV. The ASCO Post talked recently with Dr. Lowy about his goals for the Insti-

Great progress is being made in cancer research, but funding for the NCI continues to stagnate. What are your priorities for the Institute based on the current budgetary constraints, and what do you hope to accomplish? The NCI is going to continue to conduct research that goes from the most basic to the most applied. And we will continue to look for areas of greatest need and greatest opportunity. In terms of highlighting some areas we are focusing on, clearly the oncology portion of President Obama’s proposed Precision Medicine Initiative is a high-priority area for us. Another area I would like to highlight is the importance of precision medicine in cancer prevention and screening, because there has already been substantial achievement in those two areas, just as

what might be done to mitigate them. And, finally, NCI remains very interested in supporting basic research, even basic research that may not have immediate translational implications—what people sometimes refer to as basic, basic research. There is still a lot we do not understand about cancer cell growth regulation, signaling, and pathogenesis. And we look to investigator-initiated basic research to lead the way to breakthrough findings. Although those findings might not have immediate implications for today, at least a subset of those findings will have important implications for tomorrow.

Balancing Benefit and Harm How would precision cancer screening be different from current screening modalities? There are numerous ways in which one could envision changes, and the changes do not necessarily need to be in the area of precision medicine. One could imagine, for example, the development of improved imaging technology for cancer

There is still a lot we do not understand about cancer cell growth regulation, signaling, and pathogenesis. And we look to investigator-initiated basic research to lead the way to breakthrough findings. —Douglas R. Lowy, MD

there has been in the area of cancer treatment. When people hear the words “precision medicine,” many think first and foremost about treatment, but precision medicine is equally relevant in the areas of cancer prevention and screening. We are also focusing a lot of attention on cancer health disparities to understand the factors that contribute to them, including biology, lifestyle, health care access, and utilization, as well as the relative importance of those factors and

screening, which might help our ability to provide increased benefit and less harm to patients. The big problem with our current cancer screening methods is not being able to achieve a higher benefit-to-harm ratio, because although screening provides some benefit, it also provides some harm. And the overall goal of screening is to increase that benefit-to-harm ratio. The opportunities for using molecular approaches for cancer screening are also considerable, but many of them have not

ASCO 2015—Investigators Announce Patient Enrollment for NCI-MATCH Trial

nvestigators for the nationwide trial, NCI-MATCH: Molecular Analysis for Therapy Choice (EAY131), have announced that the precision medicine trial will open to patient enrollment in July. The announcement was made recently during ASCO’s Annual Meeting in Chicago. The MATCH trial seeks to determine whether targeted therapies

for people whose tumors have specific gene mutations will be effective regardless of their cancer type. NCI-MATCH will incorporate more than 20 different study drugs or drug combinations, each targeting a specific gene mutation, in order to match each patient in the trial with a therapy that targets a molecular abnormality in their tumor.

The study was co-developed by the National Cancer Institute (NCI), part of the National Institutes of Health, and the ECOG-ACRIN Cancer Research Group, part of the NCI-sponsored National Clinical Trials Network (NCTN). It is being led by ECOGACRIN. For more information, visit www.cancer.gov/nci-match. n

yet been fully explored. For example, we understand a bit about the performance of Cologuard, which was recently approved by the FDA for colorectal cancer screening, based on clinical studies. However, we do not yet have a clear notion of how the test will perform in the real world compared with some of the other more traditional approaches, such as colonoscopy. And last year, the FDA approved the first HPV DNA test for women 25 and older that can be used for primary cervical cancer screening, and it was shown to be more accurate in diagnosing cervical cancer than cytology or Pap smear screening. So, there might be additional forms of molecular screening tests that are developed for many other cancer types in the near future.

Bipartisan Support for NCI ASCO is calling on Congress to support a 7.5% increase in National Institutes of Health (NIH) funding and a proportional increase for NCI for fiscal year 2016.1 What are you asking for in the NCI’s fiscal year 2016 budget, and does Congress seem receptive to increasing NIH’s budget? The NCI fiscal year 2016 bypass budget proposed a 15% increase. The President’s budget has proposed a 3.3% increase in the NIH budget, which includes an increase for NCI. Those are the two different numbers: one proposed by the President and one proposed by the NCI in its bypass budget. As for how much enthusiasm there is in Congress for raising the current appropriation, we had a budget hearing recently with the U.S. Senate Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies. Both Chairman Roy Blunt (R–MO) as well as several other Republican members expressed their strong support for the NIH and interest in raising its budget,

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Director’s Corner

as did Ranking Member of the Committee Senator Patty Murray (D–WA) and several other Democrats. Whether their support will lead to an actual substantial increase in the NIH and NCI budgets remains to be seen, but clearly there is a lot of support for NIH and for increasing the appropriation on both sides of the aisle.

The RAS Initiative

standing Investigator Award is something we are looking forward to continuing to support. We want investigators to take risks and worry that in some funding environments, that may be more difficult to do, and this is one way in which we are trying to support those efforts. We also support the R21 Exploratory/Developmental Research Grant

Awards, which are shorter-term grants that fund more speculative projects. Fortunately, we have been able to award more of the R21 awards in the past couple of years than we had prior to that.

Looking Ahead

B:7.875 in

What advances do you see happening T:7.625 in in cancer research over the next 5 years?

In the next 5 years, we will almost certainly see a substantial expansion in the number of FDA-approved drugs for cancer. Effective immunotherapeutic agents, particularly the checkpoint inhibitors, show great promise in a number of cancers. We already have FDA approval on several immunotherapies, and

S:6.625 in

continued on page 58

In 2013, the NCI launched the RAS Initiative to improve the treatment of many cancers driven by mutant RAS genes. Please talk about some of the findings of the RAS Initiative so far. There are several active projects being pursued in the RAS Initiative where we have already seen progress. One is in the development of new assays for RAS inhibition, which can be subjected to high-throughput screening. Another is in the joint effort of the Pancreatic Cancer Action Network and the NCI’s Frederick National Laboratory for Cancer Research to award two postdoctoral fellowships to support research on KRAS mutations in pancreatic cancer. A third project is the development of a number of high-quality reagents, which will be made available to the cancer research community, so investigators can be studying material with a similar origin.

Encouraging Cancer Research When we talked a year ago, you mentioned that the NIH was experiencing a loss in cancer researchers due to reductions in funding. Has the situation stabilized, and what have been the ramifications of stagnant budgets over the past decade? Unfortunately, some people have left cancer research because of our inability to support as many investigators as we would like. On the other hand, we are certainly trying to provide strong support for early-stage investigators as well as other kinds of support for transition funding for postdoctoral fellows, for example, and for physician/scientists, so they have a greater likelihood of becoming independent. Last year, we launched the Outstanding Investigator Award, which is not designed to increase retention among cancer researchers, but rather to provide long-term support for some of our outstanding investigators, so they can work on cancer research that might be more speculative or may take longer to pursue. The Outstanding Investigator Award provides a higher dollar amount for a longer period than our other awards— up to $600,000 per year for 7 years—so the researcher has funding stability. The first round of applications has been received, but we have not yet awarded grants for those applications. The Out-

In mCRPC, is it appropriate to

INHIBIT ANDROGEN PRODUCTION BEFORE BLOCKING THE ANDROGEN RECEPTOR?* THIS APPROACH IS AN OPTION FOR TREATMENT IN ADVANCED PROSTATE CANCER.1,2 Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, prospective clinical study data on treatment sequencing in mCRPC. mCRPC=metastatic castration-resistant prostate cancer. References: 1. Sartor AO, Tangen CM, Hussain MHA, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. 2008; 112(11):2393-2400. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 10/14 016540-140607

The ASCO Post | JUNE 10, 2015

PAGE 58

Announcements

Roswell Park Cancer Institute Appoints New Leadership Team

oswell Park Cancer Institute recently announced a restructuring of its leadership. “In many cases, these new appointments represent Roswell Park Cancer Institute parlaying our own existing strengths and talents,” says President and CEO Candace Johnson, PhD. “Restructuring some of these positions allows us to use our staff’s critical knowledge in the field to effect the policies and procedures that will enhance and improve our medical and scientific work.” New appointments to and within the Roswell Park staff included the following: • Kunle Odunsi, MD, PhD, FRCOG, FACOG, was named Deputy Director of the Institute. Dr. Odunsi provides operational oversight for the scientific, clinical/research, and educational missions of Roswell Park and monitors all research-related initiatives. He is currently the Chair of Gynecologic Oncology, Executive Director of the Center for Immunotherapy, Coleader of the Tumor Immunology and Immunotherapy Program, and the M. Steven Piver Professor of Gynecologic Oncology at the Institute. • Boris Kuvshinoff II, MD, MBA, was named Chief Medical Officer. Dr. Kuvshinoff, who continues as Director of the Roswell Park Liver and Pancreas Tumor Center, directs and manages the organization’s medicalaffairs strategy, including operational areas such as clinical practice, risk management, physician recruitment, and credentialing. He also manages the Institute’s quality strategy, an ongoing initiative to improve the overall quality of the organization’s facilities and patient-care services. • Victor Filadora, MD, MBA, was

Douglas R. Lowy, MD continued from page 57

I look forward to more being approved. Over the next few years, we will have a better understanding of how well these therapies work as single agents and where they are less effective. I also expect that we will be making progress in overcoming cancer resistance and in improving outcomes for patients who develop cancer and that we will see this progress not just in adult cancers, but in pediatric cancers as well. In addition, I see opportunities for cancer prevention. One area we need to do a better job in is getting people to alter their modifiable risk factors, such as smoking and obesity, which

•

named Chief of Clinical Services. Dr. Filadora, an anesthesiologist, manages the Ambulatory Services; Perioperative Services; Sterile Processing; Pharmacy, Patient and Family Experience; Endoscopy Services; and Therapeutic Services Programs and will also provide leadership and guidance to clinical department administrators throughout the Institute. Thomas Schwaab, MD, PhD, was named Chief of Strategy, Business Development, and Outreach. Dr. Schwaab, Associate Professor of Oncology and Immunology, supervises the Institute’s business development and overall strategic development and works to continually widen the Institute’s scope of operations and growth potential at national and international levels. Everett Weiss, MD, was named Chief Medical Information Officer. Dr. Weiss promotes and optimizes Roswell Park’s use of electronic health record systems and other clinical information technology to improve the quality, safety, reliability, and efficiency of clinical workflows in the care of patients. Mary Reid, MSPH, PhD, was named Director of Cancer Screening and Survivorship. Dr. Reid, Professor of Oncology in the Department of Medicine, continues her work in Roswell Park’s pioneering Lung Cancer Screening Program and will develop other cancer screening initiatives within the Institute, working with clinical departments to expand the colon and breast screening programs. Dr. Reid is also developing a comprehensive survivorship clinical and outreach program. David Goodrich, PhD, was named Interim Chair of the Department

we know cause cancer. If we could get people to modify those risk factors, we would have a substantially greater impact on reducing cancer incidence and mortality. Finally, by having a better understanding of the causes of cancer and its early pathogenesis, we should be able to use our ever-increasing armamentarium of molecularly targeted approaches to do a better job of treating patients than we do right now. And I would see analogous potential in the area of cancer screening. I would be neglectful if I didn’t mention that we are looking forward to substantial advances in basic research. And one of the great things about basic research is we do not know exactly where

Kunle Odunsi, MD, PhD, FRCOG, FACOG

Boris Kuvshinoff II, MD, MBA

Victor Filadora, MD, MBA

Thomas Schwaab, MD, PhD

Everett Weiss, MD

Mary Reid, MSPH, PhD

David Goodrich, PhD

Julia Faller, DO, MS

James Mohler, MD

of Pharmacology and Therapeutics. Dr. Goodrich is responsible for supporting the scientific research of departmental faculty and providing leadership in developing research in high-priority fields. • Julia Faller, DO, MS, was named Medical Director of Perioperative Services. She provides day-to-day leadership and management of the operations of Roswell Park’s operating rooms, Endoscopy Suite, Post-Anes-

thesia Care Units, and Surgery Center. • James Mohler, MD, was named Associate Director of Cancer Center Support Grant Shared Resources. Dr. Mohler, Senior Vice President of Translational Research, is responsible for overseeing the shared resources funded by the grant program. These resources, which include 14 laboratories, centers, and/ or facilities, serve the common needs of cancer researchers. n

those advances are going to come from or what they will be, but I suspect we will be in a different place in the next 5 years than we are right now in terms of our understanding of cancer and our opportunities to intervene.

What would you say are the greatest challenges you face? My biggest challenge is the Solomonian problem of deciding what to fund, because we run out of money long before we run out of good ideas to test. That is by far my biggest problem. n

Greatest Challenges Will heading the NCI have an impact on your research in HPV infection and your work on cancer genes, particularly the DLC1 tumor-suppressor gene? Of necessity, I will be doing less laboratory work. I look forward to remaining engaged in the laboratory, but being Acting Director of the NCI is a very big position, and I must give it my top priority and attention.

Disclosure: Dr. Lowy has received limited royalties from Merck, GlaxoSmithKline, Indian Immunologicals Ltd., and Shantha Biotech.

Reference 1. ASCO to Congress: Get serious about putting biomedical research back on track. Statement by ASCO President Peter Paul Yu, MD, FACP, FASCO. April 29, 2015. Available at www.asco.org/advocacy/asco-congress-get-serious-about-putting-biomedicalresearch-back-track. Accessed May 19, 2015.

If she has ovarian cancer

TEST FOR BRCA

If indicated* TREAT WITH LYNPARZA

Help her continue the ﬁght with the ﬁrst approved PARP inhibitor1

* INDICATION LYNPARZA is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

SELECT SAFETY INFORMATION Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been conﬁrmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is conﬁrmed, discontinue LYNPARZA.

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

LYNPARZA demonstrated an objective response rate of 34% in patients with BRCA-mutated advanced ovarian cancer who had been treated with 3 or more lines of chemotherapy1 The efficacy of LYNPARZA was investigated in a single-arm study of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancer. A total of 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. Efficacy was based on objective response rate and duration of response.1 Objective response rate was defined as a ≥30% reduction in target lesion size, according to RECIST criteria, as measured by CT or MRI and confirmed at least 4 weeks later.2

OBJECTIVE RESPONSE RATE (95% CI: 26, 42)

PERCENTAGE OF PATIENTS WHO RESPONDED TO THERAPY

• The rate of partial response was 32% and the rate of complete response was 2%1

7.9

MEDIAN DURATION OF RESPONSE

MONTHS (95% CI: 5.6, 9.6)

Please see the following pages for additional Safety Information and Brief Summary of the full Prescribing Information.

Warnings and Precautions Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of LYNPARZA monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with LYNPARZA. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with LYNPARZA. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with LYNPARZA in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents. Monitor complete blood count testing at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue LYNPARZA. Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with LYNPARZA and initiate prompt investigation. If pneumonitis is confirmed, discontinue LYNPARZA. Embryo-Fetal Toxicity LYNPARZA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to avoid becoming pregnant while taking LYNPARZA. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of LYNPARZA.

