TAP Vol 4 Issue 11 by Harborside Press LLC

Venous Thromboembolism

| Melanomas Induced by BRAF Inhibitors

| Metastatic Gastric Cancer

VOLUME 4, ISSUE 11

JULY 10, 2013

Editor-in-Chief, James O. Armitage, MD

ASCOPost.com

Despite a Recurrence, I’m Not Surrendering My Life to Cancer

ASCO Annual Meeting Plenary Presentation

Studies Explore Role of Bevacizumab in Combination Therapies for Glioblastoma By Caroline Helwick

By Selma R. Schimmel, as told to Jo Cavallo

t the 2013 ASCO Annual Meeting, studies evaluating the addition of bevacizumab (Avastin) to standard therapy in newly diagnosed glioblastoma multiforme patients did not meet their primary endpoints. When paired with irinotecan, however, Mark R. Gilbert, MD bevacizumab showed activity in MGMT-unmethylated tumors.

Bevacizumab plus Chemoradiotherapy In a phase III study presented at the Plenary Session by Mark R. Gilbert, MD, Professor and Deputy Chair of Neuro-oncology at The University of Texas MD Anderson Cancer Center, Houston, bevacizumab added to the upfront standard of care failed to

extend median overall survival. Although progression-free survival was improved in bevacizumab recipients, it did not meet the prespecified statistical target.1 “Molecular profiling studies may uncover tumor subsets that identify patients benefiting from firstline bevacizumab, but until this subgroup has been defined, these results do not support the use of bevacizumab for newly diagnosed glioblastoma,” Dr. Gilbert said. Based on bevacizumab’s activity in recurrent disease, the Radiation Therapy Oncology Group (RTOG) 0825 trial evaluated its first-line or early use in 637 newly diagnosed patients. Patients received chemoradiotherapy (temozolomide/radiotherapy→ temozolomide; standard of care) plus placebo or

Fateful Diagnosis I did everything I could to avoid getting ovarian cancer. When I was diagnosed with breast cancer in 1983 at the age of 28, it seemed that if I didn’t take control of my care I would continued on page 107

continued on page 14

Issues in Oncology

Supreme Court Rules Human Genes May Not Be Patented By Jo Cavallo

his is the first time I’m going public with the fact that I have advanced ovarian cancer. I thought I could avoid the fate of my mother and her mother, both of whom died of ovarian cancer in their 50s, and live well past my 60s and even 70s. But at 58, I’ve had to accept that that is not likely. I live and plan my life in shorter increments now and hope that new therapies will continue to buy me more time.

Selma R. Schimmel is the Founder and CEO of Vital Options International (vitaloptions.org), a cancer communications organization, which produces The Group Room and Advocacy in Action video programs. Ms. Schimmel lives in Southern California.

MORE IN THIS ISSUE the Supreme Court justices in the case Association for Molecular Pathology v Myriad Genetics,1 which concerned patents on BRCA1 and BRCA2 genes held by Myriad Genetics. Writing for the court, Justice Clarence Thomas said, “It is undisputed that Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 The Supreme Court decision is a genes.… To be sure, victory for genetic justice. The Court [Myriad] found an important and useful gene, got it right by supporting the most but separating that gene vulnerable of all: people with genetic from its surrounding geburden whom we need to support and netic material is not an act invention.… Laws of not burden unnecessarily because they of nature, natural phenomcan’t afford the genetic test. ena, and abstract ideas are not patentable.” —Olufunmilayo I. Olopade, MD, FACP

n June 13, the U.S. Supreme Court ruled unanimously that isolated human genes may not be patented. However, the creation of synthetic forms of DNA, known as complementary DNA (cDNA), is eligible for patent protection. The decision resolves the question brought before

See Dr. Olopade’s remarks on page 22

Send your comments to editor@ASCOPost.com

ASCO Annual Meeting Lung Cancer 3, 8 Leukemia 10 Breast Cancer 20, 23 Prostate Cancer 29 Colorectal Cancer 31 Direct from ASCO 51-54 Adjuvant Trastuzumab 63 FDA Update 65-67 First-line Erlotinib in Metastatic NSCLC 68 Endometrial Carcinomas 71 Erratum 102

continued on page 22

A Harborside Press® Publication

The ASCO Post | JULY 10, 2013

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Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

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George W. Sledge, MD Indiana University

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

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Cara H. Glynn, Director of Editorial Cara@harborsidepress.com Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com

Associate Editors

Alison Freifeld, MD University of Nebraska Medical Center

Joseph S. Bailes, MD Texas Oncology

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Michael Buckley, Art Director Michael@harborsidepress.com

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Terri Caivano, Kristina O’Toole, Layout Artists Terri@harborsidepress.com Kristina@harborsidepress.com

Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center

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

Philip D. Bonomi, MD Rush University Medical Center

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Richard Boxer, MD University of Wisconsin School of Medicine and Public Health

Michael P. Link, MD Stanford University Medical Center

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Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com

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

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Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Robert W. Carlson, MD National Comprehensive Cancer Network

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Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

William T. McGivney, PhD Philadelphia, Pennsylvania

Jay S. Cooper, MD Maimonides Medical Center

James L. Mulshine, MD Rush University Medical Center

Jacek Jassem, MD Medical University of Gdansk, Poland

John Cox, DO Texas Oncology

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

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

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@ asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2013 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lee S. Schwartzberg, MD University of Tennessee Health Science Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center Samuel Silver, MD, PhD University of Michigan Health System

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liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

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

ASCOPost.com | JULY 10, 2013

PAGE 3

ASCO Annual Meeting Thoracic Oncology

Second-generation ALK Inhibitor Breakthrough Drug Promising in Early Study for Non–Small Cell Lung Cancer By Alice Goodman

ncouraging results were seen in a preliminary study of a secondgeneration ALK inhibitor in advanced ALK-positive non–small cell lung cancer (NSCLC). The drug—dubbed LDK378—achieved tumor shrinkage in almost all patients enrolled in the study,

Alice T. Shaw, MD, PhD

in all mutational subsets, in crizotinib (Xalkori)-naive and crizotinib-resistant patients, and in patients with central nervous system (CNS) metastases.1 On the basis of these positive results, LDK378 has been awarded a Breakthrough Therapy designation by the U.S. Food and Drug Administration, and Novartis is about to initiate phase III studies of this new compound.

Study Background “LDK378 is a potent, next-generation ALK inhibitor for patients with advanced ALK-positive NSCLC. It achieved durable responses and a median progression-free survival of 8.6 months,” said lead investigator Alice T. Shaw, MD, PhD, Associate Professor of Medicine at Massachusetts General Hospital in Boston, who presented the study findings at the ASCO Annual Meeting. “The drug was generally well tolerated, as most of the common ad-

verse events were grades 1 and 2.” The first-generation ALK inhibitor crizotinib achieves overall response rates of about 60% and median progressionfree survival of about 8 to 10 months in ALK-positive patients. But a majority of patients develop resistance within 1 to 2 years, and relapses commonly occur in the central nervous system. LDK378 is active against ALK and many of the known resistant forms of ALK, including the gatekeeper mutant L1196M. The study included patients with locally advanced or metastatic ALK-positive NSCLC. Central nervous system metastases were allowed. Fiftynine patients were included in the doseescalation part of the study and 79 in the dose-expansion phase. Median age was 53 years, and 88% had an ECOG performance status of 0 or 1.

Major Findings In 122 patients evaluable for response, marked activity of LDK378 was observed, with almost all—including both crizotinib-naive and crizotinib-resistant patients—showing some degree of tumor shrinkage. A total of 114 patients were treated at doses of 400 to 750 mg/d. mg/d. In these patients, the overall response rate was 58%, with a rate of 57% in crizotinib-resistant patients and 60% in crizotinib-naive patients. Virtually identical response rates were seen among patients treated at the maximal tolerated dose of 750 mg/d, and this is the dose selected for future trials, Dr. Shaw said. Median duration of response to LDK378 was 8.2 months. The 6-month progression-free survival rate was 60.7%, but these data are not yet mature, she said.

LDK378 in Non–Small Cell Lung Cancer ■ LDK378 achieved excellent responses in advanced, metastatic ALK-positive non–small cell lung cancer.

■ Responses were seen regardless of types of mutations present, including those associated with resistance to crizotinib, and in crizotinib-naive patients.

■ LDK378 has been given Breakthrough Therapy designation by the FDA.

“We saw marked systemic and CNS responses associated with prolonged progression-free survival and duration of response,” she added.

Adverse Events LDK378 was generally well tolerated, but nausea, diarrhea, vomiting, and fatigue were observed in > 50% of patients. Grade 3 or 4 adverse events occurring in at least 5% of patients included elevated ALT (19%) and elevated AST (10%). Three patients discontinued therapy due to adverse events, and there have been no

treatment-related deaths. Genotypes of 19 patients were examined, and some had resistance mutations while others did not. Responses were seen regardless of mutational subtype. n

Disclosure: Dr. Shaw has a consultant or advisory role with ARIAD, Chugai Pharma, Novartis, and Pfizer.

Reference

1. Shaw AT, Mehra R, Kim DW, et al: Clinical activity of the ALK inhibitor LDK378 in advanced, ALK positive NSCLC. 2013 ASCO Annual Meeting, Abstract 8010. Presented June 3, 2013.

EXPERT POINT OF VIEW

“T

he definition of molecular subsets of lung cancer [in terms of] driver mutations has revolutionized the care of patients with non–small cell lung cancer [NSCLC],” said formal discussant Christine M. Lovly, MD, PhD, Instructor in Medicine at Vanderbilt-Ingram Cancer Center, Nashville. ALK rearrangements occur in about 5% of all NSCLC patients, primarily in younger patients, Christine M. Lovly, MD, PhD nonsmokers, and patients with adenocarcinoma. ALK gene fusion is also found in NSCLC and other cancers, and there are various fusion partners, but these cannot be identified by current ALK fluorescence in situ hybridization (FISH) testing, the current clinical gold standard. It is not clear whether specific fusion variants affect response rates to crizotinib (Xalkori) and other ALK inhibitors, but clinical diagnostics are under development to identify particular fusions.