Use in Nursing Mothers Nursing Mothers It is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and tolerability of LYNPARZA • LYNPARZA 400 mg twice daily was evaluated as monotherapy in 223 patients with BRCA-mutated advanced ovarian cancer who had 3 or more prior lines of chemotherapy in 6 clinical trials1

Adverse Reactions Reported in ≥20% of Patients1

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

Abdominal pain/discomfort

Decreased appetite

Nausea

Vomiting

Diarrhea

Dyspepsia

Arthralgia/musculoskeletal pain

Myalgia

BLOOD AND LYMPHATIC DISORDERS

Anemia GASTROINTESTINAL DISORDERS

GENERAL DISORDERS

Fatigue/asthenia INFECTIONS AND INFESTATIONS

Nasopharyngitis/URI MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

Please see accompanying Brief Summary of Full Prescribing Information. References: 1. LYNPARZA [package insert]. Wilmington, DE: AstraZeneca; 2014. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

Laboratory Abnormalities

LYNPARZA 400 MG TWICE DAILY n=223 CTCAE GRADES 1-4 (%)

CTCAE GRADES 3-4 (%)

Decrease in hemoglobin (anemia)

Decrease in absolute neutrophil count (neutropenia)

Decrease in platelets (thrombocytopenia)

Decrease in lymphocytes (lymphopenia)

Mean corpuscular volume elevation

Increase in creatininea

Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.

The safety and tolerability of LYNPARZA were also evaluated in a randomized, placebo-controlled study1 â&#x20AC;˘ LYNPARZA 400 mg twice daily was evaluated as maintenance monotherapy in a randomized, placebo-controlled clinical trial of 96 patients with germline BRCA-mutated platinum-sensitive ovarian cancer who had received 2 or more lines of platinum-containing chemotherapy 1 â&#x20AC;˘ Frequently occurring adverse reactions and lab abnormalities were consistent with those seen in the 6 clinical trials, with the addition of back pain, headache, cough, rash, and dysgeusia 1

To learn more, including how to order LYNPARZA, please visit www.lynparza.com

The ASCO Post | JUNE 10, 2015

PAGE 64

Announcements

Daniel D. Von Hoff, MD, FACP, Receives the 2015 Wallace A. Reed, MD, Award

aniel D. Von Hoff, MD, FACP, Distinguished Professor and Physicianin-Chief of the Translational Genomics Research Institute (TGen), received the 2015 Wallace A. Reed, MD, Award on May 29 from the Arizona Medical Association (ArMA). The award recognizes

his accomplishments in advancing innovative cancer treatments, said Nathan Laufer, MD, President-Elect of ArMA. “ArMA extends its wholehearted congratulations to Dr. Daniel D. Von Hoff for his many innovative contributions to the advancement of cancer

Daniel D. Von Hoff, MD, FACP

Trim: 7.625 x 10.5

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

care, especially in the realm of pancreatic cancer,” Dr. Laufer said. Dr. Von Hoff ’s award was presented at the ArMA Annual Meeting and honors the work of physicians, community members, and organizations improving health care in Arizona. n

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates observed in practice. Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy. In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [see Clinical Studies (14) in the full Prescribing Information] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in 20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days. Table 1 Adverse Reactions Reported in 20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Adverse Reaction Blood and Lymphatic disorders Anemia Gastrointestinal disorders Abdominal pain/discomfort Decreased appetite Nausea Vomiting Diarrhea Dyspepsia General disorders Fatigue/asthenia Infections and infestations Nasopharyngitis/URI Musculoskeletal and Connective Tissue disorders Arthralgia/musculoskeletal pain Myalgia

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

43 22 64 43 31 25

8 1 3 4 1 0

21 22

0 0

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

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

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Announcements

Nancy Brinker Named May LUNGevity Hero

he LUNGevity Foundation has announced Nancy Brinker, Founder and Chief of Global Strategy of Susan G. Komen, as the May LUNGevity Hero in recognition of her decades-long dedication and trailblazing work in the fight against

cancer. A true pioneer of the advocacy movement, Ms. Brinker gave a national voice to cancer patients and their friends and families and set a model for success for today’s advocacy organizations around the world. Ms. Brinker’s passion and leadership

Trim: 7.625 x 10.5

in the quest to bring an end to breast cancer resonated with millions and mobilized women across the country to demand that breast cancer research be a key focus of the national healthcare agenda. Her belief in the power of grassroots efforts combined with corNancy Brinker

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

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

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

porate support helped to bring about a vital shift in our country’s dialogue about cancer.

History of Susan G. Komen After watching her sister Susan lose her 3-year fight with breast cancer, Ms. Brinker set out to raise funds to improve treatments and to open up the conversation, reducing the silence and stigma around breast cancer. The organization she created and named for her sister, the Susan G. Komen Breast Cancer Foundation, began in her living room with $200 and a shoebox filled with names to call for donations. Under her leadership, Susan G. Komen has grown into the world’s largest nonprofit funder of the fight against breast cancer, investing more than $2.6 billion in groundbreaking research, community health outreach, and advocacy programming in more than 30 countries. The organization has grown into an influential model for other cancer foundations in how to engage the grassroots, leverage vital corporate support, and execute successful cause marketing programs to fund meaningful mission programs. LUNGevity has built on that legacy, advocating for lung cancer patients, supporting critical research and addressing the lung cancer stigma that remains today.

Honoring Her Contributions “LUNGevity Foundation is thrilled to name global cancer community leader Nancy Brinker as the May L UNGevity Hero, for her unwavering dedication to changing outcomes for survivors and helping to put an end to the silence surrounding the disease,” said Andrea Ferris, President and Chairman of LUNGevity Foundation. “Nancy Brinker created the model for today’s cancer communities, helping organizations such as LUNGevity make significant progress in the quest to end cancer. Susan G. Komen has had an important role in making cancer a national priority, and we are fortunate to have such a strong and passionate leader beside us in this mission.” n

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Journal Spotlight Gastrointestinal Oncology

Addition of Ramucirumab to Second-Line FOLFIRI Improves Overall Survival in Metastatic Colorectal Cancer By Matthew Stenger

n the phase III RAISE trial reported in The Lancet Oncology, Josep Tabernero, MD, PhD, Head of Medical Oncology at Vall d’Hebron Institute of Oncology, Barcelona, and colleagues found that the addition of the antiangiogenic anti–vascular endothelial growth factor receptor 2 (VEGFR2) antibody ramucirumab (Cyramza) to

Study Details In this double-blind trial, 1,072 patients from 24 countries were randomly assigned between December 2010 and August 2013 to receive ramucirumab at 8 mg/kg plus FOLFIRI (n = 536) or FOLFIRI plus placebo (n = 536) every 2 weeks until disease progression or unacceptable toxicity after progression on

Predictive biomarkers to identify patients with tumors most sensitive to antiangiogenic agents would probably further improve the efficacy outcomes of trials of these drugs. Such improvements might be a necessity owing to increasing scrutiny of cost-tobenefit ratios for treatments. —Josep Tabernero, MD, PhD

second-line FOLFIRI (leucovorin, fluorouracil, irinotecan) improved overall survival in patients with metastatic colorectal cancer that had progressed on first-line bevacizumab, oxaliplatin, and fluoropyrimidine treatment.1

first-line therapy. Randomization was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population.

2015 ASCO Annual Meeting Opening Session

Role of Ramucirumab in Colorectal Cancer ■■ The addition of ramucirumab to FOLFIRI in second-line treatment increased overall survival. ■■ No unexpected adverse events were observed, and toxicities were manageable.

The ramucirumab and control groups were generally balanced for age (mean, 62 years in both, 40% ≥ 65 years in both), sex (54% and 61% male), ethnicity (76% and 77% white, 21% and 19% Asian), region (Europe for 44% in both, North America for 27% in both), Eastern Cooperative Oncology Group performance status (0 for 49% and 48%, 1 for 50% and 51%), time to progression after start of first-line treatment (≥ 6 months for 77% and 76%), KRAS mutation status (mutant in 50% and 49%), carcinoembryonic antigen level (< 200/µg/L in 73% in both), number of metastatic sites (1 in 32% and 29%, 2 in 33% and 36%, ≥ 3 in 29% and 34%), and site of primary tumor (colon in 67% in both, rectum in 33% and 32%).

Improved Overall Survival After study medication, subsequent systemic anticancer therapy was received by 54% of the ramucirumab group and 56% of the control group. Median follow-up was 21.7 months. Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4–14.5 months) in the ramucirumab group vs 11.7 months (95% CI = 10.8–12.7 months) in the control group (hazard ratio [HR] = 0.844, P = .0219). Hazard ratios favored the ramucirumab group in all evaluated subgroups, including KRAS status, time to disease progression, and region subgroups. Median progression-free survival was 5.7 months (95% CI = 5.5–6.2 months) vs 4.5 months (95% CI = 4.2–5.4 months; HR = 0.793, P < .0005), with hazard ratios favoring ramucirumab in all evaluated subgroups. Objective response rates were 13.4% vs 12.5%, (P = .63).

Adverse Events

Michael E. Porter, PhD, of Harvard Business School spoke to attendees during the Opening Session at the ASCO Annual Meeting. The focus of Dr. Porter’s talk was Value-Based Health-Care Delivery. Photo by ©ASCO/David Eulitt 2015.

Grade ≥ 3 adverse events occurred in 79% of the ramucirumab group (grade 4 in 17%) vs 62% of the control group (grade 4 in 14%). The most common were neutropenia (38% vs

23%), hypertension (11% vs 3%), diarrhea (11% vs 10%), and fatigue (12% vs 8%). Febrile neutropenia occurred in 3% vs 2%. Grade 5 adverse events consisted of bleeding/hemorrhagic events in three patients in the ramucirumab group and one in the control group, gastrointestinal (GI) hemorrhage in three and one, liver injury/failure in one and one, GI perforation in four and zero , arterial thromboembolic event in one and five, and congestive heart failure in one and two. Serious adverse events occurred in 36% vs 31% of patients. Adverse events led to dose modification in 83% vs 75% and discontinuation in 11% vs 4%. Ramucirumab dose omission, dose reduction, and discontinuation occurred in 8%, 6%, and 4%, respectively. The investigators concluded: In view of our results, the combination of ramucirumab with FOLFIRI is an effective second-line treatment for patients with metastatic colorectal carcinoma. Predictive biomarkers to identify patients with tumors most sensitive to antiangiogenic agents would probably further improve the efficacy outcomes of trials of these drugs. Such improvements might be a necessity owing to increasing scrutiny of cost-to-benefit ratios for treatments. We have begun translational research of prespecified potential biomarkers to assist in selection of patients. n Disclosure: The study was funded by Eli Lilly. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Tabernero J, Yoshino T, Cohn AL, et al: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): A randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499-508, 2015.

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Perspective

Another Angiogenesis Inhibitor Shows Benefit in Metastatic Colorectal Cancer, but Where Do We Go Next? By Weijing Sun, MD, FACP

he phase III RAISE trial—reported by Tabernero and colleagues in The Lancet Oncology1 and reviewed in this issue of The ASCO Post—demonstrated that ramucirumab (Cyramza), a fully human IgG1 monoclonal antibody to the vascular endothelial growth factor receptor 2 (VEGFR2) extracellular domain, in combination with FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan) significantly prolonged overall survival (13.3 vs 11.7 months, hazard ratio [HR] = 0.844, 95% confidence interval [CI] = 0.730–0.976, P = .0219, difference = 1.6 months) and progression-free survival (5.7 vs 4.5 months, HR = 0.793, 95% CI = 0.697–0.903, P < .0005, difference = 1.2 months) in patients with metastatic colorectal cancer whose disease progressed during or after first-line treatment with bevacizumab (Avastin), oxaliplatin, and a fluoropyrimidine. With the U.S. Food and Drug Administration approval of ramucirumab as second-line treatment of metastatic colorectal cancer in combination with FOLFIRI, there are now three agents— monoclonal antibodies or IgG1 Fcbased angiogenesis inhibitors (bevacizumab, ziv-aflibercept [ Zaltrap], and ramucirumab)—that act via selective targeting of the VEGF-A/VEGFR2 pathway available for treatment of metastatic colorectal cancer as part of a second-line combination.

study design and variations in patient selection and treatment regimens. In ML18147, all patients were treated with bevacizumab; however, about 60% of patients received an irinotecanbased regimen as their first-line therapy, and the rest received oxaliplatinbased regimens. In the VELOUR and RAISE studies, all patients were treated with oxaliplatin and fluoropyrimidine– based regimens as first-line treatment. However, only about 30% of patients had bevacizumab during their first-line therapy in the VELOUR trial. Strengths of the RAISE study are that (1) all patients had the same second-line chemotherapy (FOLFIRI) and had previous exposure to an antiangiogenic agent (bevacizumab), and (2) the study populations were closer to the patients seen in our clinical prac-

Translational study is required to improve cost-to-benefit ratios in choosing antiangiogenic-based combination treatment for an appropriate subpopulation of patients. Hopefully, the pending translational research of prespecified potential biomarkers from the RAISE trial (and other studies) will assist us in patient selection.

Three Key Studies Three randomized phase III studies—ML18147 (continuation of bevacizumab after first progression in metastatic colorectal cancer),2 VELOUR (combination of zivaflibercept with FOLFIRI in previously oxaliplatin and fluoropyrimidine–treated metastatic colorectal cancer),3 and RAISE—confirmed that inhibition of tumor angiogenesis after first-line chemotherapy (including previous exposure to antiangiogenic regimen) is effective, despite differences among these studies in Dr. Sun is Professor of Medicine, Director of GI Cancers in the Section of Hematology-Oncology, and Co-Director of the UPMC GI Cancer Center of Excellence at the University of Pittsburgh.

the RAISE (0.84), ML18147 (0.83), and VELOUR trials (0.82, in the total population and 0.86 in the subpopulation of patients who had received firstline bevacizumab). The toxicity profiles from the three agents are similar as well, with increased overall toxicities and likely antiangiogenic agent–related specific adverse events (eg, hypertension and proteinuria) in the antiangiogenesis agent arms that are all manageable with appropriate treatment. Thus, there are no major differences among these three antiangiogenic agents. However, with the approval of ramucirumab and the results of the RAISE trial, more issues have been raised, including (1) the mechanistic differences among these three antiangiogenic agents, (2) whether colorectal cancer may develop crossover tolerability/

—Weijing Sun, MD, FACP

tice who are candidates for continuing antiangiogenesis therapy after disease progression with first-line antiangiogenesis therapy, including those whose disease progressed at various times during or after first-line treatment. From these three large randomized studies, clinical benefits of these three agents (bevacizumab, ziv-aflibercept, and ramucirumab) have been demonstrated in combination with FOLFIRI. Interestingly, the increments of survival benefits from three different antiangiogenic agents are almost the same (difference in median overall survival of around 1.4 to 1.6 months and difference in median progressionfree survival of around 1.6 months). Stratified hazard ratios are similar in

resistance to these different agents, (3) potential opportunities to maximize the benefit from these three agents in the treatment of metastatic colorectal cancer, (4) potential predictive markers for these VEGF-A/VEGFR2 pathway inhibitors, (5) possibilities of using these antiangiogenic agents in combination with other biologic targeted agents, especially immune checkpoint inhibitors, and last but not least, (6) what are the cost-benefit ratios of all these agents?

VEGF Inhibitor Mechanisms As we know, pathologic angiogenesis is a key component of cancer growth and a necessary process for tumor metastasis, including in colorectal cancer. The VEGF-A/VEGFR-2 pathway is

thought to be the dominant promoter of angiogenesis. Targeting VEGF signaling is classified into three approaches: (1) VEGF-A ligand sequestering, such as with the monoclonal antibody bevacizumab and the IgG1 Fc-VEGF receptor construct, as with ziv-aflibercept; (2) antibody or antibody-like molecules that bind to VEGFR-2 and prevent receptor activation by VEGF-A, as with ramucirumab; and (3) low-molecularmass tyrosine kinase inhibitors such as sunitinib, sorafenib (Nexavar), regorafenib (Stivarga), and others. Although VEGF inhibitors are generically viewed as a class of therapeutics, each inhibitor is unique by virtue of its mode of action, interaction with a binding target, selectivity profile, and pharmacokinetic properties. Bevacizumab and ziv-aflibercept neutralize VEGF-A signaling by sequestrating the ligand and selectively blocking the VEGF signaling axis. However, efficacy may be affected by the local concentration of targeted ligand(s), which may explain the debate/controversy over appropriate bevacizumab dosage in combination with chemotherapy regimen(s). In addition, expression of VEGF-A and other ligands may increase after the loop blockade as a physiologic response to rebalance the pathway, which may partially explain the lesser benefit of ziv-aflibercept in patients with previous exposure to bevacizumab (VELOUR data). With binding to the VEGFR-2 extracellular domain, biologic efficacy of ramucirumab may be less influenced by the local concentration of VEGF-A. On the other hand, small-molecule tyrosine kinase inhibitors (eg, sorafenib, sunitinib, and regorafenib) are not exclusively selective for VEGFR-2, with most inhibiting VEGFR-1, -2, and -3 and often other kinases (eg, PDGFR, Ras/Raf, c-kit, CSF1R, and Flt-3). It is unknown whether antiangiogenic effects could be maximized with the combination of these monoclonal antibody or IgG Fcreconstructed agents with small-molecule tyrosine kinase inhibitors.

Predictive Markers A limited benefit of this class of antiangiogenic agents may be partly due continued on page 68

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Perspective Weijing Sun, MD, FACP continued from page 67

to the fact that no selection criteria have been used to enrich for patients who may be likely to derive a durable benefit from treatment. The identification of biomarkers of sensitivity or resistance to VEGF signaling inhibitors may potentially broaden the clinical impact of these agents and might even distinguish the clinical application of each agent. Some preliminary studies have shown that a low VEGF(165) b:VEGF(total) ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer4 (ie, individuals with relatively high levels may not benefit from bevacizumab); low serum angiopoietin-2 (Ang-2), an inhibitory ligand of the endothelial Tie-2 receptor, may be a predictive marker5; and low serum neuropilin-1 (NRP-1) may predict a better response and overall outcome of tivozanib, an oral VEGF tyrosine kinase inhibitor, or bevacizumab in combination with mFOLFOX6 (modified leucovorin, 5-FU, and oxaliplatin).6 Such translational study is required to improve cost-to-benefit ratios in choosing antiangiogenicbased combination treatment for an appropriate subpopulation of patients. Hopefully, the pending translational research of prespecified potential biomarkers from the RAISE trial (and other studies) will assist us in patient selection. n

colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30:3499-3506, 2012. 4. Bates DO, Catalano PJ, Symonds KE, et al: Association between VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with bevacizumab. Clin

Cancer Res 18:6384-6389, 2012. 5. Goede V, Coutelle O, Neuneier J, et al: Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br J Cancer 103:1407-1414, 2010. 6. Benson AB, Krivoshik A, Van Sant C,

et al: Neuropilin-1 as a potential biomarker of progression-free survival benefit for tivozanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in metastatic colorectal cancer: Post-hoc biomarker analysis of BATON-CRC phase II trial. AACR Angiogeneis Meeting. Abstract 24. Presented March 6, 2015.

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

References 1. Tabernero J, Yoshino T, Cohn AL, et al: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): A randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499-508, 2015. 2. Bennouna J, Sastre J, Arnold D, et al: ML18147 Study Investigators: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomised phase 3 trial. Lancet Oncol 14:29-37, 2013. 3. Van Cutsem E, Tabernero J, Lakomy R, et al: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic

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Announcements

Five Oncology Researchers Selected as Howard Hughes Medical Institute Investigators

he Howard Hughes Medical Institute announced 26 of the nation’s top biomedical researchers as investigators for the Institute. These scientists will receive the flexible support necessary to

move their research in creative new directions. The initiative represents an investment in basic biomedical research of $153 million over the next 5 years. “Scientific discovery requires original

thinking and creativity,” says Institute President Robert Tjian, PhD. “Every scientist selected has demonstrated these qualities. We don’t know this for certain, but the ideas that emerge from these labs

IN ONCOLOGY, 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. Studies have shown that the MAPK pathway plays an important role in some cancers.1 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

might one day change the world, and it’s our privilege to help make that happen.” The Institute will provide all investigators with their full salary, benefits, and a research budget over their initial 5-year appointment. The Institute will also cover other expenses, including research space and the purchase of critical equipment. Their appointment may be renewed for additional 5-year terms, each contingent on a successful scientific review. Five cancer researchers are among the 26 selected.

Sue Biggins, PhD Sue Biggins, PhD, of Fred Hutchinson Cancer Center, Seattle, studies the machinery that dividing cells use to en-

Sue Biggins, PhD

sure their daughter cells receive the correct allotment of chromosomes. Much of Dr. Biggins’s work focuses on kinetochores, structures that connect chromosomes to the long, thin microtubules that tug them to the appropriate ends of a dividing cell. She has shed light on how cells make sure that these structures— which comprise hundreds of proteins and must be reassembled every time a cell divides—are positioned in the right spot on chromosomes. Dr. Biggins also showed how a protein called Aurora B forces cells to stop and fix things if microtubules are incorrectly attached to a kinetochore, before cell division can proceed. In 2010, she purified kinetochores from yeast cells and reconstituted their attachments to microtubules for the first time.

Levi A. Garraway, MD, PhD REFERENCE: 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.

Levi A. Garraway, MD, PhD, of Dana-Farber Cancer Institute, Boston, studies how genetic and molecular alterations that lurk inside tumor cells cause cancers to grow and spread—and how this knowledge might inform new therapeutic avenues. His studies of melanoma and prostate cancers have turned up entirely new classes of cancer-causing genes. Dr. Garraway’s research group was continued on page 70

The ASCO Post | JUNE 10, 2015

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Announcements Howard Hughes Medical Institute Investigators continued from page 69

also the first to identify prevalent cancer-promoting mutations in parts of the genome that do not encode pro-

zymes play in boosting the effectiveness of immune responses, as well as spurring the growth of cancer cells. As a postdoctoral researcher, Dr. Harris discovered that an enzyme in immune cells helps produce the vast repertoire of antibodies by editing DNA in a specific way. The enzyme, activation-induced cytidine deaminase (AID), converts cytosines to uracils, creating an obvious error that cells attempt to repair, introducing mutations along the way. Dr. Harris also showed that several related enzymes alter DNA in the same way.

in breast cancer and that high levels of APOBEC3B correlate with poorer outcomes for patients. Follow-up studies from Dr. Harris and others have implicated these editing enzymes in driving mutation in many tumor types.

Joshua T. Mendell, MD, PhD Joshua T. Mendell, MD, PhD, of The University of Texas Southwestern Medical Center, Dallas, quickly established himself as a leader in determining how microRNAs influence development and disease. His first big discovery came in 2005, when he

Levi A. Garraway, MD, PhD

teins. That led to the discovery that more than 70% of melanomas harbor mutations in a stretch of regulatory DNA that switches on production of telomerase, an enzyme that helps determine cells’ longevity. Dr. Garraway is also intent on learning how tumors become resistant to cancer drugs. He and his colleagues have used systematic genetic screens to identify the ways cells are most likely to become resistant to targeted therapies. These findings are informing the design of clinical trials to evaluate combination therapies for melanoma and other cancers. Also working in the field of precision medicine, his team has adapted genomic technologies to survey patients’ tumors for hundreds of cancer gene alterations, creating tumor profiles that can be used to identify the best candidates for clinical trials and, in the future, to tailor treatments to individual patients.

Reuben S. Harris, PhD Reuben S. Harris, PhD, of the University of Minnesota, Twin Cities, studies the physiologic and pathologic functions of a family of DNA-mutating enzymes. His work is illuminating the roles that these DNA-mutating en-

The ideas that emerge from these labs might one day change the world, and it’s our privilege to help make that happen. —Robert Tjian, PhD

As an independent investigator, he demonstrated that several of these enzymes, including APOBEC3F and APOBEC3G, restrict the growth of HIV by inducing mutations in viral DNA. In

Reuben S. Harris, PhD

further studies of these and related enzymes, Dr. Harris detailed how HIV-1 defends itself by degrading APOBEC3 proteins. He recently determined that another family member, APOBEC3B, is a major source of genomic mutations

showed that a well-known cancerpromoting protein, MYC, directly stimulates production of a specific cluster of six microRNAs. He and others have since demonstrated that these microRNAs contribute to MYC’s ability to drive tumor formation. Work from Dr. Mendell’s team has revealed involvement of microRNAs in several other critical cancer pathways as well, and recently the lab showed that certain microRNAs are important for wound healing. Dr. Mendell’s group has also uncovered new mechanisms through which the abundance of microRNAs is controlled in normal tissues and in tumors. Ultimately, Dr. Mendell is interested in developing new therapies for human disease, and his work in animal models has provided persuasive evidence of the therapeutic potential

Joshua T. Mendell, MD, PhD

of microRNAs. His team slowed the growth of liver tumors in mice dramatically by giving the animals a specific microRNA that was present at lower levels in cancer cells than in healthy liver cells. The treatment killed tumor cells but preserved healthy cells, suggesting that such therapies might be well tolerated and effective.

Jennifer A. Zallen, PhD Jennifer A. Zallen, PhD, of Memorial Sloan Kettering Cancer Center, New York, and her team identified a molecular code that systematically orients cell movements throughout the embryo and orchestrates this dramatic shape change. This work, unraveling the molecular sig-

Jennifer A. Zallen, PhD

nals and biophysical forces that shape developing embryos, is an important foundation for understanding how errors in these processes lead to birth defects, kidney disease, and cancer. For a full list of the 2015 Howard Hughes Medical Institute investigators, visit http://www.hhmi.org/ news/hhmi-selects-26-nations-topbiomedical-scientists. n

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ASCOPost.com | JUNE 10, 2015

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Education in Oncology Professional Development

How and When to Give Professional Feedback A Conversation With Charlene M. Dewey, MD, MEd, FACP By Jo Cavallo

roviding students and residents with feedback on their medical performance is a key element in their learning and development and ensures that high standards are met, according to Charlene M. Dewey, MD, MEd, FACP, Assistant Dean of Educator Development; Associate Professor of Medical Education and Administration; and Associate Professor of Medicine at Vanderbilt University School of Medicine in Nashville. Without effective feedback, mistakes go unchecked, good performance is not reinforced, and students and residents will not develop

that somehow if trainees just observed what their supervisors were doing, they would be able to absorb that knowledge. Now we know that observation alone is not enough, which is why the process of feedback is so critical to trainees’ success.

A Valuable Teaching Technique Should feedback be given at a scheduled formal meeting or during daily rounds? Both. I believe that every teaching moment is an opportunity to provide feedback, and if we are not giving feedback during every teaching opportunity, something will be missed. Many

Many people think that feedback is inherently negative, and that is not true. Feedback is a purposeful instruction to improve a performance-led behavior, and if we use it in that context, it is truly a valuable teaching technique —Charlene M. Dewey, MD, MEd, FACP

the high-competency skills necessary for quality patient care or the ability to build positive working relationships with their colleagues, added Dr. Dewey. The ASCO Post talked with Dr. Dewey about the importance of providing effective feedback to medical students, residents, and other trainees; when to give feedback; and how to prepare for giving feedback.

A Two-Way Street Why is giving professional feedback to students and other trainees important? There are several main reasons. Effectively communicating what is expected of the learner sets the groundwork for professional responsibilities, medical knowledge, and good communication skills. It also enhances the professional relationship between the teacher and the learner. Teachers should feel safe in giving feedback, and learners should feel safe in receiving it. And the conversation should be a two-way street: The teacher gives feedback to the learner, and the learner gives feedback to the teacher. Feedback also serves as a window into our own behaviors and helps prevent conflicts. The clearer you are in the information you are giving, the greater the understanding will be. There used to be a lot of assumptions

people think that feedback is inherently negative, and that is not true. Feedback is a purposeful instruction to improve a performance-led behavior, and if we use it in that context, it is truly a valuable teaching technique. Also, feedback should be given in both oral and written forms. If a performance needs immediate attention, feedback should be given right away. If there is something sensitive about the observation that was made, it is best to wait until a private meeting can be held. There are two types of feedback evaluations: formative, in which the teacher is giving continuous feedback about how well the learner is doing overall; and summative, which is an assessment of the learner’s overall skills that is given at the end of a rotation. As I go through rotations with residents, I am constantly giving them feedback. Halfway through the rotation, I might sit down with a resident and ask how he or she is doing and give my observations on the areas the person has improved on and what areas still need work before the end of the rotation. Then, at the end of the rotation, I have a final discussion with residents and give them a written evaluation, which is a compilation of all the feedback I’ve given them throughout the rotation period.

Core Competency Areas What areas are covered during the formal meeting? I tend to cover the six core competency areas every physician needs to become proficient in proposed by the Accreditation Council for Graduate Medical Education (ACGME; acgme.org). They include medical knowledge, patient care, professionalism, interpersonal communication, practice-based learning and improvement, and systems-based practice.

Observe and Listen How can supervisors prepare for giving effective evaluations to students and residents? The most important quality is being a good observer and a good listener. If you are matching what you are personally observing in the student’s performance with the gold standard of the six ACGME core competencies, you will give appropriate feedback, so those are my first two tips. The third rule I follow is the 5-step reflection and feedback plan I developed. The plan includes the following steps: observe and assess first—elicit the learner’s reflection; identify the feedback focus—teacher and learner; reinforce positive behaviors; discuss changes and improvements; and sum-

Leora Horn, MD, MSc

GUEST EDITOR

ducation in Oncology focuses on faculty development, medical education curricula, fellowship training, and communication skills. The column is guest edited by Leora Horn, MD, MSc, Associate Professor of Medicine, Assistant Director of the Educator Development Program, and Clinical Director of the Thoracic Oncology Program at Vanderbilt University School of Medicine, Nashville. marize and create an improvement plan. Supervisors should communicate their evaluations concisely and clearly and not beat around the bush (see sidebar). n

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

Giving Effective Feedback

harlene M. Dewey, MD, MEd, FACP, Assistant Dean of Educator Development; Associate Professor of Medical Education and Administration; and Associate Professor of Medicine at Vanderbilt University School of Medicine in Nashville, offers these suggestions for effectively communicating feedback to trainees.

Setting the Parameters • At the start of a rotation, talk with students about their goals and objectives; create a safe learning environment; and let them know to expect feedback. • If you are giving immediate feedback to correct a negative behavior, for example, the student said something inappropriate to a patient, be sure to give specific guidance and a plan for improvement. • Evaluations should be based on direct observations, not on rumor or second-hand information.

During the Meeting • • • • •

Encourage the trainee to self-assess his or her performance. Share your impression of positive behaviors and areas that need improving. Provide suggestions for problem solving. Assess how well the trainee understood your evaluation. Provide a review of your assessment based on your observations of the learners’ skills and behaviors to be improved prior to the final evaluation. • Make plans to follow up on progress. n

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Announcements

Mount Sinai Receives $8.8 Million Grant to Further Stem Cell Research

n $8.8 million grant from the New York State Stem Cell Science Program (NYSTEM) will accelerate efforts by the Icahn School of Medicine at Mount Sinai to develop new stem cellbased treatments for chemotherapy-resistant blood cancer and other genetic blood disorders.

Ronald Hoffman, MD, Albert A. and Vera G. List Professor of Medicine, Hematology, and Medical Oncology, Professor of Gene and Cell Medicine, and Director of the Myeloproliferative Disorders Research Program at Icahn, will head this research project.

Dr. Hoffman is a leader in stem cell research, and his earlier observation of myeloproliferative neoplasms and the biology of human hematopoietic stem S:6.75” cells and progenitor cells have led to therapeutic trials to improve therapy of this disease.