Continuing Challenges LDK378 is highly potent with preclinical activity against all the mutations associated with resistance to crizotinib. The response to LDK378 in this study is comparable to that of crizotinib, Dr. Lovly noted. However, she cited the following remaining challenges: • Ascertaining presently unidentified mechanisms of resistance to ALK inhibitors and developing strategies to overcome them. • Identifying the best sequence of ALK tyrosine kinase inhibitor administration for ALK-positive lung cancer. • Anticipating mechanisms of resistance to LDK378, and developing strategies to overcome it. • Improving clinical responses with rational combination therapy, such as an HSP90 inhibitor, MEK inhibitor, mTOR inhibitor, or EGFR inhibitor. • Identifying whether differences in response rates are due to distinct fusions. n

Disclosure: Dr. Lovly has received honoraria from Abbott Molecular and the National Comprehensive Cancer Network.

The ASCO Post | JULY 10, 2013

PAGE 8

ASCO Annual Meeting Thoracic Oncology

First Positive Trial of Heat Shock Protein 90 Inhibitor in Lung Cancer That Has Progressed after First-line Therapy By Alice Goodman

he investigational heat shock protein (Hsp)90 inhibitor ganetespib plus docetaxel extended overall survival compared with docetaxel alone as second-line therapy in patients with advanced non–small cell adenocarcinoma of the lung that had progressed on firstline therapy in the randomized phase II GALAXY-1 trial, according to results presented at the ASCO Annual Meeting.1 If an ongoing phase III study of this combination confirms these findings and the FDA approves ganetespib, it would be the first new salvage therapy in this setting in a decade. “Ganetespib was well tolerated in combination with docetaxel, and overall survival was improved, especially in those patients who were at least 6 months from initial diagnosis of advanced cancer,” said lead author Suresh S. Ramalingam, MD, Professor of Hematology and Medical Oncology and Director of Medical Oncology at the Winship Cancer Institute of Emory University, Atlanta. “GALAXY-2, the phase III trial just launched, will compare the combination vs docetaxel alone in patients who are at least 6 months from initial diagnosis of advanced cancer,” he noted.2

Role of Hsp90 Hsp90 is a “chaperone” protein that helps > 200 client proteins perform their biologic function. In fact, Hsp90 is required for many proteins that drive lung cancer growth, including EGFR and ALK. Blocking Hsp90 with an inhibitor such as ganetespib disables activation of these cancerdriving proteins. Investigations of earlier-generation Hsp90 inhibitors were disappointing in terms of efficacy and safety. This is the first randomized

Visit

trial of a second-generation Hsp90 inhibitor.

Study Design The study enrolled 252 patients with advanced non–small cell lung cancer (stage IIIB/IV) that had progressed with one prior systemic therapy regimen and randomly assigned them to docetaxel plus ganetespib vs docetaxel alone as salvage therapy. Both groups were comparable at baseline. Median age was about 60 years, 56% were males, 75% were current or former smokers, 17% were from North America, and 83% were from Europe. Patients were stratified according to time from diagnosis (less than 6 months since diagnosis of advanced disease vs greater than 6 months), which was considered an in-

EXPERT POINT OF VIEW

ommenting on the ganetespib study, Marjorie G. Zauderer, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York, said that this first-in-class study suggests efficacy and represents a potential advance in lung cancer treatment. “We haven’t had any advances in a long time. We await the results of the phase III trial,” she said. Andrew D. Seidman, MD, another medical oncologist from Memorial Sloan-Kettering Cancer Center, said that heat shock protein 90 inhibitors are also being studied in breast cancer and other cancers. “This approach of harnessing a chaperone protein is applicable to other tumor types,” he stated. n Disclosure: Drs. Zauderer and Seidman reported no potential conflicts of interest.

all survival in all patients in the study by 32% (9.8 vs 7.4 months) compared with docetaxel alone. Median overall survival improved by 67% (10.7 vs 6.4 months with docetaxel alone) in patients who were more than 6 months

Ganetespib was well tolerated in combination with docetaxel, and overall survival was improved, especially in those patients who were at least 6 months from initial diagnosis of advanced cancer. —Suresh S. Ramalingam, MD

dicator of sensitivity to prior therapy, Dr. Ramalingam said. The combination was well tolerated, with safety findings similar to what is known about both ganetespib and docetaxel. Mild to moderate diarrhea was observed but was manageable with antidiarrheal medications. Grade 3/4 adverse events included neutropenia, fatigue, anemia, and febrile neutropenia, which occurred with a similar incidence in the two arms.

Survival Data The combination of ganetespib plus docetaxel improved median over-

from initial diagnosis, a significant difference (P < .01). The observed improvement in survival does not appear to be associated with EGFR or KRAS mutational status, Dr. Ramalingam commented. Median progression-free survival was 4.5 months on the combina-

tion and 3.2 months with docetaxel alone, representing a 16% reduction in risk of progression. Dr. Ramalingam did not report on the study’s primary endpoint—the effect of the combination on progression-free survival in patients with a KRAS mutation—noting that these data are not mature. n Disclosure: Dr. Ramalingam has served in a consulting or advisory role with Synta, but has not received any financial compensation.

References 1. Ramalingam SR, Goss GD, Andric ZG, et al: A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1). Abstract CRA8007. Presented June 3, 2013. 2. Fennell DA, Goss GD, Socinski MA, et al: GALAXY-2 trial: A randomized phase III study of ganetespib in combination with docetaxel versus docetaxel alone in patients with advanced non-small cell lung adenocarcinoma. 2013 ASCO Annual Meeting. Abstract TPS8126. Presented June 1, 2013.

Ganetespib Trial in Lung Cancer ■ A randomized phase II trial found that the heat shock protein 90 inhibitor

ganetespib plus docetaxel improved survival vs docetaxel alone as secondline salvage therapy in progressive non–small cell lung cancer.

■ If confirmed, this will be the first new agent in the second-line setting in over 10 years.

website at ASCOPost.com

NOW ENROLLING – A RANDOMIZED PHASE lll STUDY

A Phase III study of the pan-PI3K inhibitor buparlisib (BKM120) with fulvestrant in patients with HR+/HER2−, aromatase inhibitor-treated, locally advanced or metastatic breast cancer who progressed on or after mTOR inhibitor Postmenopausal women with HR+/HER2–, inoperable, locally advanced or metastatic breast cancer previously treated with an aromatase inhibitor (N≈615) Evidence of progression on or after mTOR inhibitor-based therapy No more than one prior line of chemotherapy for metastatic disease Archival tumor tissue for analysis of PI3K pathway activation

Molecular pre-screening*

ECOG Performance Status ≤2

Randomization (2:1)

Additional inclusion/exclusion criteria apply.

Buparlisib + fulvestrant

Placebo + fulvestrant

Primary endpoint: Progression-free survival Key secondary endpoint: Overall survival *Molecular pre-screening for PI3K activation status can occur at any time prior to randomization after obtaining pre-screening informed consent.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

Buparlisib (BKM120) is an investigational new drug. Efficacy and safety have not been established. There is no guarantee that buparlisib will become commercially available. For more information Contact your local Novartis representative. Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (USA only). Visit www.clinicaltrials.gov (NCT01633060). Visit the PRI3M program website at www.pri3m.com or scan the QR code.

Pioneering Research of PI3K inhibitors in Malignancies

www.pri3m.com Novartis Pharmaceuticals Corporation East Hanover, NJ 07936-1080

February 2013

G-BKE-1061803

Novartis Pharma AG CH-4002, Basel, Switzerland

The ASCO Post | JULY 10, 2013

PAGE 10

ASCO Annual Meeting Hematology

Idelalisib, Obinutuzumab Show Encouraging Results in CLL Studies By Alice Goodman

trio of presentations at the ASCO Annual Meeting focused on two promising investigational drugs for the treatment of chronic lymphocytic leukemia (CLL). These two drugs—idelalisib and obinutuzumab—join a list of new approaches showing potential.

Idelalisib Alone A phase I dose-ranging study of treatment with idelalisib for up to 48 weeks achieved a lymph node response of 81% and overall response rate of 72%.1 Responses were seen at all dose levels and in patients with high-risk mutations. The best nodal response was observed at doses of 150 mg twice daily, which is the recommended phase II dose. The trial enrolled 54 patients with CLL; 70% had refractory disease and had received a median of five prior therapies. A total of 31 patients discontinued treatment due to progressive disease and other causes, and 23 entered an extension phase (10 are still in remission). “Idelalisib is a highly selective inhibitor of PI3K�, �,, which impacts upon multiple pathways that are involved in cell

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survival and proliferation. Idelalisib was well tolerated, with no dose-limiting toxicities. The best responses were seen at higher doses,” said lead author Jennifer R. Brown, MD, PhD, Director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, Boston. The pattern of response to single-agent idelalisib showed a rapid decline in lymphoid mass accompanied by a rise in lymphocyte count, Dr. Brown said. Median time to response was 1 month, and median duration of response was 16.8 months. Treatment with idelalisib improved baseline cytopenias, which were seen in many patients (63% had low platelets, 46% had low hematocrit/anemia, and 28% had low neutrophils). Progression-free survival was 17.1 months, and median overall survival has not yet been reached.

Idelalisib plus Rituximab In a phase II single-arm study with an extension phase, idelalisib in combination with rituximab (Rituxan) achieved an overall response rate of 97% (19% complete response and 78% partial

Novel Agents for CLL ■ A promising strategy in newly diagnosed chronic lymphocytic leukemia

(CLL) that requires treatment, idelalisib combined with rituximab achieved almost universal responses in this setting.

■ Obinutuzumab in combination with chlorambucil achieved excellent

results in a pivotal phase III trial in elderly CLL patients with comorbidities.

response) in 64 patients who had not received any prior CLL therapy but required therapy at the time of study entry.2 At 24 months, 93% of participants had achieved progression-free survival. The addition of rituximab shifted the pattern of response seen in the phase I study reported by Dr. Brown, showing a nodal response at 8 weeks, as well as a rapid decline of lymphocytosis. At 48 weeks, median lymphocyte count returned to normal. “Idelalisib plus rituximab is a highly active combination in treatment-naive CLL. The high overall response rate and durable disease control observed in this phase II study suggest that idelalisib plus rituximab could become an important new therapeutic option for CLL pa-

EXPERT POINT OF VIEW

hese three excellent, encouraging, tantalizing studies show that we really are making progress in the treatment of chronic CLL, whereas 10 to 12 years ago, we had no real progress to report,” stated Kanti R. Rai, MD, Chief, CLL Research Program, North Shore-LIJ Medical Center, New Hyde Park, NY.

Idelalisib The phase I study by Dr. Brown and colleagues showed that idelalisib is unquestionably an attractive drug that was extremely effective in relapsed/refractory poor prognosis patients, he noted. “The drug achieved a dramatic shrinkage of lymph nodes never before seen after 7 to 8 days of therapy and staying power in lymph node shrinkage, but concern was raised about the increase in blood lymphocyte numbers. This led to the idea to combine idelalisib with rituximab [Rituxan], as was done in the study by Dr. O’Brien and colleagues,” Dr. Rai explained. “The addition of rituximab prevented the rise in lymphocyte count and achieved greater than 50% shrinkage of bulky lymphadenopathy.”

An important aspect of Dr. O’Brien’s trial is the population of older, sicker patients who have been neglected in clinical trials, even though CLL is a disease of the elderly and many have comorbidities, he continued. In this group of patients aged 65 and older, overall response rate was 97% and complete reponse rate was 19%. “This demonstrated that elderly patients, when given the combination of idelalisib and rituximab, have enormously positive results and tolerable toxicity. The adverse events such as diarrhea and pneumonia suggest that in the future we will have to learn how to use this combination effectively and more safely,” he stated.

Obinutuzumab The pivotal phase III III study of obinutuzumab confirmed that chlorambucil (Leukeran) may be an effective drug if used in combination with a monoclonal antibody, Dr. Rai continued. “In the United States, we have ‘thrown out’ chlorambucil, but the combination with obinutuzumab is extraordinarily more effective and probably more toxic, and we need to

Kanti R. Rai, MD

learn how to use this combination,” he stated. “Chlorambucil offers hope—not as a single agent, but in combination,” he emphasized. “I believe we should not be frightened by the toxicity seen with chlorambucil and obinutuzumab. We should go further with this and learn how to use it,” Dr. Rai said. “With at least 10 new drugs for CLL in the pipeline [including genetically engineered T cells through the introduction of a chimeric antigen receptor, or CART cells], this is a time for optimism, showing us what is next in CLL,” he concluded. n Disclosure: Dr. Rai reported no potential conflicts of interest.

tients new to treatment,” said Susan M. O’Brien, MD, Ashbel Smith Professor in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston. “No disease progression was observed in the study, including patients with 17p deletions and TP53 mutations,” she added. The most common adverse effect was diarrhea and laboratory abnormalities in transaminases. Myelosuppression was infrequent. The rate of infection of any grade was 67%; 23% of patients had infections classified as grade 3 or higher. Patients completing 48 weeks of therapy and free of progression could continue on an extension study; 43 patients completed 48 weeks, and 40 entered the extension phase. At the time of the ASCO Annual Meeting, 33 were still on treatment. During the primary and extension study, grade 33 diarrhea and/or colitis occurred in 33% of patients, and were the most common reasons for late discontinuations. Dr. O’Brien and colleagues found that this could be managed with budesonide if colitis and diarrhea were recognized early. Grade 3 or higher pneumonia was reported in 17% of patients, and grade 3 or higher transaminase elevations were seen in 23%.

Obinutuzumab In older, sicker patients with CLL, the combination of chlorambucil (Leukeran) and obinutuzumab (GA101) improved progression-free survival and complete response rate over chlorambucil, according to final results of a pivotal phase III trial.3 The combination of chlorambucil and obinutuzumab doubled progression-free survival compared with chlorambucil alone, from 10.9 to 23 months (P < .0001). Like rituximab, binutuzumab is an anti-CD20 monoclonal antibody, but it binds more strongly to B cells and may be more effective than rituximab per preclinical evidence. continued on page 12

Coming soon

Another option in short-acting G-CSF therapy

Âť FDA and EMA approved Brought to you by Tevaâ&#x20AC;&#x201D;a global leader experienced in developing and manufacturing biologics. Teva has a substantial portfolio of more than 50 oncology products in the US.

Learn more at tbofilgrastim.com Indication Tbo-filgrastim is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Important Safety Information Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue tbo-filgrastim and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving tbo-filgrastim. Acute respiratory distress syndrome (ARDS) can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving tbo-filgrastim for ARDS. Discontinue tbo-filgrastim in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue tbo-filgrastim in patients with serious allergic reactions. Do not administer tbo-filgrastim to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 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 tbo-filgrastim in patients with sickle cell disease. Discontinue tbo-filgrastim in patients undergoing a sickle cell crisis. The granulocyte colony-stimulating factor (G-CSF) receptor, through which tbo-filgrastim acts, has been found on tumor cell lines. The possibility that tbo-filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which tbo-filgrastim is not approved, cannot be excluded. The most common treatment-emergent adverse reaction that occurred in patients treated with tbo-filgrastim 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 Prescribing Information on adjacent page.

The ASCO Post | JULY 10, 2013

PAGE 12

ASCO Annual Meeting Novel Agents for CLL continued from page 10

“This is the first large phase III trial in elderly patients with comorbidities, a real-world population. Chlorambucil is the drug often used in these patients, because there is no conclusive evidence that any currently available therapy is superior to chlorambucil in older patients,”

explained lead author Valentin Goede, MD, Resident at the University of Cologne, Germany. The study had three stages: stage 1a compared obinutuzumab/chlorambucil (238 patients) vs chlorambucil (118 patients); stage 1b compared rituximab/ chlorambucil (233 patients) vs chlorambucil (118 patients); and stage 2

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR tbo-filgrastim Injection for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Tbo-filgrastim 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 tbo-filgrastim, discontinue tbo-filgrastim 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 tbo-filgrastim, for ARDS. Discontinue tbo-filgrastim 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 tbo-filgrastim in patients with serious allergic reactions. Do not administer tbo-filgrastim 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 tbo-filgrastim in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which tbo-filgrastim acts has been found on tumor cell lines. The possibility that tbo-filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which tbo-filgrastim 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)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with tbo-filgrastim 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. Tbo-filgrastim 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 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 tbo-filgrastim 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. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with tbo-filgrastim at the recommended dose and was numerically two times more frequent

Jennifer R. Brown, MD, PhD

than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% tbo-filgrastim, 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 tbo-filgrastim. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving tbo-filgrastim has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between tbo-filgrastim 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 There are no adequate and well-controlled studies of tbo-filgrastim in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. Tbo-filgrastim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the 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 (AUC0-24) 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 tbo-filgrastim 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 tbo-filgrastim in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of tbo-filgrastim, 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 tbo-filgrastim 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 tbo-filgrastim have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported.

Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA North Wales, PA 19454 Product of Israel FIL-40085

August 2012

This brief summary is based on the tbo-filgrastim full Prescribing Information.

Susan M. O’Brien, MD

Valentin Goede, MD

compared obinutuzumab/chlorambucil vs rituximab/chlorambucil. Results reported at the Annual Meeting focused on stage 1a and 1b. The head-to-head comparison of chlorambucil plus either obinutuzumab or rituximab will be presented later. In stage 1a, the overall response rate at the end of treatment was 76% with the combination of chlorambucil/obinutuzumab vs 30% for chlorambucil alone. The complete response rate was 22% vs 0%, respectively, and partial response rate was 53.3% vs 30.2%. In stage 1a, minimal residual disease–negative status in peripheral blood was achieved in 31.1% vs 0%. In stage 1b, overall response rate was 65.9% with rituximab/chlorambucil vs 30% with chlorambucil alone, complete response rate was 8.3% vs 0%, and partial response rate was 57.8% vs 30%. Minimal residual disease–negative status in peripheral blood was achieved in 2% vs 0%. Investigator-assessed progressionfree survival in stage 1a was a median of 23 months for obinutuzumab plus chlorambucil vs 11 months for chlorambucil alone, representing an 86% reduction in risk of disease progression favoring the combination. Investigatorassessed progression-free survival in stage 1b was 16 months for rituximab/ chlorambucil vs 11 months for chlorambucil alone, representing a 68% reduction in risk of disease progression. Increased rates of grade 3 or higher neutropenia were seen in both combinations, but the rate was 34% with the obinutuzumab combination and 25% with the rituximab combination vs 15% with chlorambucil alone. Grade 3 or higher infusion-related reactions occurred in 21% of the obinutuzumab/chlorambucil group, but this was only with the first infusion, Dr. Goede said. n

Disclosure: Drs. Brown and O’Brien have received research funding from Gilead Sciences. Dr. Goede is a consultant or advisor for and has received honoraria and research funding from Roche. References available at www.ASCOPost.com.

ASCOPost.com | JULY 10, 2013

PAGE 13

ASCO Annual Meeting Expert’s Corner

ASCO Will Change with the Times

A Conversation with ASCO President Clifford A. Hudis, MD, FACP By Caroline Helwick

t the 2013 ASCO Annual Meeting, The ASCO Post caught up with new President Clifford A. Hudis, MD, Chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York, for a glimpse of his plans for ASCO in the coming year, and his thoughts on being elected ASCO President for 2013–2014.

Goals In broad strokes, what are the overarching goals of your presidency? I envision several new things for ASCO. We will bring forward the ASCO Board’s strategic initiatives from the Board Retreat led this past spring by Sandy Swain [Sandra M. Swain, MD, FACP, Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center, Washington, DC], including a focus on team care in oncology and a focus on the definition of value in oncology. We are going to begin to confront the growing problem of obesity and energy balance as it relates to cancer. In addition to these initiatives, leading into our 50th Annual Meeting we will use this year to critically reflect on what we have done in the past, but more importantly what we need to do going forward, in order to best serve our members and their patients in the coming years. My goal is not for us to simply say how great we are but instead to use the occasion of the 50th anniversary to think hard and honestly about how the world is changing and how ASCO needs to change with it to have an even greater impact going forward. I think we are approaching a similar point of inflection in clinical care and scientific advances. We are currently investing in infrastructure, and people are asking, “What are we getting?” with the plethora of genomic studies, electronic medical records, “big data,” and so forth. I think the answer is that

we are getting better, more accurate, and more efficient care. Specifically, I am optimistic that we will turn a corner in medicine, as society turned a corner 2 decades ago, and see remarkable and measurable productivity gains in multiple directions. I think we will start to develop ways to leverage all the information we now have at our fingertips, learn from it, and do things more efficiently, all of which will lead to higher quality care with better outcomes.