“We are grateful to NYSTEM for providing a unique opportunity to move our discoveries in the laboratory to a clinical setting,” said Dr. Hoffman. “We are able to build upon 30 years of work to develop new treatment options for our patients.” n

Increasing Stem Cells Collected Specifically, the grant is expected to advance ongoing research efforts seeking to increase the number of stem cells in cord blood collections. Blood stem cell transplantation is the only potential therapy available for most patients with blood cancers. To obtain blood stem cells for transplant, doctors use cord blood collections, which contain only limited numbers of stem cells. Mount Sinai researchers have developed a method to increase the number of collected stem cells to 35 times that of the average collected now. The grant will move this research ahead to clinical trials in collaboration with biotechnology firms NeoStem and AllCells, leaders in cellular therapy.

Contact

The ASCO Post

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

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

Attack from multiple angles COMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro • These tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

• Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®treated patients. Discontinue COMETRIQ in patients with perforation or fistula. • Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

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Announcements

Jonathan L. Finlay, MB, ChB, FRCP, Recipient of the Elizabeth and Richard Germain Endowed Chair in Pediatric Cancer

uring the Wyss Family Symposium, hosted by Nationwide Children’s Hospital May 11–12, Jonathan L. Finlay, MB, ChB, FRCP, Director of Neuro-Oncology at Na-

tionwide Children’s, was announced as the first recipient of the Elizabeth and S:6.75” Richard Germain Endowed Chair in Pediatric Cancer. Dr. Finlay is also Professor of Pedi-

atrics at The Ohio State University College of Medicine. He is an expert in pediatric brain tumors and has authored or coauthored more than 200 peerreviewed publications in leading medi-

cal journals and more than 80 review articles and book chapters. Prior to coming to Nationwide Children’s, Dr. Finlay was the Director of the Neural continued on page 74

Statistically significant efficacy in patients with progressive, metastatic MTC • COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within 14 months prior to study entry PROD

• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001) • Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)

• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the planned interim analysis

PFS

1.0

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0.9 0.8 0.6

HR=0.28 95% CI: 0.19, 0.40 P<0.0001

0.7 0.5 0.4

median

4.0 4.0

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11.2 11.2 months months

months months

0.2

Probability of patients who are progression free

AE/AS

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

31 3

12 2

2 0

1 0

Months 219 111

121 35

78 11

55 6

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%). Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. Please see accompanying brief summary of Prescribing Information, including Boxed Warnings. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088. Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

SIGNOFF

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No. of patients at risk:

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COORDINATED ATTACK

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Announcements Jonathan L. Finlay, MB, ChB, FRCP continued from page 73

Tumors Program at Children’s Hospital Los Angeles, and served as Professor of Pediatrics, Neurology, and Neurological Surgery at the Keck School of Medicine, University of Southern California. Dr. Finlay is the principal investigator

Jonathan L. Finlay, MB, ChB, FRCP

of the “Head Start” series and is readying to conduct the fourth “Head Start” installment. One of the first research initiatives to operate within the newly established National Experimental Therapeutics (NEXT) Consortium, the “Head Start 4” protocol is a tailoredS:6.75” radiotherapy-avoiding approach to the treatment of newly diagnosed malignant central nervous sys-

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140-mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100-mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60-mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None. 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

tem tumors of young children. For many children, the treatment of this type of cancer can have long-term negative impacts on their development and overall health. The goal of this particular initiative is to use a brief but intensive course of chemotherapy both to improve the cure rate and the quality of survival through minimizing long-term side effects. n

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation. 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia. 4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain. 5 Palmar-plantar erythrodysesthesia syndrome. 1

B:17.

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Announcements

Martin McMahon, PhD, Joins Research Team at Huntsman Cancer Institute

PROD ED AE/AS CW CD

DATE

SIGNOFF

T:10.25”

noma research excellence and impact.” In his new role as HCI Senior Director of Preclinical Translation, Dr. McMahon will serve as a member of the HCI Executive Leadership Board, with key responsibilities in strategic planning and development of the cancer center. “With the arrival of Dr. McMahon, HCI will be able to take new initiatives in the development of preclinical models, essential to the discovery of not only new treatments for cancer, but prevention strategies as well,” said Bradley Cairns, PhD, HCI Senior Director of Basic Science. “His laboratory will actively pursue the design and evaluation of treatments that will combat the mutant protein BRAF, known to be at the root of many cancers.” Dr. McMahon is the current President of the Society for Melanoma Research. “I am honored and very excited to join the faculty of the Department of Dermatology and the HCI at this most exciting time in the battle against cancer,” Dr. McMahon said. “What excites me most is the opportunity to work closely with the entire team at HCI to build the research infrastructure required to transform clinical outcomes for our patients.” n

Disk

B:11.25”

—Martin McMahon, PhD

S:9.75”

Stage 2: Systolic ≥160 mmHg or Diastolic ≥100 mmHg

Placebo N=1073 (%) 15

What excites me most is the opportunity to work closely with the entire team at HCI to build the research infrastructure required to transform clinical outcomes for our patients.

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ HYPERTENSION, JNC1 STAGE N=2113 (%) Normal: Grade 0: Systolic 4 <120 mmHg and Diastolic <80 mmHg Pre-hypertension: Systolic 34 ≥120 mmHg or Diastolic ≥80 mmHg Stage 1: Systolic ≥140 mmHg or 46 Diastolic ≥90 mmHg

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. 17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ. • COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash. • COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking. • COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss. • To contact their healthcare provider before any planned surgeries, including dental procedures. • COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking. • Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ. • Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water. • Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment. Reference ID: 3223542 Distributed by Exelixis, Inc. 11/2012

to improve cancer treatments.” John Zone, MD, Chair of Dermatology, said, “Dr. McMahon’s recruitment illustrates a great partnership between HCI and the Department of Dermatology. Utah has the highest incidence of melanoma in the United States, and Dr. McMahon’s expertise will advance our strategic goal of expanding our mela-

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Malignant: Diastolic 0 0 ≥120 mmHg 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose.

“Dr. McMahon is a distinguished scientist who is passionate about improving cancer outcomes,” said Mary Beckerle, PhD, CEO and Director of HCI. “He is a natural leader who will play a major role in advancing the development of HCI research discoveries

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade 3-4 All Grades Grade 3-4 Grades CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

Guzik Distinguished Professor of Cancer Biology at the University of California, San Francisco, and Assistant Director of Professional Education and Coleader of S:6.75” the Helen Diller Family Comprehensive Cancer Center Developmental Therapeutics Program.

artin McMahon, PhD, will join Huntsman Cancer Institute (HCI) at the University of Utah in August 2015 as Professor in the Department of Dermatology and HCI Senior Director of Preclinical Translation. Dr. McMahon is currently the Efim

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2015-2016 Oncology Meetings June 13th International Conference on Malignant Lymphoma (ICML) June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2 Yale ASCO® Review 2015: Highlights of the Annual Meeting June 19 • New Haven, Connecticut For more information: https://transact.med.yale.edu/cme/ conferences/conference_index. asp?ID=1149&linkID=0 EACR-AACR-SIC Special Conference June 20-23 • Florence, Italy For more information: www.ecco-org.eu/eas2015 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 CAP-ACP 2015 Annual Meeting June 20-23 • Montreal, Canada For more information: www.cap-acp.org International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/ International Conference on Prostate Cancer June 22-24 • Orlando, Florida For more information: http://prostatecancer.cancersummit.org

The World NSCLC Summit 2015 Boston June 23-24 • Boston, Massachusetts For more information: http://nsclc.skygenix.com MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/ ASCO Review 2015 June 26 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/live/ courses/2015/ASCO15/default.asp 2nd EACR Special Conference on Cancer Genomics June 28-July 1 • Cambridge, United Kingdom For more information: www.eacr.org IO360–Immuno-Oncology 360o June 29-June 30 • New York, New York For more information: http://theconferenceforum.org/ conferences/immuno-oncology-360/ overview/

July 7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp Gynecologic Oncology Group July 15-19 • Denver, Colorado For more information: www.gog.org

2015-2016

14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com The 13th Annual Scientific Meeting of JSMO July 16-18 • Sapporo, Japan For more information: www.congre.co.jp/jsmo2015/en/ index.html NRG Oncology Meeting July 16-19 • Denver, Colorado For more information: www.gog.org Palliative Medicine and Supportive Oncology 2015 July 23-25 • Cleveland, Ohio For more information: www.clevelandclinicmeded.com/ live/courses/pallmed15/overview. asp APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28-August 1 • Washington, DC For more information: www.apos-society.org 16th Annual International Lung Cancer Congress® July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/ meetings/16th-International-LungCancer-Congress

Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/ Advances in Cancer Immunotherapy™ July 31 • Pittsburgh, Pennsylvania For more information: www.sitcancer.org/sitc-meetings/ aci2015/pa

August Best of ASCO - San Francisco August 7-8 • San Francisco, California For more information: http://boa.asco.org/ World Congress on Cancer and Prevention Methods August 27-29 • Dubai, United Arab Emirates For more information: http://scientificfuture.com/ oncology-2015/ ASCO Multidisciplinary Cancer Management Course (MCMC) August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses

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2015-2016 Oncology Meetings Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/ European Society for Medical Oncology Academy 2015 August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

American Society of Head and Neck Radiology (ASHNR) Annual Meeting September 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ ashnr-annual-meeting/

September

American Society of Hematology (ASH) Meeting on Hematologic Malignancies September 17-19 • Chicago, Illinois For more information: www.hematology.org/Malignancies/

2015 World Molecular Imaging Congress September 2-5 • Honolulu, Hawaii For more information: www.wmis.org/meetings/

ISEH 44th Annual Scientific Meeting September 17-19 • Kyoto, Japan For more information: www.iseh.org/?page=Meeting

International Palliative Care Workshop September 3-5 • Fez, Morocco For more information: www.asco.org/international-programs/ international-palliative-care-workshops

HPV 2015–30th International Papillomavirus Conference September 17-21 • Lisbon, Portugal For more information: www.hpv2015.org

25th World Congress of the International Association of Surgeons, Gastroenterologists, and Oncologists September 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org

ILCA 2015 —The International Liver Cancer Association’s 9th Annual Conference September 4-6 • Paris, France For more information: www.ilca2015.org

2nd International Symposium of the Cancer Research Center of Lyon (CRCL) September 21-23 • Lyon, France For more information: www.crclsymposium2015.fr 4th Annual Conference on Immunotherapy in Pediatric Oncology (CIPO2015) September 25-26 • Seattle, Washington For more information: www.seattlechildrens.org/research/ childhood-cancer/CIPO-2015/ 2015 Breast Cancer Symposium September 25-27 • San Francisco, California For more information: http://breastcasym.org

5th World Congress on Cancer Therapy September 28-30 • Atlanta, Georgia For more information: http://cancer.global-summit.com/ america/

October CAP ’15-The Pathologists’ MeetingTM (College of American Pathologists) October 4-7 • Nashville, Tennessee For more information: www.thepathologistsmeeting.org American College of Surgeons Clinical Congress October 4-8 • Chicago, Illinois For more information: www.facs.org/meetings_events/ future_congress/future 30th Annual Harvard “Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis, and Immunology” October 5-8 • Boston, Massachusetts For more information: http://steele.mgh.harvard.edu/ tumorcourse 20th World Congress on Advances in Oncology and 18th International Symposium on Molecular Medicine October 8-10 • Athens, Greece For more information: www.spandidos-publications.com/ pages/conference

European Cancer Congress (ECC 2015) September 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/ European-Cancer-Congress-2015

ASTRO’s 57th Annual Meeting October 18-21 • San Antonio, Texas For more information: www.astro.org/Meetings-andEvents/2015-Annual-Meeting/Index. aspx ACCC 32nd National Oncology Conference October 21-24 • Portland, Oregon For more information: www.accc-cancer.org/meetings/ calendar.asp ESGO 2015-International Meeting of the European Society of Gynaecological Oncology October 24-27 • Nice, France For more information: http://esgo2015.esgo.org

Lynn Sage Breast Cancer Symposium October 29-November 1 • Chicago, Illinois For more information: www.lynnsagebreastcancer.org

November

Congress of the International Society of Pediatric Oncology October 8-11 • Cape Town, South Africa For more information: http://siop2015.kenes.com Palliative Care in Oncology Symposium October 9-10 • Boston, Massachusetts For more information: http://pallonc.org

16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org 25th World Congress of Lymphology September 7-11 • San Francisco, California For more information: www.lymphology2015.com

2015-2016

National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies™ October 16-17 • San Francisco, California For more information: www.nccn.org/professionals/ meetings/hematological/default.aspx

Chemotherapy Foundation Symposium November 4-6 • New York, New York For more information: www. chemotherapyfoundationsymposium .org SITC 30th Anniversary Annual Meeting November 4-8 • National Harbor, Maryland For more information: www.ncer.org/sitc-meetings/sitc2015

APPROVED IN THE FIRST LINE FOR PATIENTS WITH WT KRAS* mCRC

VECTIBIX

FOLFOX In an exploratory analysis of the PRIME† study, Vectibix® improves median OS in the first line by 4.4 months vs FOLFOX alone in WT KRAS mCRC1

+4.4 MONTHS MEDIAN OS1

• Phase

3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC

• Vectibix®

+ FOLFOX extended the prespecified major efficacy measure of PFS vs FOLFOX alone (9.6 months vs 8.0 months, respectively)

• In

an exploratory analysis of OS, median OS in Vectibix® -treated patients was 23.8 months vs 19.4 months with FOLFOX alone

• No

benefits in OS or PFS were observed in patients with mutant RAS 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 RAS-mutant mCRC or for whom RAS mutation status is unknown.

Important Safety Information WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. • In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis).

Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. • Vectibix® is not indicated for the treatment of patients with colorectal

cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as“RAS”.

• Retrospective subset analyses across several randomized clinical trials

were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents.

Important Safety Information • Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors

received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01–1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone.

• Progressively

decreasing serum magnesium levels leading to severe (grade 3–4) hypomagnesemia occurred in up to 7% of patients in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of

patients experienced severe infusion reactions (NCI-CTC grades 3–4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe

diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal

and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.

• In

patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

• Exposure

to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

• Keratitis

and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.

• 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.

• 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).

Visit VectibixData.com to learn more

mCRC = metastatic colorectal cancer; OS = overall survival; PFS = progression-free survival; WT = wild type. *Exon 2 on codons 12 or 13. † PRIME = The Panitumumab Randomized Trial In Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy. Reference: 1. Vectibix® (panitumumab) prescribing information, Amgen. Please see Brief Summary of full Prescribing Information on adjacent pages.