Technology Can you elaborate on how emerging technology is changing cancer care? The disease we call cancer is divided into more than 200 diseases already, and it is about to become further sub-

delivering the highest quality information at the point of care. At the same time, being a doctor means engaging empathetically with our patients and their families, offering better understanding of treatments, side effects, and toxicities, and managing these optimally. To do this well, doctors will need to know more and more about a larger and larger range of treatments, and have the ability to manage patients with more subtle complaints and issues. Having access to more data and decision-making tools will greatly help us.

Presidency How will being ASCO President change your personal/professional life? Fortunately, I work in a very large

It’s an exciting time to be a doctor, especially one who treats patients with cancer. We are seeing advances being made at an unprecedented level, and they hold the promise of revolution in terms of outcomes of a cancer diagnosis. —Clifford A. Hudis, MD, FACP

divided because of what we are leaning about the molecular biology of tumors. This means that it will be even harder for anyone treating a range of diseases to keep up with all of the accelerating advances in every disease. It also means that patients who have a “common” disease may, in fact, have one that is actually an orphan. So, on the one hand, we will all need access to the kind of information that IBM’s Watson [computer that won Jeopardy!] and ASCO’s CancerLinQ might deliver. We may someday have these tools on mobile devices as well as our desktops. These are important initiatives that offer the promise of

cancer center that has committed to supporting me through this time, and I have a great team that is stepping up to help me maintain my practice and research. Much of this is possible because of electronic communications and the ability to work remotely, which makes balancing these responsibilities much easier now than it may have been in the past. In terms of my personal life, my wife and I are very busy professionally and our children are in college. We are lucky to have this opportunity come at this point in our lives when we can afford the time and the focus.

Election Have you considered why ASCO elected you President? I am not sure I can answer that! At ASCO, our desire is to make sure that everyone who is interested in serving has the opportunity. I believe that there are thousands of ASCO members who would make great leaders for this organization. With 33,000 members, the talent pool is enormous. I’m just fortunate to have been able to be so engaged with the organization and work with so many great people, and to be in the right place at the right time to stand for election. I am reminded of something I heard a few years ago when my son was entering college. The Dean at one of his friend’s schools made an observation at the beginning of the academic year, that as thrilled as he was with the freshman class of that competitive college, he was aware that he could have had the admissions committee reject 100% of those students and accept an equal number of other applicants from the applicant pool, and there would be no discernible difference in the nature of the class. I feel that way—just lucky to have this opportunity but humbled by the skills and leadership abilities I see in so many other ASCO members. Simply put, I do not believe that I’m the only person who could lead ASCO, but I am honored and thrilled to have the chance. It’s an exciting time to be a doctor, especially one who treats patients with cancer. We are seeing advances being made at an unprecedented level, and they hold the promise of revolution in terms of outcomes of a cancer diagnosis. I chose cancer medicine about 25 years ago because, even then, it was obvious to me that this field held the great promise of clinical benefit tied to exciting science. It’s truer today than ever. n

The ASCO Post | JULY 10, 2013

PAGE 14

ASCO Annual Meeting Plenary Presentation

Bevacizumab in Glioblastoma continued from page 1

chemoradiotherapy plus bevacizumab at 10 mg/kg every 2 weeks. Patients in the control arm could cross over to receive bevacizumab at disease progression, which 41% did. Overall survival and progressionfree survival were the co–primary endpoints of the study. The P values for statistical significance were .046 for overall survival and .004 for progression-free survival.

No Improvement in Co–Primary Endpoints After a median follow-up of 20.5 months, median overall survival was 15.7 months with bevacizumab and 16.1 months with standard therapy (hazard ratio [HR] = 1.13; P = .021) and median progression-free survival was 10.7 and 7.3 months, respectively (HR = 0.79; P = .007). A prespecified analysis of subgroups was performed based on MGMT promoter methylation and a 9-gene signature at baseline. Outcomes in the pooled treatment arms revealed interesting differences. Median overall survival for patients with MGMT-methylated tumors was 23.2 months, compared with 14.3 months for MGMT-unmethylated status (HR for unmethylated/methylated = 2.10; P < .001). Median progressionfree survival was 14.1 vs 8.2 months, respectively (HR for unmethylated/ methylated = 1.67; P < .001). The analysis did not identify a group of patients who derived benefit from first-line bevacizumab. “There was no definable group with an overall survival benefit with bevacizumab,” Dr. Gilbert reported. A number of patient-reported outcomes and measures of neurocognitive function worsened over time in the bevacizumab arm. “Symptom burden, neurocognitive function and qualityof-life data show an overall decline over time on first-line bevacizumab, pos-

EXPERT POINT OF VIEW

oward A. Fine, MD, Chief of Hematology/Oncology at New York University Langone Medical Center and Director of the NYU Brain Tumor Center, served as formal discussant of the RTOG 0825 study at the Plenary Session. He noted the strong rationale for studying bevacizumab in glioblastoma, which is a

diagnosed disease.” In addition, bevacizumab affects the biology and imaging of glioblastomas, making interpretation of trial data challenging, he said.

“we may be trading a steroid toxicity signal for a bevacizumab toxicity signal.… We still need to understand the biology to pin down the antitumor vs antiedema activity.”

Confounding Factors

Research Recommendations

Also discussing the bevacizumab studies was Albert Lai, MD, PhD, Assistant Clinical Professor in the Adult Brain Tumors section at the University of California, Los Angeles, Medical Center. “Most of us believe that bevacizumab does help patients, but how do we show it?” he asked. The potential for an overall survival benefit, Howard A. Fine, MD Albert Lai, MD, PhD which has not yet been demonstrated, would be highly vascular tumor that overex- confounded by crossovers in the studpresses vascular endothelial growth ies so far, he pointed out. “If bevacifactor (VEGF). Promising phase II zumab crossover is unavoidable, then studies in recurrent glioblastoma led the overall survival question becomes to FDA approval of bevacizumab in an issue of the timing of bevacizumab 2009, but the upfront setting may use, and it will be difficult to show a present unique challenges. benefit,” he predicted. “Glioblastoma progression through “For progression-free survival we bevacizumab is often associated with have some positive results, but what increased tumor cell invasiveness that do they mean clinically?” he added. appears to be VEGF- and largely anHe suggested that maintenance giogenesis-independent,” he said. “This of function may be the most relevant may, in part, be the reason why the data endpoint, and, if so, “we need to thordo not currently support the routine oughly and rigorously evaluate this,” use of bevacizumab as part of upfront he said. He further suggested that treatment in most patients with newly while bevacizumab is steroid-sparing, sibly reflecting unrecognized tumor progression because of the effects of antiangiogenic treatment on brain tumor imaging,” he said. Adverse events, including hypertension, thrombosis, wound issues, bowel perforation, hemorrhage, and neutropenia, were more common with bevacizumab.

Predicting Response Based on analysis of RTOG 0825

Bevacizumab Upfront in Glioblastoma ■ In newly diagnosed patients with glioblastoma multiforme, bevacizumab added to standard treatment did not improve overall survival or progression-free survival in the RTOG 0825 study.

■ The AVAglio study, similar in design, showed no overall survival benefit, but progression-free survival was extended with bevacizumab.

■ The phase II GLARIUS trial, on the other hand, demonstrated a 70%

reduction in the risk of progression with bevacizumab plus irinotecan in patients with MGMT-unmethylated tumors.

data, a correlative project called PRoB-GBM aimed to identify patients likely to respond to bevacizumab using molecular biomarkers. As reported by Erik P. Sulman, MD, PhD, Assistant Professor of Radiation Oncology at MD Anderson,2 the researchers used residual tissue from the MGMT/molecular stratification portion of the study in 234 patients to build the predictive model, characterizing 71% of the samples as genetically “favorable” and 29% as “unfavorable.” The upfront use of bevacizumab extended survival in patients with a PRoB-favorable molecular profile (20.3 months), compared to those with a PRoB-unfavorable profile (10.4 months)—a highly significant difference (P < .0001) that was not observed with standard therapy or with bevacizumab in the salvage setting.

Dr. Fine and Dr. Lai suggested that in the future, researchers should attempt to: • define radiographic, genetic, molecular and clinical biomarkers of glioblastomas that will most likely benefit from bevacizumab • include primary endpoints other than progression-free and overall survival • explore bevacizumab in combination with new agents that inhibit anti-VEGF–associated invasiveness • share data from all studies to resolve the discrepancies in quality-of-life and neurocognitive outcomes, as shown in RTOG 0825 and AVAglio “Despite these new data demonstrating its limitations, bevacizumab represents the single most important therapeutic agent in glioblastoma multiforme since temozolomide. Ongoing and future trials will better define how and when it should be optimally used in these patients,” Dr. Fine concluded. n

Disclosure: Drs. Fine and Lai reported no potential conflicts of interest.

AVAglio Study Similar findings were reported by Roger Henriksson, MD, PhD, Head of Experimental Research at Umeå University in Sweden, for the AVAglio study (see page 19), which had an identical study design and similar median overall survival (17 months in each arm) and median progression-free survival (10.6 months with bevacizumab vs 6.2 months with standard care, HR = 0.64, P < .0001).3 However, in AVAglio, healthrelated quality-of-life was improved for patients receiving bevacizumab, which differed from RTOG 0825. In AVAglio, this was measured using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). continued on page 18

DECODE metastatic melanoma. EXTEND survival. The first BRAF inhibitor shown to significantly extend overall survival (OS) vs dacarbazine in BRAF V600E (+) patients with unresectable or metastatic melanoma.1*

Indication and Usage: ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information on Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7-8 weeks. Potential risk factors included age ≥65 years, prior skin cancer, and chronic sun exposure. All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

*Trial design (N=675): patients with BRAFV600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF® (vemurafenib) tablets 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval. At the time of updated analysis (February 1, 2012 data cut-off), there were 199 deaths and 166 deaths in the ZELBORAF and dacarbazine arms, respectively.1,2

DECODE metastatic melanoma.

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

HR=0.44 (95% CI, 0.33-0.59), P<0.0001

Percentage surviving

80 60 Not reached

7.9

40 20 0

10 12 14 OS (months)

ZELBORAF (n=337)

Dacarbazine (n=338)

HR=hazard ratio CI=confidence interval *Trial design (N=675): patients with BRAFV600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. In both data analyses, results were censored at crossover.1,3 † At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine. ‡ There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

56% reduction in risk of death from any cause in patients treated with ZELBORAF® (vemurafenib) tablets vs dacarbazine (HR=0.44, P<0.0001; 95% CI, 0.33-0.59) Indication and Usage ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information (cont’d) Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, generalized rash and erythema, or hypotension, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT prolongation Exposure-dependent QT prolongation has been reported, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes.

Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval. Monitor ECG and electrolytes before treatment and after dose modification. Monitor ECGs at day 15, monthly during the first 3 months of treatment, every 3 months thereafter, or more often as clinically indicated. If the QTc exceeds 500 ms, temporarily interrupt ZELBORAF, correct electrolyte abnormalities, and control cardiac risk factors for QT prolongation. Re-initiate treatment at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. Liver laboratory abnormalities Liver laboratory abnormalities have occurred. Monitor liver enzymes and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity has been reported. Advise patients to avoid sun exposure and use adequate sun protection. For intolerable grade 2 or greater photosensitivity, dose modifications are recommended.

Learn more at Zelboraf.com/DECODE

SURVIVAL Significant OS improvement confirmed in an updated analysis§|| OS update at post-hoc analysis1¶ 100

HR=0.70 (95% CI, 0.57-0.87), P<0.001

Percentage surviving

80 60

13.6 9.7

Patients crossing over to ZELBORAF were censored.1 At the time of updated analysis (February 1, 2012 data cut-off), median follow-up was 12.45 months (range, 0.4-24.0 months) for ZELBORAF patients vs 9.45 months (range, 0.0-22.5 months) for those taking dacarbazine. Beyond 18 and 15 months for ZELBORAF and dacarbazine, respectively, the curves are not reliable due to limited follow-up.1,2 ¶ At the time of updated analysis, there were 199 deaths and 166 deaths in the ZELBORAF and dacarbazine arms, respectively.2 §

20 0

22 24

OS (months) Updated analysis of ZELBORAF

Updated analysis of dacarbazine

Median OS reached at 13.6 months with ZELBORAF: ~4-month improvement over dacarbazine median OS of 9.7 months (95% CI, 12.0-15.2 months vs 7.9-12.8 months)1,2 Ophthalmologic Reactions Serious ophthalmologic reactions, including uveitis and retinal vein occlusion, have been reported. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Routinely monitor patients for uveitis. Additionally, blurry vision, iritis, and photophobia were observed. New Primary Malignant Melanoma New primary melanomas were reported in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitor for skin lesions as outlined on previous page [see cuSCC]. Use in Pregnancy: Pregnancy Category D Apprise patients who are pregnant or who may become pregnant that ZELBORAF may cause fetal harm. BRAF Testing Confirmation of BRAFV600E(+) melanoma is required for appropriate patient selection. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.

The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. Presented at: the 48th Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. 2. Data on file. Genentech, Inc. 3. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/ drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed March 27, 2013.

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ASCO Annual Meeting Bevacizumab in Glioblastoma continued from page 14

Bevacizumab/Irinotecan in MGMT-unmethylated Tumors More encouraging results were reported for the phase II GLARIUS study, reported as a late-breaking abstract by Ulrich Herrlinger, MD, ZELBORAF ® (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. 5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. 5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values. 5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)]. 5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn. For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)]. 5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2. 5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)]. 5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

Professor of Clinical Neurooncology at the University of Bonn, Germany.4 In GLARIUS, 182 patients with MGMT-unmethylated glioblastoma received bevacizumab plus irinotecan or temozolomide, all given with radiation therapy at the standard dose for 6 weeks. Patients in the experimental arm received four cycles of bevaci-

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

zumab over 6 weeks of radiation, then bevacizumab plus irinotecan every 2 weeks until progression. Patients in the temozolomide arm received six courses of temozolomide. At 6 months, progression-free survival was significantly higher with bevacizumab/irinotecan: 9.74 vs 5.99 months (HR = 0.30; P <

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities*

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

Disclosure: Dr. Gilbert has a consultant/ advisory role with and has received honoraria from EMD Serono, Genentech, Merck, and Novartis, as well as research funding from Genentech, GlaxoSmithKline, and Merck. Dr. Sulman has received honoraria from Merck. Dr. Henriksson is a consultant or advisor for Roche and has received honoraria from Roche. Dr. Herrlinger is a consultant or advisor for Roche and has received honoraria and research funding from Medac and Roche.

Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 7 DRUG INTERACTIONS Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes with ZELBORAF* Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug. 4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritus 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)]. Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action. Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women. Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus. Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established. Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly disorders patients (≥ 65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine. Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC†# 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. disorders Cough Injury, poisoning and procedural complications Sunburn

.0001). Overall survival, the secondary endpoint, was also significantly longer, in spite of a 63% crossover rate: 16.6 vs 14.8 months (HR = .60; P = .031). The experimental arm also required less steroid use, Dr. Herrlinger reported. Patients in the experimental arm experienced more grade 3/4 vascular events, whereas those on temozolomide had more hematotoxicity. n

References 1. Gilbert MR, Dignam J, Won M, et al: RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab in patients with newly diagnosed glioblastoma. 2013 ASCO Annual Meeting. Abstract 1. Presented June 2, 2013. 2. Sulman EP, Won M, Blumenthal DT, et al: Molecular predictors of outcome and response to bevacizumab (BEV) based on analysis of RTOG 0825, a phase III trial comparing chemoradiation (CRT) with and without BEV in patients with newly diagnosed glioblastoma (GBM). 2013 ASCO Annual Meeting. Abstract LBA2010. Presented June 2, 2013. 3. Henriksson R, Bottomley A, Mason W, et al: Progression-free survival and health-related quality of life in AVAglio, a phase III study of bevacizumab, temozolomide and radiotherapy in newly diagnosed glioblastoma. 2013 ASCO Annual Meeting. Abstract 2005. Presented June 1, 2013. 4. Herrlinger U, Schaefer N, Steinbach JP, et al: Bevacizumab, irinotecan, and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-non-methylated glioblastoma patients: First results from the randomized multicenter GLARIUD trial. 2013 ASCO Annual Meeting. Abstract LBA2000. Presented June 1, 2013. Additional perspective on page 19

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PAGE 19

ASCO Annual Meeting Bevacizumab in Glioblastoma: Another Perspective By Roger Henriksson, MD, Warren Mason, MD, FRCPC, Olivier Chinot, MD, and Wolfgang Wick, MD, on behalf of the AVAglio Steering Committee

iven the results of the AVAglio trial, we feel that a more balanced discussion about the role of bevacizumab (Avastin) in patients with newly diagnosed glioblastoma is in order. The accompanying article in The ASCO Post suggests that bevacizumab has no benefit in newly diagnosed glioblastoma; data reported at ASCO by Henriksson et al1 and Wick et al2 have, however, highlighted the benefits of the combination of bevacizumab plus standard of care in this disease. We have summarized the key data below.

assessment was included as a mandatory secondary endpoint in this study. Compliance with health-related quality of life questionnaires was high in this study, compared with other studies in glioblastoma. The prespecified primary healthrelated quality of life analysis demonstrated significantly longer deterioration-free survival in global health status, physical functioning, social functioning, motor dysfunction, and communication deficit for patients receiving bevacizumab plus standard of

placebo arm (66 vs 47%, respectively) were able to discontinue corticosteroid use if they were taking corticosteroids at baseline. For patients off corticosteroids at baseline, those in the bevacizumab arm had a longer time to steroid initiation compared with those in the placebo arm (HR = 0.71, 95% CI = 0.57–0.88, P = .0018, 12.3 vs 3.7 months, respectively).1 Based on these data, we conclude that the addition of bevacizumab to standard of care can extend progression-free survival, as well as providing

Progression-free Survival We would first like to underline that AVAglio was a large phase III registration trial, including more than 920 patients worldwide, which assessed the benefit of adding bevacizumab to standard of care in the first-line treatment of patients with glioblastoma. The co-primary endpoints of AVAglio were investigator-assessed progression-free survival and overall survival. The trial was to be considered positive if the criteria for either one of thse endpoints were met. The progression-free survival coprimary endpoint was met, with a statistically significant and clinically meaningful improvement in progression-free survival reported in the bevacizumab arm (bevacizumab plus standard of care) compared with the placebo arm (placebo plus standard of care), with medians of of 10.6 vs 6.2 months (hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.55–0.74, P < .0001).2,3

Quality of Life AVAglio also reported further measures of clinical benefit with bevacizumab. The importance of healthrelated quality of life for glioblastoma therapy was acknowledged by the AVAglio study investigators, and accordingly health-related quality of life Dr. Henriksson is Head of the Regional Cancer Center, Stockholm, and Head of Experimental Research at Umeå University, Sweden; Dr. Mason is a medical oncologist in the Brain Tumour Clinic at Princess Margaret Hospital, Toronto, Ontario, Canada; Dr. Chinot is Head of the Neuro-Oncology Department at Aix-Marseille University, Marseille, France; and Dr. Wick is Chairman of Neuro-Oncology and Director of the National Tumor Center at the University of Heidelberg, Germany.

We believe that bevacizumab currently represents the most important therapeutic agent for glioblastoma aside from the standard of care. — Roger Henriksson, MD, et al

care vs placebo plus standard of care.1 Additional comprehensive post-hoc analyses were consistent with the conclusion that patients treated with bevacizumab plus standard of care had maintained health-related quality of life during their progression-free time.1

Other Endpoints Bevacizumab-treated patients also had a longer time to deterioration in Karnofsky performance status (HR = 0.65, 95% CI = 0.56–0.75, P < .0001) and a longer time during which a Karnofsky performance status ≥ 70 was maintained (9 vs 6 months), indicating that these patients were able to maintain functional independence for longer during their progression-free time, compared with their counterparts in the placebo arm.1 Maintained functional independence is considered an important treatment goal in glioblastoma therapy. The AVAglio study also assessed corticosteroid use as a measure of clinical benefit. The negative effects of corticosteroid use on neurocognitive function and quality of life are well documented. In AVAglio, more patients in the bevacizumab arm than

a meaningful clinical benefit as measured by health-related quality of life, functional status, and corticosteroid requirements.