KING SIZE (6 pt condensed type) S:9.25”

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

VECT15CDLA0437_B_Vectibix_BS_9.25x13_v23_Mar2015_r11_MBS.indd 1

Study 1

SYSTEM ORGAN CLASS Preferred Term

Vectibix® Plus Best Supportive Care (N = 229)

Best Supportive Care (N = 234)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

1 (< 1)

EYE DISORDERS Growth of eyelashes

13 (6)

GASTROINTESTINAL DISORDERS Nausea

52 (23)

2 (< 1)

37 (16)

Diarrhea

49 (21)

4 (2)

26 (11)

Vomiting

43 (19)

6 (3)

28 (12)

Stomatitis

15 (7)

2 (< 1)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue

60 (26)

10 (4)

34 (15)

Mucosal inflammation

15 (7)

1 (< 1)

2 (< 1)

57 (25)

4 (2)

7 (3)

INFECTIONS AND INFESTATIONS Paronychia RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Dyspnea

41 (18)

12 (5)

30 (13)

Cough

34 (15)

1 (< 1)

17 (7)

Erythema

150 (66)

13 (6)

2 (< 1)

Pruritus

132 (58)

6 (3)

4 (2)

Acneiform dermatitis

131 (57)

17 (7)

2 (< 1)

Rash

51 (22)

3 (1)

2 (< 1)

Skin fissures

45 (20)

3 (1)

1 (< 1)

Exfoliative rash

41 (18)

4 (2)

Acne

31 (14)

3 (1)

Dry skin

23 (10)

Nail disorder

22 (10)

Skin exfoliation

21 (9)

2 (< 1)

Skin ulcer

13 (6)

1 (< 1)

8 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

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

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

58 (18)

5 (2)

10 (3)

Diarrhea

201 (62)

59 (18)

169 (52)

29 (9)

Stomatitis

87 (27)

15 (5)

42 (13)

1 (< 1)

EYE DISORDERS Conjunctivitis GASTROINTESTINAL DISORDERS

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Mucosal inflammation

82 (25)

14 (4)

53 (16)

1 (< 1)

Asthenia

79 (25)

16 (5)

62 (19)

11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

22 (7)

Anorexia

116 (36)

14 (4)

85 (26)

6 (2)

INFECTIONS AND INFESTATIONS Paronychia

Vectibix® Plus FOLFOX (n = 322) SYSTEM ORGAN CLASS Preferred Term

FOLFOX Alone (n = 327)

Any Grade n (%)

Grade 3-4 n (%)

Any Grade n (%)

Grade 3-4 n (%)

179 (56) 104 (32) 75 (23) 68 (21) 50 (16) 50 (16) 47 (15) 44 (14) 32 (10)

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1)

24 (7)

1 (< 1)

10 (3) 4 (1)

14 (4) 13 (4) 14 (4) 1 (< 1) 30 (9) 1 (< 1) 4 (1)

30 (9)

4 (1)

9 (3)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

2 (< 1)

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

INVESTIGATIONS Weight decreased METABOLISM AND NUTRITION DISORDERS Hypomagnesemia

96 (30)

21 (7)

26 (8)

1 (< 1)

Hypokalemia

68 (21)

32 (10)

42 (13)

15 (5)

Dehydration

26 (8)

8 (2)

10 (3)

5 (2)

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Epistaxis

46 (14)

30 (9)

This brief summary is based on the Vectibix ® Prescribing Information v23, 03/15. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2015 Amgen Inc. All rights reserved. v23 03/15

4/27/15 6:12 PM

S:13”

INDICATIONS AND USAGE Metastatic Colorectal Cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies (14.2)]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1)]. Limitation of Use Vectibix® is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1)]. DOSAGE AND ADMINISTRATION Patient Selection Prior to initiation of treatment with Vectibix®, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose Modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Dermatologic and Soft Tissue Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immunerelated effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as “RAS ” [see Indications and Usage (1.1), Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14)]. Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents [see Indications and Usage (1.1), and Clinical Pharmacology (12.1)]. Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone [see Indications and Usage (1.1)]. Electrolyte Depletion/Monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1, 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. Acute Renal Failure in Combination with Chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. Ocular Toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. Increased Mortality and Toxicity with Vectibix® in Combination with Bevacizumab and Chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in RAS- and KRAS-Mutant mCRC [see Indications and Usage (1.1) and Warnings and Precautions (5.2)] • Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)]

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

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In Memoriam

Alan C. Sartorelli, PhD, Pioneer in Targeted Chemotherapy and AACR Past President, Dies at Age 83

lan C. Sartorelli, PhD, Alfred Gilman Professor of Pharmacology at Yale University School of Medicine, Past President of the American Association for Cancer Research (AACR), and a Fellow of the AACR Academy, died on April 30, 2015.

Alan C. Sartorelli, PhD

A pioneer in cancer chemotherapy, Dr. Sartorelli was one of the first scientists to recognize the importance of matching the right drug to the right tumor. His work was at the forefront of the research that led to the current personalized approach to each cancer based on a patient’s genetic makeup. More recently, his work involved designing, synthesizing, and evaluating candidate cancer drugs on the basis of

the molecular mechanism of action by which they exert their anticancer effects and the mechanisms by which malignant cells sometimes circumvent the cytodestructive action of drugs.

A Pioneer Across All Categories Dr. Sartorelli received a bachelor of science degree from Northeastern University, a master’s in chemistry from Middlebury College, and a doctorate from the University of Wisconsin. His early training was at the McArdle Institute for Cancer Research. He later joined the faculty of the Yale University School of Medicine, served as Chairman of the Department of Pharmacology from 1977 to 1984, and as Director of the Yale Comprehensive Cancer Center from 1984 to 1993. During his term as Director, he launched one of the first mobile mammography vans in the country. He served the National Cancer Institute for several decades as a member of a number of committees and advisory groups. He was President of the AACR from 1986 to 1987 and was a member of the AACR Board of Directors from 1975

to 1978 and again from 1984 to 1987. During his term as AACR President, he established the series of focused special conferences in cancer research, a thriving program that continues to expand today, and was an early advocate for an Associate Member category for young investigators. Associate Members, who are the future of the cancer field, now encompass about one-third of the AACR membership. He served as President of the Association of American Cancer Institutes in 1987. “Not only was Dr. Sartorelli way ahead of his time in developing therapeutics, he realized early on the role of genetics in targeted cancer therapy,” said AACR CEO Margaret Foti, PhD, MD. “He will be sorely missed by all of us in the AACR.”

Major Contributions to Scientific Literature “He was a strong supporter of expanding the AACR’s publishing program beyond our flagship journal Cancer Research and was a valued advisor and close friend. Because of his innovative spirit and inspirational leadership, he was

able to uniquely conceptualize how the AACR could become even more contributory to the multidisciplinary field of cancer research,” Dr. Foti added. As an author of nearly 500 research papers, Dr. Sartorelli maintained a lifelong interest in scientific literature. He manifested his unique editorial expertise in scientific journal publishing when he was Chair of the AACR Publications Committee from 1981 to 1988 and urged the organization to start a molecular biology journal (Cell Growth & Differentiation, which evolved into Molecular Cancer Research). His committee also oversaw the change in frequency of Cancer Research to twice monthly in 1987 and worked to secure additional funding for the journal. He was a longtime Associate Editor of Cancer Research, Executive Editor of Biochemical Pharmacology Journal, and the founding editor of Pharmacology and Therapeutics. Dr. Sartorelli shared a love of music with his late wife, Alice. An opera buff and student of voice and guitar, he served as Chair of the Shubert Opera Board in New Haven, Connecticut. n

Carol A. Kruse, PhD, Pioneer in Brain Cancer Research and Immunotherapy, Dies at Age 61

arol A. Kruse, PhD, a University of California, Los Angeles (UCLA) scientist and recognized leader in immunologic therapy for brain cancer, recently passed away in Los Angeles after a 6-month battle with an aggressive form of cancer. She was 61. Dr. Kruse was a UCLA Professor of Neurosurgery and Member of UCLA’s Jonsson Comprehensive Cancer Center, where she was pioneering effective immunotherapies for brain cancer patients. At the time of her passing, she was working on better understanding the immune-resistance mechanisms used by tumor cells to facilitate the development of alternative therapies for

Carol A. Kruse, PhD

treating patients with primary malignant brain tumors. Dr. Kruse is best known for having conceived of allogeneic cytotoxic T lymphocytes (or AlloCTL), which target brain tumors by their expression of the HLA class I of human leu-

kocyte antigens. Through research grants and private funding, she initiated two separate clinical trials to treat primary brain tumor patients with AlloCTL. Over the course of her career, Dr. Kruse served in National Institutes of Health study sections and committees and sat on the editorial boards of many prestigious research journals. She also was invited to speak as a guest lecturer at multiple institutions, including UCLA. Dr. Kruse supported basic research for over 25 years. She mentored dozens of graduate and postdoctoral students and research assistants and is

responsible for training many individuals who went on to become leaders in their field. Dr. Kruse received both her bachelor’s and master’s degrees at Colorado State University and earned her PhD at UCLA. After a fellowship at Caltech, she joined the faculty of the University of Colorado Medical School, where she established a new program on brain tumor research. Subsequently, she moved to San Diego and then joined the faculty at UCLA. She is survived by her husband, Laz Gerschenson, MD; her three children, Jeffrey, Gregory, and Mariana; and her granddaughter, Juliana. n



In Memoriam

Carol A. Kruse, PhD Alan C. Sartorelli, PhD 1953 – 2015 1931 – 2015 

The ASCO Post | JUNE 10, 2015

PAGE 82

In Memoriam

Meir Wetzler, MD, RPCI Leukemia Chief, Dies at Age 60

eir Wetzler, MD, Chief of the Leukemia Section at Roswell Park Cancer Institute and University at Buffalo (UB) Professor of Medicine, died on February 23 from injuries sustained during a skiing accident in Colorado. He was 60 years old. Nationally prominent in his field, Dr. Wetzler helped set the standard of care for patients with chronic myelogenous leukemia (CML). Born in Israel, Dr. Wetzler earned his medical degree from Hebrew University Hadassah Medical School and complet-

arly articles and served on the CML Treatment Committee of the National Comprehensive Cancer Network. Colleagues remember him as an accomplished, compassionate physician, as well as a dedicated mentor to medical students, residents, and fellows.

“All of us who worked with him and interacted with him are better people because we knew Meir. He will be sorely missed,” said Alex Adjei, MD, PhD, Chief of UB’s Division of Oncology, UB Professor of Medicine, and Chairman of Roswell Park’s De-

partment of Medicine. Dr. Wetzler was named numerous times to the Castle Connolly list of America’s Top Doctors. Dr. Wetzler is survived by his wife, Chana; two daughters, Mor and Shira; and two sons, Adam and Modi. n

ADVERTORIAL

Meir Wetzler, MD

ed his internal medicine residency at that school’s affiliated Kaplan Hospital. He completed his fellowship training in medical oncology, clinical immunology, and biological therapy at the University of Texas MD Anderson Cancer Center. Dr. Wetzler joined Roswell Park in 1994. In addition to serving as Chief of its Leukemia Section, he chaired its Pharmacy and Therapeutics Committee, co-chaired the Scientific Review Committee, and oversaw the leukemia tissue biorepository, among other responsibilities. He worked tirelessly to attract new clinical trials to the cancer institute. Dr. Wetzler joined UB’s faculty in 1999 as an Associate Professor, rising to the rank of Professor in 2005. Dr. Wetzler’s research focused on three areas: the role of the breakpoint cluster region gene in chronic and acute leukemias, the involvement of cytokines and their signal transduction in leukemogenesis, and the development of immunotherapy for leukemia. He authored more than 100 schol-

 In Memoriam Meir Wetzler, MD

1954 – 2015 

Cancer Stem Cells

Signal Pathways

Understanding M

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

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

EDU-NPS-0009

12/2014

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

ASCOPost.com | JUNE 10, 2015

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Announcements

Margaret Foti Recognized as 2015 Honoree of the ‘One Hundred’ by Massachusetts General Hospital Cancer Center

argaret Foti, PhD, MD (hc), CEO of the American Association for Cancer Research (AACR), was honored for her “dedication and commitment to solving cancer through re-

search” and for her “passionate advocacy for increased federal funding for cancer research and biomedical science,” at Massachusetts General Hospital Cancer Center’s eighth annual “One Hundred”

gala, held on May 26 in Boston. Massachusetts General Hospital Cancer Center established the “one hundred” as an awareness and fundraising initiative that celebrates hope in the can-

Margaret Foti, PhD, MD (hc)

Regrowth

Metastasis

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

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

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

www.bostonbiomedical.com

cer community. Each year, 100 individuals and groups—caregivers, researchers, philanthropists, advocates, and volunteers from around the world—whose commitment to the fight against cancer inspires others to take action are selected through a public nomination process and celebrated at a spring gala. “I am deeply honored to be recognized by Massachusetts General Hospital Cancer Center as a 2015 honoree of the One Hundred,” said Dr. Foti. “It is really humbling for me to share this recognition with so many inspiring women, men, children, and organizations that have made remarkable contributions to this important cause. The personal stories of the one hundred honorees are a testament to the courage and strength of purpose shown by those who have faced a cancer diagnosis and by those who have provided vital support to others in their fight against cancer. Working collaboratively with individuals and organizations like these is a cornerstone of the AACR’s mission, because if we are to accelerate the pace of progress against the insidious group of diseases we call cancer, we must bring together people and organizations from around the globe.”

Excellence in Leadership During Dr. Foti’s tenure as CEO of the AACR, her leadership has been instrumental in increasing the organization’s membership, which has grown from about 3,000 to 35,000 laboratory, translational, and clinical researchers; population scientists; other health-care professionals; and cancer advocates, residing in 101 countries. In addition, the organization’s comprehensive program of national and international conferences and educational workshops has flourished, with attendance at the AACR Annual Meeting 2015 reaching a record-breaking high of nearly 19,300. n

The ASCO Post | JUNE 10, 2015

PAGE 84

Patient’s Corner

Cancer Will Always Be Part of My Life

After five bouts of cancer over 39 years, I’ve learned not to squander any day. By Colleen Sullivan, as told to Jo Cavallo

y first experience with cancer was when I was just 9 years old, and a lump the size of an egg popped out on the right side of my neck. A biopsy of the tumor found that it was Hodgkin lymphoma, and I was given huge doses of external-beam radiotherapy applied to my neck, chest, and underarm lymph nodes. That was 39 years ago, before the late effects of high-dose radiation were known, which, I’ve been told, may have resulted in the onset of two of my three other cancers (thyroid cancer and esophageal cancer) as well as heart disease.

Coping With Multiple Diagnoses Although being diagnosed with Hodgkin lymphoma at such a young age was difficult to cope with, it was its recurrence 3 years later that had an even greater impact on my life and was more difficult to accept. At age 12, I was just reaching adolescence and becoming aware of boys. Losing my hair to chemotherapy, missing months of school, and living in isolation while I went through therapy were traumatic. In addition to the chemotherapy, I had surgery to spot any cancer progression and to remove my spleen. I was told that the chemotherapy and surgery left me unable to have children, which, fortunately, turned out not to be the case. After 6 months of treatment, I was once again cancer-free and remained that way until 2001, when I was diagnosed and treated successfully for secondary thyroid cancer. Six years later, I noticed a lump in my left breast. While the discovery was alarming, it was not completely surprising. Both my maternal and paternal

grandmothers died of breast cancer, and my mother is a three-time breast cancer survivor, so when the biopsy came back positive, I decided to have a contralateral prophylactic mastectomy and reconstructive surgery and get tested for the BRCA gene mutation, which came back positive for BRCA2. My mother and sister have also tested positive for

wonderful young adults. I also have a beautiful new granddaughter to spoil, so despite all my illnesses, life has been good to me. It turned out, however, that cancer was not quite through with me. In the summer of 2014, I began feeling pressure in the back of my mouth when swallowing food, and a red flag went

Despite all that has happened, I’m grateful for the wonderful life I’m still able to have. And I’m grateful to my family and health-care team, who inspire me and give me the courage to face the future. —Colleen Sullivan

the BRCA2 gene mutation, and a few months ago, we learned that several members of my father’s family are also BRCA2 carriers—my father, who died of colon cancer a few years ago, most likely also carried the genetic mutation.

Living With the Aftermath It was during my surgery and adjuvant chemotherapy for breast cancer that I learned my aortic heart valve, badly damaged from the radiation I had received decades before, would have to be replaced. Two years later, a severe blood infection sent me back into the operating room for additional heart surgery to replace the artificial aortic valve as well as two other heart valves. For 7 years after my breast cancer diagnosis and heart surgeries, I remained in good health. I was able to raise my four children and see them grow into

up. I’ve learned over the past 4 decades not to ignore any signal that cancer may be rearing its ugly head, and I immediately called my oncologist and told him about my symptoms. Because I’ve been dealing with cancer for most of my life, I see my oncologist every 6 months, and we have a wonderful relationship. He not only takes my concerns seriously, he encourages me to tell him about any problem I’m having, no matter how insignificant it may sound, and I feel he is my partner in helping me stay alive. When I told him about my problem swallowing and that I thought I needed a PET scan, he readily agreed. The test showed a mass behind my heart, and a biopsy confirmed esophageal cancer. Of all the cancers and related health problems I’ve had as a consequence of those cancers, this latest experience

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare. • ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship. Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

was perhaps the most difficult for me to overcome. I was prescribed neoaduvant chemotherapy to shrink the tumor and then had an esophagectomy, which included the removal of a small part of my stomach as well. A portion of my stomach was then pulled up into my chest and made into my new esophagus. The surgery and its aftermath have been grueling to live with. A feeding tube was temporarily inserted directly into my stomach following the surgery so I could receive nourishment, and I had esophageal dilation to stretch my new esophagus and make it easier for me to swallow food. But the recovery has been slow and difficult, and I still have trouble eating solid food and maintaining a healthy weight.

Long-Term Prognosis In conversations I’ve had over the years with my oncologist about my various cancers, I’ve asked him about my long-term prognosis. He says there is no definitive answer he can give me, so I’ve just learned to live with the uncertainty and not squander any day. For as long as I can remember, cancer has been part of my life, but I don’t think it will kill me. The numerous treatments have caused permanent hair loss, ruined my teeth, and launched me into premature menopause. Yet, despite all that has happened, I’m grateful for the wonderful life I’m still able to have. And I’m grateful to my family and healthcare team, who inspire me and give me the courage to face the future. I’m hoping I don’t have to face cancer again, but if I do, I’m comforted by the fact that I will persevere. n Colleen Sullivan lives in Pittsburgh.

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

Trusted to take a bite out * of G-CSF acquisition costs GRANIX® has gained >34% share of the US short-acting G-CSF hospital market in its first 17 months1 » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)2 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)2 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)2 » Offering a presentation for self-administration

Indication

» GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information

» Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of March 2015. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices. References: 1. This information is an estimate derived from the use of information under license from the following IMS Health Information Service: IMS National Sales Perspective, GRANIX micrograms by non-federal hospital channel March 2015. IMS expressly reserves all rights, including rights of copying, distribution, and republication (micrograms calculated as eaches x strength). 2. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40680 May 2015. Printed in USA.

The ASCO Post | JUNE 10, 2015

PAGE 86

Announcements

Gerstner Family Foundation Commits $10 Million to Broad Institute

road Institute of MIT and Harvard announced a $10 million gift from the Gerstner Family Foundation, which will expand cancer research at Broad Institute and broaden collaborations with Dana-Farber/Harvard Cancer Center and Memorial Sloan Ket-

tering Cancer Center. The research will focus on the changes tumors undergo as they become resistant to drugs—the biggest hurdle to conquering the disease. The Gerstner Family Foundation gift will allow Broad Institute to identify the mechanisms that drive cancer

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

724-43396

drug resistance and pave the way for new treatments. “Cancer treatment has seen amazing progress over the past decade,” said Eric Lander, PhD, President and Director of Broad Institute. “However, many cancer treatments are only

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40580 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Job Number: 21279 Revision No: 0 Date: 05/14/15

temporary. Curing cancer will require solving the problem of drug resistance. This critical next phase of cancer research is becoming a reality, thanks to the Gerstner Family Foundation’s generous gift.”

Eric Lander, PhD

Funding a New Approach The Gerstner Family Foundation gift will support a two-pronged approach to the problem of cancer drug resistance: one based in the laboratory and the other in partnership with clinical researchers. First, researchers at Broad Institute will systematically and comprehensively identify the mechanism of drug resistance, using CRISPR genomeediting technology. This revolutionary tool was developed in part at the Broad Institute and allows researchers to use experimental models to rapidly test which genes are responsible for cancer drug resistance in a laboratory setting. Second, Broad Institute is partnering with two of the world’s leading cancer centers— Dana-Farber/Harvard Cancer Center and Memorial Sloan Kettering Cancer Center—to launch the largest study to date of pretreatment and drug-resistant tumors. By comparing the genome sequence of pretreatment tumors to resistant tumors, researchers hope to identify the mutations that cause resistance. At the same time, a Broad Institute team will build on efforts to develop ‘blood-based’ tumor biopsies. They are techniques to isolate and study rare tumor cells in a patient’s bloodstream. If successful, they would provide doctors a much less invasive alternative to more traditional biopsies. Broad Institute researchers will focus on improving methods to conduct genome sequencing of some circulating tumor cells. The Gerstner Family Foundation has invested over $50 million in biomedical research over the past 20 years with leading institutions across the United States. n

ASCOPost.com | JUNE 10, 2015

PAGE 87

In the News Supportive Care

Incidence of Fractures Is ‘Compellingly Higher’ After Hematopoietic Stem Cell Transplantation By Charlotte Bath

he incidence of fractures is “compellingly higher” after receiving hematopoietic stem cell transplantation, according to a retrospective study of patients receiving transplants for treatment of multiple myeloma, other hematologic malignancies, and some solid tumors (mostly breast and ovarian) as well as a small number of patients being treated for other diseases. This finding led the study authors to recommend that all patients undergoing or planning to undergo stem cell transplantation have their bone health assessed early in their treatment and, if indicated, start measures to prevent bone loss and fractures. The study involved a total of 7,620 patients who underwent a stem cell transplant at The University of Texas MD Anderson Cancer Center, Houston, from 1997 to 2011 and were observed until the end of 2013 “to ascertain occurrence of fractures,” the MD Anderson researchers reported in the Journal of Clinical Oncology.1 Results of the study were

also summarized in other publications, including The Lancet Oncology.2 Fractures developed in 602 patients (8%), which is a significantly greater incidence than among the general population in almost all subgroups. “The striking difference was an approximately eight times greater risk in females and an approximately seven to nine times greater risk in males aged 45 to 64 years old when compared with the National Health Interview Survey and National Hospital Discharge Survey fracture rates,” the investigators noted. In an interview with The ASCO Post, the study’s corresponding author, Huifang Linda Lu, MD, PhD, commented that part of the higher fracture rate among women might be attributed to early menopause, but “the average age of men in the study was about 49 and 50, and at that age, men don’t just fracture.” The cause of these striking differences in women and younger men “has got to be something related to ma-

lignancy and the stem cell transplant,” said Dr. Lu, who is Associate Professor, Rheumatology and Clinical Immunology at MD Anderson.

Factors Linked to Higher Risk Being older than 50 years at the time of transplantation and receiving an autologous transplant are two factors that place patients at a greater risk of fracture, the study found. All patients were older than 18, and 52.5% were older than 50. More than 50% of the patients died before experiencing a fracture. Among the 602 patients who developed a fracture were 11% of patients (419) who had an autologous transplant vs 5% of patients (183) who had an allogeneic transplant. “We are currently investigating the risk factors associated with these two groups of patients. One plausible explanation is that patients with multiple myeloma often receive an autologous transplant,” Dr. Lu said. “Multiple myeloma in itself can af-

fect bone,” she continued. “The pathophysiology of multiple myeloma affecting bone involves several mechanisms. One is generalized osteoporosis that might have a continued adverse effect even after the [transplant]. This may contribute to the increased risk for fractures in this population.” Multiple myeloma was the reason for hematopoietic stem cell transplantation in 22% of patients. The most common reason, responsible for 67% of the patients in the study, was a hematologic malignancy other than multiple myeloma. In addition, 11% of the patients had solid tumors or “hematologic conditions like aplastic anemia, myeloid dysplasia, or myelodysplastic syndrome, which are not considered cancer but are managed with protocols very similar to the leukemia transplants,” Dr. Lu explained. “The majority of the indications for [hematopoietic stem cell transplantation] for solid tumors in our study was continued on page 88

Expect Questions About Preventing Fractures After Stem Cell Transplant By Charlotte Bath

oes the finding that the incidence of fractures is “compellingly higher” after hematopoietic stem cell transplantation mean that physicians counseling patients about transplant should feel compelled to discuss the fracture risks? Huifang Linda Lu, MD, PhD, the corresponding author of the study finding that higher fracture rate, told The ASCO Post, “Physicians spend a significant amount of their time counseling patients about their underlying

Dr. Lu is Associate Professor, Rheumatology and Clinical Immunology at The University of Texas MD Anderson Cancer Center, Houston, where the study was conducted. Among 7,620 patients undergoing stem cell transplant from 1997 to 2011 at MD Anderson, 602 (8%) developed a fracture. This was significantly greater than the fracture rate of the U.S. general population for almost all subgroups, the researchers reported, with a “striking difference”

It is necessary to discuss the risk of bone loss with patients and urge them to take an active role in preventing fractures posttransplant. —Huifang Linda Lu, MD, PhD

malignancy and treatment plan. In addition, risks of having the transplant and its long-term complications are also discussed. It is necessary to discuss the risk of bone loss with patients and urge them to take an active role in preventing fractures posttransplant.

of approximately eight times greater risk in females and seven to nine times greater risk in males aged 45 to 64. The study identified several potential factors associated with a higher risk of fracture, such as a diagnosis of multiple myeloma, older age at transplanta-

tion, and having autologous rather than allogeneic transplantation. “However, there are many other potential risk factors that may have adverse effects on bone that need to be further investigated,” Dr. Lu stated. “Although our results did identify some potential risk factors we believe that maintenance of bone following [stem cell transplant] is a complex process and not completely understood, and hence, all patients undergoing a transplant should be considered at risk.”

Encourage Exercise, Discourage Smoking The active role for patients in preventing bone loss and fractures should include physical exercise and fall prevention. Patients also should be encouraged to avoid tobacco and minimize excessive alcohol intake, which “some studies have shown to be independent risk factors for fractures,” Dr. Lu noted. In addition, avoiding excessive alcohol reduces risk of falls that could lead to fractures. “Adequate intake of calcium, mag-

nesium, and vitamin D is essential for general bone health. Hormone replacement therapy should be considered when appropriate,” Dr. Lu continued. “There are pharmacologic interventions to prevent bone loss, but none can replace the importance of bone loss prevention by utilizing basic bone health measures such as calcium, vitamin D supplementation, weight-bearing exercise, and minimizing the use of bone-damaging medication as much as possible,” Dr. Lu added. “Pharmacologic interventions such as bisphosphonates are being used to prevent and treat bone loss following [stem cell transplant]; however, pharmacologic reagents carry their own risks.” n

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

Reference 1. Pundole XN, Barbo AG, Lin H, et al: Increased incidence of fractures in recipients of hematopoietic stem-cell transplantation. J Clin Oncol 33:13641370, 2015.

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In the News Fractures After Stem Cell Transplant continued from page 87

breast cancer. These patients suffer from common risk factors for bone loss as postmenopausal women do. This may be one possible explanation for the observed increased risk. However, this represents a very small percentage of the

overall study population.” Dr. Lu pointed out that the breast cancer patients were enrolled about 15 years ago, “before we had the powerful hormonal ablation therapy.” These patients would have been “completely out of choices. There were no aromatase inhibitors, and there was not a lot to offer.” There are many other options now, she noted.

Supportive Therapies May Increase Risk The similarity between the increased rates of fractures observed in patients undergoing solid organ transplant and stem cell transplant “suggests that transplantation and the associated supportive therapies administered may play a key role in the increased risk of fractures,” according

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to the study report. Supportive therapies cited in the report include myeloablative conditioning regimens, high-dose steroids, and cyclosporine. “These are just a few. Glucocorticoids may be the strongest supportive therapy of all and have been demonstrated individually either in vitro or in vivo to adversely affect bone. The effect of these supportive therapies on bone after [hematopoietic stem cell transplantation] has to be further evaluated,” Dr. Lu noted. “Steroids are probably the most effective immunosuppressive medication to treat graft-vs-host disease after [stem cell transplant],” Dr. Lu added. “Whenever possible a steroid-sparing reagent should be tried to avoid steroid use. Our stem cell transplant colleagues are constantly researching new reagents or combination therapies that are steroid sparing.” Patients may have “associated comorbidities, lifestyle factors, and genetic predispositions that may increase the risk of fractures following [hematopoietic stem cell transplantation],” the researchers noted. The investigation of genetic predispositions that may increase the risk of fractures following transplant “is slowly emerging,” Dr. Lu noted. “Little is known yet about the genes and genetic variants that regulate bone mass and susceptibility to fractures.” Dr. Lu and colleagues are currently looking into lifestyle factors that might be altered to reduce bone loss and the risk of fractures. “These patients often suffer prolonged illness and become sedentary, not carrying out any routine weight-bearing exercise such as walking. Exercise helps in maintaining bone mass and preventing fractures. Exercise alone or in combination with occupational therapy has been shown to reduce fractures by about 25% to 50% in some studies of elderly patients in the general population,” Dr. Lu stated. Exercise is important before and after diagnosis and transplantation. “Patients should not stop exercising and at least continue to walk,” Dr. Lu said. “Walking could be the simplest form of weight-bearing exercise. If it is continued throughout cancer treatment, before the stem cell transplant and after, that would do a whole lot of good for the patient’s bone health,” she said. “Certainly a bedridden situation causes a lot of bone loss rapidly,” Dr. Lu continued. She noted that at MD Anderson, a program of physical therapy instituted several years ago gets patients on their feet soon after transplant sur-

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In the News

gery. “It is as simple as having a patient walk around the nurses’ station several times a day very early after the stem cell transplant. We noticed a reduction in bone and joint complications.”

they may have experienced additional insults to the bone such as steroids to prevent and treat graft-vs-host disease, being bedridden for a prolonged period, and immobilization due to [stem cell

Transplantation and the associated supportive therapies administered may play a key role in the increased risk of fractures…. The effect of these supportive therapies on bone after [hematopoietic stem cell transplantation] has to be further evaluated.

cians give advice to their patients. Dr. Lu said that she and colleagues are hoping to have information on that study ready to present at ASCO’s Annual Meeting in 2016. At this year’s Annual Meeting, a poster presentation by Xerxes N. Pundole, MD, MPH, Graduate Research Assistant, General Internal Medicine–Section of Rheumatology, MD Anderson Cancer Center, and the lead author of the current study,

—Huifang Linda Lu, MD, PhD

Assess Bone Health Early Patients undergoing or planning to undergo hematopoietic stem cell transplantation should have their bone health assessed early in their treatment and, if indicated, should start preventive therapy to avoid bone loss and fractures, the researchers advised in the study report, recommending a dual energy x-ray absorptiometry (DXA) scan at baseline. “The DXA scan is the current standard method to screen for bone health in the general population and is also utilized following [stem cell transplantation]. However, fractures have been seen in patients with nonosteoporotic bone mineral density, and hence, an overall comprehensive assessment of fracture risk along with the DXA scan is important,” Dr. Lu explained. “We also recommend a DXA scan at 6 months,” she continued. “One practical reason is that if patients missed the opportunity to have their bone health evaluated at the time of transplant, most patients’ health status stabilizes in time and they do have an opportunity to have their bone health screened at 6 months posttransplant.” She added, “Even when patients do get a DXA scan at baseline, they may still have acquired significant bone mineral density loss in the first 6 months, as

transplant] and its complications. Consequently, the risk profile of patients to develop a fracture could change in the early posttransplant period.” Dr. Lu acknowledged that while the 6-month assessment is recommended, “realistically, this may not happen. But if physicians across the board all keep this in mind, that gives patients a better chance at being educated on bone health.” While loss of bone mineral density can persist for years, “there are no guidelines” for follow-up DXA scans, Dr. Lu noted.