Study Differences There are differences between the Radiation Therapy Oncology Group (RTOG) 0825 trial and the AVAglio study that should be acknowledged. The progression-free survival was significant in AVAglio, but not in the RTOG 0825 trial. The discrepancy between the two studies may be related to the statistical plan, the methodology, and/or the interpretation of the data. The health-related quality of life analysis for AVAglio also yielded contrasting results, despite using tools similar to those in RTOG 0825 (EORTC Quality of Life Questionnaires, QLQC30, and BN20). We observed that health-related quality of life was maintained for a longer duration in the bevacizumab arm, without any detrimental effect of bevacizumab, and we believe these results are reinforced by the high quality of the data collected in AVAglio, partly due to an outstanding compliance with the questionnaires throughout treatment.

Conclusions In the context of this debilitating disease, which has seen no improvements in therapy since 2005 despite the evaluation of numerous promising treatments, we believe (in agreement with ASCO discussant Howard A. Fine, MD [see page 14]), that bevacizumab currently represents the single most important therapeutic agent for glioblastoma aside from the standard of care. Moreover, according to the new data from RTOG 0825 and AVAglio, which do not concern recurrent therapy, bevacizumab may be useful in the upfront setting. n

Disclosure: Dr. Henriksson has received compensation for serving on the steering committee for this trial from F. HoffmannLa Roche. Dr. Mason has acted as a consultant for F. Hoffmann-La Roche and received compensation for serving on the steering committee for the AVAglio trial from F. Hoffmann-La Roche. Dr. Chinot has received honoraria from F. HoffmannLa Roche, AstraZeneca, and MSD, acted as a consultant for F. Hoffmann-La Roche, received research support from F. HoffmannLa Roche and Schering–Plough, and received compensation for serving on the steering committee for the AVAglio trial from F. Hoffmann-La Roche. Dr. Wick has acted as a consultant for F. Hoffmann-La Roche and Eli Lilly, received research support from Boehringer Ingelheim, Alogenix, and MSD, and received compensation for serving on the steering committee for the AVAglio trial from F. Hoffmann-La Roche.

References 1. Henriksson R, Bottomley A, Mason W, et al: Progression-free survival (PFS) and health-related quality of life (HRQoL) in AVAglio, a phase III study of bevacizumab (Bv), temozolomide (T), and radiotherapy (RT) in newly diagnosed glioblastoma (GBM). 2013 ASCO Annual Meeting. Abstract 2005. Presented June 1, 2013. 2. Wick W, Cloughesy TF, Nishikawa R, et al: Tumor response based on adapted Macdonald criteria and assessment of pseudoprogression (PsPD) in the phase III AVAglio trial of bevacizumab (Bv) plus temozolomide (T) plus radiotherapy (RT) in newly diagnosed glioblastoma (GBM). 2013 ASCO Annual Meeting. Abstract 2002. Presented June 1, 2013. 3. Chinot O, Wick W, Mason W, et al: Phase III trial of bevacizumab added to standard radiotherapy and temozolomide for newly-diagnosed glioblastoma: Mature progression-free survival and preliminary overall survival results in AVAglio. Neuro-Oncol 14(suppl):Abstract OT-03, 2012.

The ASCO Post | JULY 10, 2013

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ASCO Annual Meeting Breast Cancer

Search for Biomarkers of mTOR Inhibitor Benefit in Breast Cancer Fails to Pan Out By Caroline Helwick

he search for a biomarker of benefit from mTOR inhibitors in breast cancer fell flat in an exploratory genetic analysis of the

Gabriel N. Hortobagyi, MD, FACP

BOLERO-2 trial, presented at the 2013 ASCO Annual Meeting by Gabriel N. Hortobagyi, MD, FACP, Professor of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.1 The biomarker analysis involved 3,230 exons of 182 oncogenes and tumor-suppressor genes that were sequenced using next-generation sequencing on 309 tissue samples. Kaplan-Meier curves and summary descriptive statistics were calculated for each genetic alteration.

BOLERO-2 Outcomes In BOLERO-2, median progression-free survival was 7.8 months with everolimus (Afinitor) and 3.2

months with placebo—a 55% reduction in risk.2 Clinical outcomes for the next-generation sequencing population were similar, confirming that the sample was representative of the study population. Next-generation sequencing identified almost 1,500 sequence alterations, 24 rearrangements, and about 550 copy number variations. The average tumor sample contained 4.1 genetic alterations, and at least one known somatic alteration was identified in 219 patients. The genetic pathways harboring the most genetic alterations were PIK3CA (48%), CCND1 (31%), TP53 (23%), and FGFR1 (18%), Dr. Hortobagyi reported. As background, activating mutations in the catalytic domain of PI3K have been identified in about onethird of estrogen receptor–positive tumors. Up to one-third of patients with breast cancer show reduced expression of PTEN, and this has been associated with poor response to tamoxifen.

Equivalent Benefit across Subgroups There was a positive treatment effect in favor of everolimus across the various key genetic marker subgroups, pointing to the inability to identify subsets of patients most likely to benefit from the drug.

Biomarkers in BOLERO-2 ■ An exploratory biomarker analysis from the BOLERO-2 trial, using next-

generation sequencing, identified no genetic biomarkers that might help select patients for treatment with everolimus.

■ Patients with minimal alterations in key pathways appeared to derive the most benefit from the mTOR inhibitor, vs placebo.

New from The ASCO Post

EXPERT POINT OF VIEW

he results of the next-generation sequencing analysis of the BOLERO-2 samples showed that specific activating PIK3CA mutations are not in themselves predictive of clinical benefit from mTOR inhibitors, possibly because there are other ways to activate mTOR independently of PI3K. “It is probably more likely to predict response to specific PI3K inhibitors,” suggested the paper’s discussant, Stephen R.D. Johnston, MA, MD, PhD, Professor of Breast Cancer Medicine at The Royal Marsden Hospital in the United Kingdom. It appears that the more “normal” the estrogen receptor–positive cancer cell (ie, the fewer the mutations), the better the benefit from mTOR inhibitors, he noted. “Therefore we still should select for treatment on the basis of clinical criteria suggesting acquired resistance to previous nonsteroidal aromatase inhibitors. Perhaps future patients with multiple genetic alterations could avoid treatment and its associated toxicity,” Dr. Johnston suggested. n Disclosure: Dr. Johnston reported no potential conflicts of interest.

“This retrospective exploratory analysis found no predictive marker of everolimus efficacy in subgroups defined by each of the four most frequently altered genes and pathways, when assessed individually,” Dr. Hortobagyi reported. A greater benefit from everolimus treatment was derived in patients with minimal genetic alterations in PIK3CA/PTEN/CCND1 or FGFR1/2 genes combined, which represented 76% of the nextgeneration sequencing population. Patients with a single alteration in one of these pathways had a median progression-free survival of 214 days with everolimus, compared to 77 days with placebo (hazard ratio [HR] = .26). For those with multiple alterations, median progression-free survival was 138 and 128 days, respectively (HR = .28). Dr. Hortobagyi suggested that

the results, if validated, “may help to generate new hypotheses for combinations of novel targeted therapies as treatment for hormone receptor–positive/HER2-negative breast cancer.” n

Disclosure: Dr. Hortobagyi serves as a consultant to and receives research support (via his institution) from Novartis.

References 1. Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, et al: Correlation of molecular alterations with efficacy of everolimus in hormone receptor-positive, HER2-negative advanced breast cancer: Results from BOLERO-2. 2013 ASCO Annual Meeting. Abstract LBA509. Presnted June 3, 2013. 2. Hortobagyi GN, Piccart M, Rugo H, et al: Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. 2011 San Antonio Breast Cancer Symposium. Abstract S3-7. Presented December 8, 2011

NOW APPROVED IN A NEW INDICATION

Astellas and the Flying Star logo are trademarks of Astellas Pharma Inc. Tarceva is a trademark of OSI Pharmaceuticals, LLC, Farmingdale, NY 11735, USA, an affiliate of Astellas Pharma US, Inc. ÂŠ2013 OSI Pharmaceuticals, LLC, an affiliate of Astellas Pharma US, Inc., and Genentech, Inc. All rights reserved. 013E-071-8094 TAR0001879200 5/13

The ASCO Post | JULY 10, 2013

PAGE 22

ASCO Annual Meeting Human Genes Patent continued from page 1

The patents were challenged by scientists and health-care professionals concerned that their ability to help patients and conduct research had been undermined. In a statement posted on Myriad’s website,2 Peter D. Meldrum, President and CEO of Myriad, responded favorably to the Court’s decision, saying, “We believe the Court appropriately upheld our claims on cDNA, and underscored the patent eligibility of our method claims, ensuring strong intellectual property protection of our BRACAnalysis test moving forward.

More than 250,000 patients rely upon our BRACAnalysis test annually, and we remain focused on saving and improving peoples’ lives and lowering overall health-care costs.”

Price for Genetic Testing May Be Reduced Currently, the Myriad genetic test for BRCA1 and BRCA2 mutations costs more than $3,000 and is not always covered by insurance. Now that the Supreme Court has ruled that Myriad’s claims directed solely to the isolated human genes BRCA1 and BRCA2 are no longer valid and other companies will be allowed to develop their

Landmark Ruling ■ The Supreme Court ruled unanimously that isolated human genes may not

be patented. However, artificially constructed genes are eligible for patents because they are inventions and do not exist in nature. The decision concerned patents on BRCA1 and BRCA2 genes held by Myriad Genetics.