Xerxes N. Pundole, MD, MPH

summarized data from a phase III openlabel randomized trial at MD Anderson showing that intravenous ibandronate prevented bone loss in the lumbar spine

among adult recipients of allogeneic stem cell transplant.3 However, the treatment did not completely prevent bone loss at the femoral neck and total hip. As a result of that study, “we know more,” Dr. Lu said, although there are still questions about what would be the optimal drug for prevention of bone loss in transplant recipients. n

Disclosure: Drs. Lu and Pundole reported no potential conflicts of interest.

References 1. Pundole XN, Barbo AG, Lin H, et al: Increased incidence of fractures in recipients of hematopoietic stem-cell transplantation. J Clin Oncol 33:1364-1370, 2015. 2. Bagcchi S: Stem-cell transplantation increases fracture risk. Lancet Oncol 16:e201, 2015. 3. Pundole X, Champlin RE, Popat UR, et al: A randomized controlled trial of ibandronate for the prevention of bone loss following allogeneic stem cell transplantation. 2015 ASCO Annual Meeting. Abstract 7029. Presented May 31, 2015.

ASCO-American Cancer Society Award and Lecture

Ongoing and Future Studies To better understand the process of bone loss, Dr. Lu and her colleagues are evaluating a comprehensive set of risk factors for fracture development. The retrospective study will include more than 5,000 patients treated with stem cell transplant at MD Anderson Cancer Center. “The more we work on this area— we started with just simple bone health—the more questions we have,” Dr. Lu noted. Since 90% of patients receiving stem cell transplant do not fracture, perhaps data from those patients can provide more clues about who is and is not at higher risk and help physi-

2015 ASCO Annual Meeting—Clifford Hudis, MD, FACP, ASCO Past President (left) and Otis W. Brawley, MD, FACP, Chief Medical Officer for the American Cancer Society (ACS) (right) presented the ASCO-ACS Award to Ernest Hawk, MD, (center) at the ASCO Annual Meeting on Monday, June 1, 2015. Photo by ©ASCO/David Eulitt 2015.

Don’t Miss These Important Reports in This Issue of The ASCO Post Laurence H. Baker, DO, on the Costs and Patient Volunteering in Clinical Trials see page 1

David B. Dix, MD, on Intensified Treatment in Certain Wilms Tumor Patients see page 12

Visit The ASCO Post online at ASCOPost.com

Brandy Edwards, MD, on the Cost-Effectiveness of Bilateral Prophylactic Mastectomies see page 14

The ASCO Post | JUNE 10, 2015

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Lab Notes

Ongoing Molecular Research in the Science of Oncology PREDICTING OUTCOMES Effect of ERG Gene Status on Progression-Free Survival With Abiraterone in CastrationResistant Prostate Cancer

Gene fusions resulting in androgen receptor–modulated ERG gene overexpression can be found in up to 70% of patients with metastatic castration-resistant prostate cancer. In a study reported in Clinical Can-

cer Research, Attard and colleagues assessed the effect of ERG rearrangement on outcomes in the phase III COU-AA-302 trial comparing abiraterone (Zytiga) and prednisone vs prednisone in chemotherapy-naive

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patients with metastatic disease. ERG status was identified for 348 of 1,088 patients in the trial, with ERG rearrangement in 121 (35%). Patients with ERG fusion secondary to deletion of 21q22 and increased copy number of fusion sequences (class 2+ Edel) had significantly longer radiographic progression-free survival after receiving abiraterone and prednisone (22 vs 5.4 months, hazard ratio [HR] = 0.31, P = .0033). The combination of abiraterone and prednisone was also associated with a significant improvement among patients with no ERG fusion (16.7 vs 8.3 months, HR = 0.53, P = .0002) or other types of ERG rearrangement, although the magnitude of improvement was not as large. The investigators concluded: “Both ERG-rearranged and wild-type cancers had a significant improvement in [radiographic progressionfree survival] with abiraterone and prednisone in the COU-AA-302 trial. However, our data suggest that 2+ Edel cancers, accounting for 15% of all patients with a confirmed ERG status and previously associated with a worse outcome, derived the greatest benefit.” Attard G, et al: Clin Cancer Res 21:1621-1627, 2015.

POLE Proofreading Mutations Predict Better Outcome in Endometrial Cancer In a study reported in the Journal of the National Cancer Institute, Church and colleagues assessed whether proofreading mutations in POLE (which encodes the DNA polymerase epsilon catalytic subunit) were associated with prognosis in endometrial cancer. Such mutations have been reported in approximately 7% of endometrial cancers. Targeted POLE sequencing in 788 patients from the PORTEC-1 and -2 trials identified mutations in 48 of them (6.1%), with the presence of mutation being associated with a high tumor grade (P < .001). Patients with mutations had a lower frequency of tumor recurrence (6.2% vs 14.1%) and endometrial cancer death (2.3% vs 9.7%). In the total cohort, the reductions in recurrence-free survival (hazard ratio [HR] = 0.43, P = .15) and cancerspecific survival (HR = 0.19, P = .11) were not significant on multivariate

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Lab Notes

analysis. However, among 109 patients with grade 3 tumors, tumor recurrence was observed in 0 of 15 patients with POLE-mutant disease vs 29 of the 94 (30.9%) with wild-type cancers, with recurrence-free survival being significantly improved on multivariate analysis (HR = 0.11, P = .03). In an additional series of 628 patients, endometrial cancer–related events occurred in 0 of 33 patients with POLE-mutant disease. For the pooled cohorts, patients with POLEmutant disease had significantly improved recurrence free-survival (HR = 0.33, P = .03), with an improvement approaching significance in cancer-specific survival (HR = 0.26, P = .06). The investigators concluded: “POLE proofreading mutations predict favorable [endometrial cancer] prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in [endometrial cancer].” Church DN, et al: J Natl Cancer Inst 107:402, 2014 (print January 2015).

lation also promoted dendritic cell maturation in tumor fragments by activating NFκB in the dendritic cells. Blocking of HLA class I prevented the enhanced outgrowth of CD8-positive T cells with anti–4-1BB, indicating that ongoing HLA class I–mediated antigen presentation in early tumor fragment cultures plays a role

in influencing tumor-specific CD8positive tumor-infiltrating lymphocyte outgrowth. The investigators concluded: “Our results highlight a previously unrecognized concept in tumor-infiltrating lymphocyte [adoptive cell therapy] that the tumor microenvironment can be dynamically regu-

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lated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics.” n Chacon JA, et al: Clin Cancer Res 21:611-621, 2015. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

IMMUNOTHERAPY Ex Vivo Manipulation of Tumor Microenvironment Improves Expansion of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy In a study reported in Clinical Cancer Research, Chacon and colleagues found that ex vivo manipulation of the tumor microenvironment could enhance expansion of tumor-infiltrating lymphocytes for use in adoptive cell therapy. The addition of an agonistic anti–4-1BB antibody during initial tumor fragment culture to provide in situ 4-1BB costimulation resulted in activation of 4-1BB signaling in early cultured tumor fragments and acceleration of the rate of outgrowth of memory CD8-positive tumorinfiltrating lymphocytes, which were highly enriched for melanoma antigen specificity. This was accompanied by nuclear factor (NF)κB activation, induction of T-cell survival and memory genes, and enhanced interleukin-2 responsiveness in CD8-positive T cells in and emerging from the tumor fragments. Early addition of 4-1BB costimu-

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The ASCO Post | JUNE 10, 2015

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In the Literature

Emerging Clinical Data on Cancer Management CHRONIC MYELOID LEUKEMIA First-Line Imatinib With Early Switch to Nilotinib May Be Preferable to First-Line Use of More Potent Agents in CML Using imatinib to treat chronicphase chronic myeloid leukemia (CP-CML) first line, with selective switching to nilotinib (Tasigna) “leads to excellent molecular response and survival” and “may be preferable to universal first-line use of more potent agents, considering efficacy, toxicity, and economic factors,” Australian Leukemia and Lymphoma Group investigators reported in Blood. These conclusions were based on results from the Therapeutic Intensification in De Novo Leukemia (TIDEL)-II study, which built on the previous TIDEL-I study of intensified imatinib for patients failing to achieve interim treatment targets. TIDEL-II incorporated two additional approaches—escalating the imatinib dose to 800 mg/d in patients with imatinib plasma trough serum concentration < 1,000 ng/mL and “a prompt switch to the more potent tyrosine kinase inhibitor nilotinib for either imatinib intolerance or a suboptimal response, as defined by molecular targets,” the researchers explained. A total of 210 patients with CPCML were enrolled into two sequential cohorts of 105 patients each. Patients had to be older than age 16 and within 6 months of diagnosis. The median age was 48 in cohort 1 and 49 in cohort 2.

Cohort 1 was 49% female, and cohort 2 was 39% female. The primary endpoint was confirmed major molecular response, defined as BCR-ABL1 ≤ 0.1%, on the International Scale. All patients started with imatinib at 600 mg/d. If imatinib plasma trough levels were < 1,000 ng/mL when assessed at day 22, imatinib was escalated to 800 mg/d. “Patients were then assessed against molecular targets: BCRABL1 ≤ 10%, ≤ 1%, and ≤ 0.1% at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target were escalated to imatinib 800 mg/d and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target were switched to nilotinib directly, as were patients with intolerance or loss of response in either cohort,” the researchers wrote.

Key Data “At 2 years, 55% of patients remained on imatinib, and 30% on nilotinib,” the investigators reported. Only 12% failed to achieve an early molecular response, defined as BCRABL1 ≤ 10% at 3 months. Confirmed major molecular responses occurred in 64% of patients at 12 months and 73% at 24 months. Complete molecular response, defined as two consecutive measurements of undetectable BCRABL1 within 3 months, was achieved in 11% of patients at 12 months and 25% at 24 months. Overall survival was 96%, and transformation-free survival was 95%

at 3 years. “These results compare very favorably with other current first-line tyrosine kinase inhibitor studies in CPCML patients, including the first-line use of nilotinib or dasatinib [(Sprycel)],” the authors noted. The most common severe adverse event associated with imatinib was cytopenia, especially at the beginning of study treatment. Biochemical abnormalities, including elevated serum liver or pancreatic enzymes, and allergic skin reactions were common with both imatinib and nilotinib treatments. “Arthralgia, gastrointestinal disturbances, and edema were also commonly reported with imatinib. Although postulating that “imatinib 800 mg/d may be beneficial for selected patients,” the investigators found that only about “11% of patients can maintain imatinib 800 mg/d and achieve a major molecular response on this dose, suggesting that the importance of high-dose imatinib may be secondary to therapy switching based on intolerance or failure to reach molecular targets.” The outcome for patients switching to nilotinib was generally favorable for patients with imatinib intolerance. “In contrast, the benefit of nilotinib switching in patients who failed to achieve early TIDEL-II targets is not clearly demonstrated in our cohorts,” the researchers wrote, noting that this “is a likely consequence” of the low early molecular response failure rate. Yeung DT, et al: Blood 125:915-923, 2015.

ESOPHAGEAL CANCER More Extensive Lymph Node Clearance During Surgery for Esophageal Cancer May Not Improve Survival

A population-based cohort study “indicates that more extensive lymph node clearance during surgery for esophageal cancer may not improve survival,” Maartje van der Schaaf, MD, PhD, of the Karolinska Institutet, Stockholm, and colleagues reported in the Journal of the National Cancer Institute. “These results challenge current clinical guidelines, and further research is needed to change clinical practice,” the researchers asserted. The study included 1,044 patients with esophageal cancer who had undergone esophagectomy between

1987 and 2010 in Sweden and were followed until 2012. Most patients (84.9%) were younger than 75 years old and male (74.8%). “Analyzed as a linear variable, a higher number of lymph nodes removed did not influence the overall 5-year mortality,” the investigators stated. The adjusted hazard ratio (HR) was 1.00, with a 95% confidence interval (CI) of 0.99 to 1.01. “Patients in the third (7–15 nodes) and fourth (16–114 nodes) quartiles of removed nodes did not demonstrate any decreased overall 5-year mortality compared with those in the lowest two quartiles (< 7 nodes; HR = 1.13, 95% CI = 0.95–1.35 and HR = 1.17, 95% CI = 0.94–1.46, respectively).” The authors noted that their results “are in line with two well-designed studies that found no survival difference between a more extensive lymphadenectomy via transthoracic esophagectomy and a more limited lymphadenectomy by a transhiatal approach.” In addition, “a randomized trial comparing two-field with threefield lymphadenectomy found no difference in survival.” The current study, the authors added, “indicates that extensive lymphadenectomy might even increase mortality in early tumor stages.” In stages Tis to T1, “the hazard ratios indicated a worse survival with more lymphadenectomy using the median as cutoff (HR = 1.53, 95% CI = 1.13–2.06),” the researchers reported. “Increased lymph node removal did not decrease mortality in any specific T stage. A greater number of metastatic nodes and a higher positive-tonegative node ratio were associated with strongly increased mortality. All results were similar when disease-specific mortality was analyzed,” according to the study report. “A tailored lymphadenectomy that enables selective removal of metastatic nodes while leaving nonmetastatic nodes in place might be ideal, but it is currently difficult to identify metastatic nodes,” the investigators wrote. “Improvements in preoperative nodal staging and new biomarkers that can visualize metastatic nodes could tailor future nodal removal.” n van der Schaaf M, et al: J Natl Cancer Inst 107(5):djv043, 2015. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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PAGE 94

Perspective Laurence H. Baker, DO continued from page 1

be a critique of any individual or group but rather a rallying cry, urging us to join together to make changes in health-care delivery that respect the primacy of patients who choose to enroll in a clinical trial.

SWOG S0033 In the fall of 2000, the National Cancer Institute (NCI) invited several clinical investigators to plan a clinical trial for patients with gastrointestinal stromal tumor (GIST) and strong evidence of metastasis. Before imatinib, the median survival of this patient population was a few short months, and the response rate for the best cytotoxic chemotherapy was less than 5%. Phase II studies both in the United States and in Europe had shown remarkable and unprecedented clinical benefit from imatinib. It was clear from the phase II studies that the drug was beneficial; we just didn’t realize how beneficial. Novartis agreed to provide the drug and was a major initiator of this meeting. At the end of the day, the investigators agreed to a study proposed by George Demetri, MD, of Dana-Farber Cancer Institute, that asked the simple question of dosage: Is 800 mg/d better than 400 mg/d? (This study preceded the identification of kit mutational analysis as a predictive biomarker.)

The investigators also agreed that the clinical trial should be coordinated by SWOG. The S0033 trial accrued more than 690 patients in 8 months. As Charles Coltman, MD, who was SWOG Chair at the time, would say, “This trial set a new indoor record for accrual.” At the next year’s ASCO Annual Meeting, I joked that we had accrued 150% of all known cases of metastatic GIST.