■ Costs for genetic testing for BRCA1 and BRCA2, which currently average

more than $3,000, may now come down as other companies develop their own tests for these genetic mutations, making them affordable to more women.

own tests for these genetic mutations, prices may come down, making them affordable to more women at high risk for breast and ovarian cancers. “Competition drives innovation. The cost of genetic sequencing has been coming down since 1994, but the price for doing BRCA1 and BRCA2 testing has been going up because there has been no competition,” said Olufunmilayo I. Olopade, MD, FACP, Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics and Director of the Center for Clinical Cancer Genetics at the University of Chicago Medicine. “The Supreme Court decision is a victory for genetic justice. The Court got it right by supporting the most vulnerable of all: people with genetic burden whom we need to support and not burden unnecessarily because they can’t afford the genetic test.” Praise for the ruling also came from Francis S. Collins, MD, PhD, Director of the National Institutes of Health, who said in a statement, “The decision represents a victory for all those eagerly awaiting more individualized, gene-

based approaches to medical care. The right to control exclusively the use of a patient’s genes could have made it more difficult to access new tests and treatments that rely on novel technologies that can quickly determine the sequence of any of the estimated 20,000 genes in the human genome. Such approaches form the cornerstone of the rapidly emerging field of personalized medicine, in which diagnostic, therapeutic, and preventive strategies can be tailored to each person’s unique genetic makeup.” n

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

References 1. Association for Molecular Pathology et al v Myriad Genetics, Inc, et al. Available at http://www.supremecourt.gov/ opinions/12pdf/12-398_1b7d.pdf. Accessed June 20, 2013. 2. Myriad Genetics, Inc: Supreme Court upholds Myriad’s cDNA patent claims: Court also highlights patent eligibility of method claims. Available at http://investor.myriad.com/releasedetail.cfm?releaseID=771232. Accessed June 20, 2013.

ASCO Impact Report Indicates Strong Interest in New Treatments for Melanoma and Cervical Cancer

ew treatments for melanoma and cervical cancer were cited as the most important subjects of new clinical information presented at the 2013 ASCO Annual Meerting, according to the second annual ASCO Impact Report released recently by Encuity Research. New treatments for melanoma, with an emphasis on PD-1 treatments, were cited by 31% of respondents, while advances in the treatment of cervical cancer were cited by 20% of respondents, as the most important new clinical information at the meeting.

Annual Meeting Reported As Valuable The ASCO Impact Report is based on a survey of 100 oncologists who attended the 2013 ASCO Annual Meeting and is

designed to gauge physician perceptions about the Annual Meeting and its effect on clinical practice. Respondents to the survey found ASCO to be valuable overall, with half of physicians having rated the event as very or extremely valuable, and 86% reporting that this year’s Annual Meeting was equal to or more valuable than the 2012 Annual Meeting. The ASCO Impact Report provides an encompassing view of ASCO attendees’ intent to change treatment plans and their perceptions of clinical information presented. Their ratings of information offered by pharmaceutical and biotech companies are also measured. For more information and to download a copy of the ASCO Impact Report, visit http://www .encuity.com/ASCO. n

Chicago–The 2013 ASCO Annual Meeting was held May 31 to June 4 at McCormick Place. Watch future issues of The ASCO Post for continuing comprehensive coverage of the meeting.

ASCOPost.com | JULY 10, 2013

PAGE 23

ASCO Annual Meeting Breast Cancer

Benefit for Dual HER2 Targeting in Neoadjuvant Breast Cancer Regimen Restricted to Subset of Patients By Caroline Helwick

s a neoadjuvant regimen for HER2-positive early breast cancer, the use of two HER2-directed agents was no more effective than trastuzumab (Herceptin) alone in producing pathologic complete responses, although one subset of patients did benefit from this approach, according to the results of the Cancer and Leukemia Group B (CALGB) 40601 trial

Lisa A. Carey, MD

reported at the 2013 ASCO Annual Meeting by Lisa A. Carey, MD, Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research at The University of North Carolina at Chapel Hill.1 “The addition of lapatinib [Tykerb] to 16 weeks of weekly trastuzumab/ paclitaxel did not meet the predefined criteria for a significant increase in

pathologic complete responses,” she announced at the Annual Meeting. “The numerical increase is modest. We now need to determine which tumors can benefit from treatment with dual vs single HER2 targeting.” The study did show higher pathologic complete response rates, however, among the molecular subtype defined as HER2-enriched. CALGB 40601 questioned whether patients with stage II or III HER2positive breast cancer could benefit more from two anti-HER2 agents vs single-agent trastuzumab, plus chemotherapy in the adjuvant setting. “Early evidence in stage IV disease and in the neoadjuvant setting have suggested that dual targeting may be beneficial, using mainly lapatinib or pertuzumab [plus trastuzumab],” she said. “There are adjuvant trials in progress evaluating dual targeting (ALTTO, Aphinity), so this question is quite relevant.” Patients were randomly assigned to receive trastuzumab/paclitaxel, trastuzumab/paclitaxel plus lapatinib, or lapatinib/paclitaxel, all given for 16 weeks prior to surgery. (The third arm was discontinued early due to lack of efficacy and is not part of this analysis.)

EXPERT POINT OF VIEW

riya Rastogi, MD, Associate Professor of Medicine at the University of Pittsburgh Medical Center, discussed the findings at the session. She noted that previous studies have also shown higher pathologic complete response rates among HER2-enriched patients who were hormone receptor–negative, and higher rates in more aggressive subtypes. “CALGB 40601 is consistent with research from similar studies demonstrating increased pathologic complete responses with dual Priya Rastogi, MD blockade plus chemotherapy, vs single agents,” at least in a subset of patients, she said. She noted that the study was most similar to NSABP B-41, as in both studies the trastuzumab/chemotherapy arm performed better than anticipated. In NSABP B-41, pathologic complete response rates were 52.5% with trastuzumab and 62% with dual blockade (P = .095), while in the current study these rates were 46% and 56%, respectively (P = .12). In general, dual blockade consistently increases pathologic complete response rates, reaching 61% to 77% in the hormone receptor–negative subtype, she noted. But dual blockade also adds toxicity and expense, and since it does not benefit all patients, researchers must identify a means of predicting which patients benefit from it, she added. n Disclosure: Dr. Rastogi reported no potential conflicts of interest.

Dual HER2 Targeting for Neoadjuvant Therapy ■ CALGB 40601 showed a numerical but not a statistically significant

difference in the achievement of pathologic complete responses with the addition of lapatinib to trastuzumab, vs trastuzumab alone (plus paclitaxel).

■ Patients with hormone receptor–negative tumors had higher pathologic

complete response rates after dual blockade (77% vs 55%), especially the HER2-enriched subset (89% vs 80%).

Intravenous paclitaxel 80 mg/m2 was given once weekly while lapatinib was given orally at a daily dose of 750 mg. Trastuzumab was given intravenously at a loading dose of 4 mg/kg and then at 2 mg/kg once a week. The primary endpoint was pathologic complete response, defined as the absence of invasive cancer in the breast.

Response Rates Differ by Hormone Receptor Status The rates of pathologic complete response in the breast were 56% for the three-drug combination and 46% for trastuzumab/paclitaxel, but this 10% difference was not statistically significant. By hormone receptor status, some differences did emerge. Patients with hormone receptor–negative tumors had higher pathologic complete response rates after dual blockade (77% vs 55%), but the differences were modest in the hormone receptor–positive tumors (42% vs 39%). In either group, the improvement with the addition of lapatinib was not significant (Fig. 1). When the definition of pathologic complete response incorporated the axillae, results were similar to what

was seen in the breast alone, with pathologic complete response rates of 52% with dual targeting and 43% with the single agent in the overall population. Rates in the hormone receptor– positive group were 42% vs 38%, and in the hormone receptor–negative group were 66% vs 51%, respectively, she said. Grade 3 and 4 toxicities were higher with the addition of lapatinib. Dr. Carey noted that other neoadjuvant studies of HER2 inhibition have shown numerical differences with the addition of a second anti-HER2 agent, and two were statistically significant: NeoSPHERE (pertuzumab plus trastuzumab and docetaxel) and NeoALTTO (lapatinib plus trastuzumab and weekly paclitaxel). “What jumps out is that pathologic complete response is numerically increased with dual targeting, and while this was significant in NeoSPHERE and NeoALTTO, the differences were not significant in our study,” she said, suggesting that underlying differences in study populations might explain this discordance. continued on page 29

100%

77%

90% 80% 70% 60%

42%

50%

55%

31%

37%

39%

40% 30% 20% 10% 0%

T H L (69)

T H (69)

T L (35)

HR-positive (n=173)

T H L (47)

T H (49)

T L (35)

HR-negative (n=123)

Fig.1: CALGB 40601: Pathologic complete response rates in breast cancer by hormone receptor status. Abbreviations: H = trastuzumab; HR = hormone receptor; L = lapatinib; T = paclitaxel. Courtesy of Lisa A. Carey, MD.1

INDICATION: Iclusig™ (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase

chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Iclusig (ponatinib) Unlock efficacy for resistant or intolerant CML and Ph+ ALL patients ™

IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY See full prescribing information for complete boxed warning • Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. • Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity. Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, has occurred in Iclusig-treated patients. Overall, 11% of patients experienced an arterial thrombosis event of any grade, and serious arterial thrombosis occurred in 8% of Iclusigtreated patients. 30 of 34 patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors. Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. Hepatotoxicity: Hepatotoxicity that has resulted in liver failure and death occurred in 3 Iclusig-treated patients with BP-CML or Ph+ ALL. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver

function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated. Congestive Heart Failure: Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure (CHF) or left ventricular dysfunction (LVD), with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of CHF or LVD. Monitor patients for signs or symptoms consistent with CHF and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious CHF. Hypertension: Eight patients treated with Iclusig (2%) experienced treatmentemergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations. Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage: Serious bleeding events occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients.

C H R O N I C P H A S E C M L (C P - C M L ) More than half of CP-CML patients resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy achieved MCyR.

44%

(144/267)

MCyR 95% CI: 48-60 (118/267)

CCyR 95% CI: 38-50 Most patients who achieved MCyR also achieved CCyR.

Median duration of follow-up was 10 months.1

Efficacy in T315I 70% of CP-CML patients with the T315I mutation (45/64) achieved MCyR (95% CI: 58-81), and 66% (42/64) achieved CCyR (95% CI: 53-77). Iclusig is a 45 mg oral tablet taken once daily with or without food.

Learn more about Iclusig’s efficacy in patients with the T315I mutation and all phases of resistant or intolerant CML and Ph+ ALL at Iclusig.com.