‘Third D’ of Clinical Research In 2012, I recognized that we had a cadre of more than 100 patients who had survived 10 years since starting imatinib.

discussion section stating that the patients had to pay for their drug to “teach their doctors” that they could survive for a decade or longer with widespread metastatic cancer. Those six authors were firm that in their “opinion [this] did not belong in the discussion of a scientific manuscript”—or at least that opinion did not belong. Before the study was initiated, SWOG failed to insist that the drug be provided by its manufacturer to those patients who had volunteered for the clinical trial. In addition, the NCI failed to insist that Novartis agree to continue to provide its drug to those patients

Everyone is aware of the challenges patients face on a daily basis. No doubt there are bigger challenges than being forced to pay for drugs after volunteering for a clinical trial. But to continue this practice just seems wrong. —Laurence H. Baker, DO

We studied these long-term surviving patients in order to learn what characteristics had permitted this extraordinary response and survival. I drafted a manuscript with the help of the SWOG Statistical Center’s Cathryn Rankin, MS, and John Crowley, PhD. Six of the 13 coauthors strongly objected to a paragraph I had written in the

enrolled in the trial who were still benefitting. When Novartis volunteered to provide the drug to NCI/SWOG for the clinical trial, it already knew that the FDA had agreed to approve the investigational new drug for this GIST indication and thus would allow the drug to be sold for this new indication. This meant that once it became approved, each patient had to pay for his own drug. Our patients and their oncologists are of course grateful for the discovery and development of imatinib, but there are three D’s in clinical research: discovery, development, and delivery. Bill Gates and the Gates Foundation were the first to remind us about the third D: delivery. This essay, in part, is intended to address our delivery of potentially lifesaving drugs. Too often, academic oncologists don’t pay enough attention to the issue of drug delivery.

Queries for Pharma and NCI

2015 ASCO Annual Meeting—ASCO CEO Allen S. Lichter, MD, FASCO, congratulates outgoing ASCO President Peter Paul Yu, MD, FACP, FASCO, during the President's Dinner at the Annual Meeting on Friday, May 29, 2015. ©ASCO/Scott Morgan 2015

I invite my colleagues in the pharmaceutical companies to respond to these challenging queries: For 30 years or more, drugs were provided to all patients enrolled in National Institutes of Health clinical trials at no cost, even after the trial ended. Why the change in practice?

All pharmaceutical companies proclaim that their efforts are first and foremost to benefit patients. Is the change in practice consistent with these noble mission statements? When pharmaceutical companies justify drug pricing, they include discussion of the high cost of “discovery and development.” For example, a very conservative estimate suggests that if 100 patients took imatinib as in our trial for the past 10 years, the total cost for the drug would be $80 million paid to Novartis. Does the estimate of the discovery and development costs deduct the estimated income derived from selling the drug to study participants (ie, $80 million)? I also challenge my colleagues at the NCI: Why did you allow and accept this change in the delivery of drugs to patients who have volunteered for a clinical trial?

Queries for Oncologists I raise the following question to oncologists who value clinical trials, particularly those supported by the NCI and its National Clinical Trials Network: What would happen if we were to refuse to open a study that did not provide continued use of the drug for enrolled patients who are benefitting from the study drug once the trial has ended? And I pose this question to my oncology colleagues who manage these patients’ ongoing care: Is there anything we can do about this unjust practice? Oncologists at Memorial Sloan Kettering elected not to include the drug ziv-aflibercept (Zaltrap) in their formulary, in large part because of the price. In response, Sanofi dramatically lowered the price. So there has been success in voicing disapproval and, in turn, convincing pharmaceutical companies to lower their prices. Everyone is aware of the challenges patients face on a daily basis. No doubt there are bigger challenges than being forced to pay for drugs after volunteering for a clinical trial. But to continue this practice just seems wrong! n Disclosure: Dr. Baker has received grant support from the National Institutes of Health and the Gates Foundation. Hyatt Corporation provides a suite, but no grant support. He is President of the Board of the Hope Foundation and on the data safety monitoring board for CytRx and Morphotek. He has also served on advisory boards for Merck and Millenium.

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Clinical Trials

ASCO Announces First-Ever Clinical Trial

SCO announced its first-ever clinical trial, which will offer patients with advanced cancer access to molecularly targeted cancer drugs and collect “realworld” data on clinical outcomes, to help learn the best uses of these drugs outside of indications approved by the U.S. Food and Drug Administration (FDA). Plans for the Targeted Agent and Profiling Utilization Registry (TAPUR) study, including the participation of major pharmaceutical companies that will contribute free drugs, were discussed June 1 at the 2015 ASCO Annual Meeting in Chicago. The ASCO-sponsored prospective,

cancer treatments across many tumor types,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, FASCO. “Perhaps even more importantly, T APUR will involve community-based research programs, where the majority of cancer patients receive treatment, and will provide education and support to community oncologists to help them interpret complex genomic tests.”

Next Steps for TAPUR In the coming months, an Institutional Review Board will review the study protocol and consent form. In addition, ASCO

We are leveraging ASCO’s unique ability to bring together a diverse group of collaborators to undertake something that’s never been done before, all while simplifying access to multiple cancer treatments across many tumor types. —Richard L. Schilsky, MD, FASCO

nonrandomized clinical trial will collect information on the antitumor activity and toxicity of commercially available, targeted cancer drugs in a range of cancer types, including any advanced solid tumor, multiple myeloma, or non-Hodgkin lymphoma, with a genomic variation known to be a drug target. “Oncologists often use therapies approved for a specific cancer indication to treat people with other types of advanced cancer, but we very rarely learn from that experience to benefit other patients,” said ASCO Immediate Past President Peter Paul Yu, MD, FACP, FASCO. “TAPUR will document the real-world experience of patients who receive commercially available, targeted anticancer drugs and will describe the effectiveness and side effects of a range of targeted agents available in this study.” ASCO will organize the operational aspects of the study, including the participation of multiple collaborators who are central to TAPUR’s success. TAPUR will involve not only patients and physicians, but also ASCO oversight committees, pharmaceutical companies, technology firms, and community-based study sites—representing a uniquely innovative and inclusive approach to studying the use of molecularly targeted cancer drugs. “We are leveraging ASCO’s unique ability to bring together a diverse group of collaborators to undertake something that’s never been done before, all while simplifying access to multiple

has established three oversight committees, each of which will include patient representatives, clinical oncologists, statisticians, and genomics specialists.

Patient Participation TAPUR is designed to include a broader patient population than is typically enrolled in clinical trials. It will accept patients who have any advanced solid tumor, multiple myeloma, or B-cell non-Hodgkin lymphoma who are no longer responding to standard anticancer treatment or for whom no acceptable treatment is available. Patients will be screened to determine if they are healthy enough to participate based on broad inclusion/exclusion criteria. If and when a patient meets the defined trial criteria, their treating physician will select a drug from among those available in the TAPUR study protocol that targets the identified genomic variation in the patient’s tumor. If a relevant drug-target match is not described in the protocol, a physician may consult the Molecular Tumor Board, which will review the clinical and genomic features of the case and suggest potential therapies on or off the study. All patients who receive treatment through TAPUR will be monitored for standard toxicity and efficacy outcomes, including tumor response, progression-free and overall survival, and duration of treatment. Patients participating in TAPUR will receive the anticancer drugs at no charge. It is expected that routine clini-

cal care costs will be covered by the patient’s insurance plan.

Participating Organizations ASCO has invited a number of pharmaceutical companies to provide marketed, targeted drugs and additional resources to support the development of the new study’s infrastructure. At the time of this announcement, ASCO reported that AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Genentech, and Pfizer have signed memoranda of understanding, agreeing to participate in the TAPUR study. “At least 13 drugs that target more than 15 unique genomic variants will be provided by these companies. We are extremely grateful for the generosity of these companies, without whose support TAPUR would not be possible,” said Dr. Yu. “We anticipate additional companies will sign on and are extremely encouraged with the level of interest we have received so far.” ASCO will launch the TAPUR study at clinical sites that comprise the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan, and the Carolinas Healthcare System, with the ultimate goal of expanding nationally. Two technology companies will provide key support to manage, analyze, and interpret the study data. Syapse will provide its Syapse Precision Medicine Platform to automate the study workflow and the Molecular Tumor Board process and capture structured data from participating practices. Illumina will provide its NextBio knowledge base platform to support

and inform the case review by the Molecular Tumor Board, as well as to explore aggregate data analytics. Finally, ASCO will collaborate and share data with the Netherlands Center for Personalized Cancer Treatment, which is conducting a clinical trial using a study protocol very similar to TAPUR. “We are very fortunate that this leading cancer center has the same focus as TAPUR,” said Dr. Schilsky. “Technological advancements will allow us to pool our information in a seamless fashion and give us the ability to learn from the experience of a larger group of patients.”

Patient Advocates to Play a Key Role Patient advocates will play a central role throughout the study, providing guidance and oversight support. Jane Perlmutter, PhD, a cancer survivor and nationally recognized patient advocate, is lending her expertise in trial development, and will help coordinate patient advocate recruitment and training for the study. “TAPUR has enormous potential to improve our understanding of the effectiveness of currently available therapies in treating cancers with genomic variations, and to learn from patients who are treated with off-label drugs,” said Dr. Perlmutter. “I applaud ASCO for undertaking this important study and believe its findings will improve cancer care, especially for those with advanced cancer, for whom traditional therapies are no longer working.” For more information about TAPUR, please visit www.asco.org/ TAPUR. n

2015 ASCO Annual Meeting

General view at the 2015 ASCO Annual Meeting, Saturday, May 30 to June 2, 2015, held at the McCormick Place Convention Center in Chicago. Over 35,000 physicians, researchers, and health-care professionals from over 100 countries attended this 51st Annual Meeting. See next month's issue of The ASCO Post for continued coverage or visit ASCOPost.com. Photo by ©ASCO/Rodney White 2015.

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. Patients older than 65 years are at greater risk for hepatotoxicity [see Use in Specific Populations (8.5)]. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the groups receiving VOTRIENT and placebo, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients who received placebo on the trial had postbaseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction

(LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. In a randomized RCC trial of VOTRIENT compared with sunitinib, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared with baseline or a decline in LVEF of ≥10% compared with baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 13% (47/362) of patients on VOTRIENT compared with 11% (42/369) of patients on sunitinib. Congestive heart failure occurred in 0.5% of patients on each arm. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. 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 hemorrhage, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 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 (5.15.10, 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 Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 Adverse % % % % % % Reactions Diarrhea 52 3 <1 9 <1 0 Hypertension 40 4 0 10 <1 0 Hair color changes 38 <1 0 3 0 0 Nausea 26 <1 0 9 0 0 Anorexia 22 2 0 10 <1 0 Vomiting 21 2 <1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmarplantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below: Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms. Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

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Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC Who Received VOTRIENT and More Commonly (≥5%) in Patients Who Received VOTRIENT Versus Placebo VOTRIENT Placebo (N = 290) (N = 145) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 Parameters % % % % % % Hematologic Leukopenia 37 0 0 6 0 0 Neutropenia 34 1 <1 6 0 0 Thrombocytopenia 32 <1 <1 5 0 <1 Lymphocytopenia 31 4 <1 24 1 0 Chemistry ALT increased 53 10 2 22 1 0 AST increased 53 7 <1 19 <1 0 Glucose increased 41 <1 0 33 1 0 Total bilirubin increased 36 3 <1 10 1 <1 Phosphorus decreased 34 4 0 11 0 0 Sodium decreased 31 4 1 24 4 0 Magnesium decreased 26 <1 1 14 0 0 Glucose decreased 17 0 <1 3 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a singlearm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to <1% (1/145) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post-approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Eye Disorders: Retinal detachment/tear. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs that Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or BCRP should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant Use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs that Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and Cmax). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. 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 (preweaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning Day 21 postpartum (post-weaning). In the postweaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In pooled clinical trials with VOTRIENT, 30% (618/2080) of patients were aged >65 years. Patients aged >65 years had an increase in ALT elevations of >3 X ULN compared to patients aged <65 years (23% versus 18%) [see Warnings and Precautions (5.1)]. In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Postimplantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • 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 ©2015, the GSK group of companies. All rights reserved. Revised: 4/2015 VTR:14BRS Novartis recently acquired this product from GSK. To ensure a seamless transition, GSK is continuing to provide support for this product and related programs on behalf of Novartis at this time.

VOTRIENT® (pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1

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

VOTRIENT Placebo

11.1

MONTHS

9.2

MONTHS

7.4

Months

8 6 4

MONTHS

4.2

2.8

MONTHS

4.2

MONTHS

2 0

HR 0.46; 95% CI 0.34-0.62 (P<0.001) All patients

HR 0.40; 95% CI 0.27-0.60 (P<0.001) First-line patients

HR 0.54; 95% CI 0.35-0.84 (P<0.001) Cytokine-pretreated patients

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC of clear cell or predominantly clear cell histology were randomized (2:1) to receive either VOTRIENT 800 mg (n=290) once daily or placebo (n=145). The study included first-line patients receiving VOTRIENT (n=155) or placebo (n=78) as well as cytokine-pretreated patients receiving VOTRIENT (n=135) or placebo (n=67).

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. In a randomized RCC trial of VOTRIENT compared with sunitinib, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 13% (47/362) of patients on VOTRIENT compared with 11% (42/369) of patients on sunitinib. CHF occurred in 0.5% of patients on each arm. Monitor blood pressure (BP), and manage promptly using a combination of antihypertensive therapy and dose modification of VOTRIENT (interruption and reinitiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of CHF. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal (GI) hemorrhage in the past 6 months. • Arterial Thromboembolic Events: Arterial thromboembolic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients 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. Do not use VOTRIENT in patients who have had an arterial thromboembolic event in the past 6 months.

• Venous Thromboembolic Events (VTEs): VTEs have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. • Thrombotic Microangiopathy (TMA): TMA, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. • GI Perforation and Fistula: In RCC trials, GI perforation or fistula was reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events, and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension (HTN): HTN, including hypertensive crisis, has occurred in clinical trials. HTN occurs early in the course of treatment (approximately 40% of cases occurred by Day 9, and 90% of cases occurred in the first 18 weeks). BP should be well controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased BP promptly with standard antihypertensive therapy and dose reduction or interruption of VOTRIENT, as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if HTN is severe and persistent despite antihypertensive therapy and dose

reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of HTN. • 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 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein at baseline and periodically as clinically indicated. Interrupt treatment for 24-hour urine protein ≥3 grams, and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms, and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, GI hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. • Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation

Once-daily oral dosing1

VOTRIENT: Summary of serious and common adverse reactions1

• 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

• Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

• Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure

• 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

• If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In advanced RCC, initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced RCC trial, 42% of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose reduced

• Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting

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

Pazopanib (VOTRIENT®) has a Category 1 recommendation as a ﬁrst-line therapy in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for relapsed or Stage IV unresectable RCC of predominant clear cell histology. NCCN Guidelines® also include therapies other than pazopanib (VOTRIENT®) as ﬁrst-line options.3

Important Safety Information for VOTRIENT (cont’d) during early postnatal development, and resulted in toxicity to the lungs, liver, heart, and kidney, and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their health care provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. • Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. • Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. • Drug Interactions: Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases

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

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.

• Adverse Reactions in the Randomized RCC Trial: A dose interruption was required for 42% of patients on VOTRIENT. The VOTRIENT dose was reduced for 36% of patients. The most common adverse reactions (≥20%) for VOTRIENT vs placebo were diarrhea (52% vs 9%), HTN (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT vs placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GSK; 2015. 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 v3.2015. ©National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed April 13, 2015. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Novartis recently acquired this product from GSK. To ensure a seamless transition, GSK is continuing to provide support for this product and related programs on behalf of Novartis at this time.

VOTRIENT.com/HCP/aRCC

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

5/15

VRT-1114203

EFFICACY LIGHTS THE WAY

VOTRIENT is indicated for the treatment of advanced renal cell carcinoma (RCC).1 FDA-approved for treatment of advanced RCC since 2009

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® (pazopanib) tablets WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Patients older than 65 years are at an increased risk. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with preexisting moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant preexisting cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (eg, calcium, magnesium, potassium) within the normal range should be performed.

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. Novartis recently acquired this product from GSK. To ensure a seamless transition, GSK is continuing to provide support for this product and related programs on behalf of Novartis at this time.

EFFICACY LIGHTS THE WAY