Tablet is not shown at actual size. Iclusig was evaluated in a single-arm, open-label, international, multicenter trial. All patients were administered 45 mg of Iclusig once daily. Patients were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML [BP-CML]/Ph+ ALL), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation. The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR).

The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage. Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated. Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended. Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy. Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig. The most common non-hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia. Please see the brief summary of the Prescribing Information on the following pages, including the Boxed Warning. Note: Unless otherwise indicated, data presented are from Iclusig [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2012. Reference: 1. Data on file.

BRIEF SUMMARY Iclusig (ponatinib) Rx only Please consult full Prescribing Information, including Boxed Warning, available at Iclusig.com.

WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY Arterial Thrombosis: • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

required urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Treatment-emergent hypertension occurred in 67% of patients (300/449) [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations. 5.5

Clinical pancreatitis occurred in 6% (28/449) of patients (5% grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Hepatotoxicity: • Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. 1

INDICATIONS AND USAGE

5.6

This indication is based upon response rate [see Clinical Studies (14)]. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig. CONTRAINDICATIONS

5.7

WARNINGS AND PRECAUTIONS

5.1

Thrombosis and Thromboembolism Arterial Thrombosis

In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%).

Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients.

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Serious arterial thrombosis occurred in 8% (34/449) of Iclusig-treated patients. Twenty-one patients required a revascularization procedure (16 patients with coronary revascularization, 4 patients with peripheral arterial revascularization, and 1 patient with cerebrovascular revascularization). Overall, fifty-one patients (11%) experienced an arterial thrombosis event of any grade.

5.8

Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

Serious cerebrovascular events were reported in 2% (8/449) of Iclusig-treated patients. Two patients experienced hemorrhagic conversion of the initial ischemic event. Four patients developed stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, middle cerebral artery). Serious peripheral arterial events were reported in 2% (7/449) of Iclusig-treated patients. Three patients developed digital or distal extremity necrosis; 2 of these patients had diabetes mellitus and peripheral arterial disease and required amputations. Thirty of 34 Iclusig-treated patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors (e.g., myocardial infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking). Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3)].

5.9

5.10 Tumor Lysis Syndrome Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Both cases occurred in patients with advanced CML. Hyperuricemia occurred in 7% (30/449) of patients, the majority had chronic phase CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig. 5.11 Compromised Wound Healing and Gastrointestinal Perforation No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Hepatotoxicity Hepatotoxicity that has resulted in liver failure and death occurred in Iclusig-treated patients. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts. The incidence of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing. 5.12 Embryo-Fetal Toxicity Iclusig can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Ponatinib caused embryo-fetal toxicity in rats at exposures lower than human exposures at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig [see Use in Specific Populations (8.1)].

Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)]. 5.3

Congestive Heart Failure Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure or left ventricular dysfunction, with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious congestive heart failure [see Dosage and Administration (2.3)].

5.4

Hypertension Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. These patients

Myelosuppression Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with accelerated phase CML (AP-CML), blast phase CML (BP-CML) and Ph+ ALL than in patients with chronic phase CML (CP-CML). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended [see Dosage and Administration (2.2)].

Venous Thromboembolism Venous thromboembolic events occurred in 3% of Iclusig-treated patients, including deep venous thrombosis (9 patients), pulmonary embolism (4 patients), and 1 case each of portal vein thrombosis, and retinal vein thrombosis. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

Cardiac Arrhythmias Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).

Myocardial infarction or worsening coronary artery disease was the most common arterial thrombosis event and occurred in 21 patients (5%) of Iclusig-treated patients. Eleven of these patients developed congestive heart failure concurrent or subsequent to the myocardial ischemic event.

5.2

Fluid Retention Fluid retention events judged as serious occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. Serious fluid retention events in more than 1 patient included: pericardial effusion (6/449, 1%), pleural effusion (5/449, 1%), and ascites (2/449, <1%).

None 5

Hemorrhage Serious bleeding events, occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.9)]. Interrupt Iclusig for serious or severe hemorrhage [see Dosage and Administration (2.3)].

Iclusig™ (ponatinib) is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

Pancreatitis

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following adverse reactions are discussed in greater detail in other sections of the prescribing information: • Thrombosis and Thromboembolism [see Warnings and Precautions (5.1)] • Hepatotoxicity [see Warnings and Precautions (5.2) and Dosage and Administration (2.3)] • Congestive Heart Failure [see Warnings and Precautions (5.3)]

• Hypertension [see Warnings and Precautions (5.4)] • Pancreatitis [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)] • Hemorrhage [see Warnings and Precautions (5.6)] • Fluid Retention [see Warnings and Precautions (5.7)] • Cardiac Arrhythmias [see Warnings and Precautions (5.8)] • Myelosuppression [see Dosage and Administration (2.2) and Warnings and Precautions (5.9)] The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. At the time of analysis, the median duration of treatment with Iclusig was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg, or 83%, of the expected 45 mg dose. Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 4. Overall, the most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. The rates of treatment-emergent adverse events resulting in discontinuation were 13% in CPCML, 11% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%). Dose modifications (dose delays or dose reduction) due to adverse reactions occurred in 74% of the patients. The most common adverse reactions (≥5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%). Table 4: Adverse Reactions Occurring in >10% of Patients, Any Group CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) System Organ Class Any CTCAE Any CTCAE Any CTCAE Any CTCAE Grade Grade Grade Grade Grade Grade Grade Grade (%) 3/4 (%) 3/4 (%) 3/4 (%) 3/4 (%) (%) (%) (%) Cardiac or Vascular disorders Hypertension (a) 68 39 71 36 65 26 53 31 Arterial ischemia (b) 13 7 12 6 8 5 3 0 Cardiac Failure (c) 6 4 6 2 15 11 6 6 Gastrointestinal disorders Abdominal pain (d) 49 10 40 8 34 6 44 6 Constipation 37 2 24 2 26 0 47 3 Nausea 23 1 27 0 32 2 22 0 Diarrhea 16 1 26 0 18 3 13 3 Vomiting 13 2 24 0 23 2 22 0 Oral mucositis (e) 10 1 15 1 23 0 9 3 GI hemorrhage (f) 2 <1 8 1 11 5 9 6 Blood and lymphatic system disorders Febrile neutropenia 1 <1 4 4 11 11 25 25 Infections and infestations Sepsis 1 1 5 5 8 8 22 22 Pneumonia 3 2 11 9 13 11 9 3 Urinary tract infection 7 1 12 1 0 0 9 0 Upper respiratory tract infection 11 1 8 0 11 2 0 0 Nasopharyngitis 9 0 12 0 3 0 3 0 Cellulitis 2 1 4 2 11 3 0 0 Nervous system disorders Headache 39 3 28 0 31 3 25 0 Peripheral neuropathy (g) 13 2 8 0 8 0 6 0 Dizziness 11 0 5 0 5 0 3 0 Respiratory, thoracic, and mediastinal disorders Pleural effusion 3 1 11 2 13 0 19 3 Cough 12 0 17 0 18 0 6 0 Dyspnea 11 2 15 2 21 7 6 0 Skin and subcutaneous tissue disorders Rash and related conditions 54 5 48 8 39 5 34 6 Dry skin 39 2 27 1 24 2 25 0 Musculoskeletal and connective tissue disorders Arthralgia 26 2 31 1 19 0 13 0 Myalgia 22 1 20 0 16 0 6 0 Pain in extremity 17 2 17 0 13 0 9 0 Back pain 15 1 11 2 16 2 13 0 Muscle spasms 12 0 5 0 5 0 13 0 Bone pain 12 <1 12 1 11 3 9 3 General disorders and administration site conditions Fatigue or asthenia 39 3 36 6 35 5 31 3 Pyrexia 23 1 31 5 32 3 25 0 Edema, peripheral 13 <1 19 0 13 0 22 0 Pain 8 <1 7 0 16 3 6 3 Chills 7 0 11 0 13 2 9 0 Metabolism and nutrition disorders Decreased appetite 8 <1 12 1 8 0 31 0 Investigations Weight decreased 6 <1 7 0 5 0 13 0 Psychiatric disorders 0 12 0 8 0 9 0 Insomnia 7

Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity. Treatment-emergent, all causality events (a) derived from blood pressure (BP) measurement recorded monthly while on trial (b) includes cardiac, central nervous system, and peripheral arterial ischemia (c) includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure (d) includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort (e) includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration (f) includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage (g) includes burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, polyneuropathy

Table 5: Serious Adverse Reactions (SAR) Cardiovascular disorders Arterial ischemic event Myocardial infarction or worsening coronary artery disease Stroke or TIA Peripheral arterial disease Hemorrhage CNS hemorrhage Gastrointestinal hemorrhage Cardiac failure Effusions* Atrial fibrillation Venous thromboembolism Hypertension Gastrointestinal disorders Pancreatitis Abdominal pain Blood and lymphatic system disorders Febrile neutropenia Thrombocytopenia Anemia Infections Pneumonia Sepsis General Pyrexia

N (%) 34 (8%) 21 (5%) 8 (2%) 7 (2%) 22 (4%) 10 (2%) 10 (2%) 20 (4%) 13 (3%) 11 (2%) 10 (2%) 8 (2%) 23 (5%) 17 (4%) 13 (3%) 13 (3%) 12 (2%) 24 (4%) 11 (2%) 14 (3%)

*includes pericardial effusion, pleural effusion, and ascites

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 6). Table 6: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Laboratory Test CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) (%) (%) (%) (%) Hematology Thrombocytopenia 36 47 57 47 (platelet count decreased) Neutropenia (ANC decreased) 24 51 55 63 Leukopenia (WBC decreased) 14 35 53 63 Anemia (Hgb decreased) 9 26 55 34 Lymphopenia 10 26 37 22 ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count *Reported using NCI-CTC-AE v 4.0

Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test Safety Population N=449 Any Grade* Grade 3/4 (%) (%) Liver function tests ALT increased 53 8 AST increased 41 4 Alkaline phosphatase increased 37 2 Albumin decreased 28 1 Bilirubin increased 19 1 Pancreatic enzymes Lipase increased 41 15 Amylase increased 3 <1 Chemistry Glucose increased 58 6 Phosphorus decreased 57 8 Calcium decreased 52 1 Sodium decreased 29 5 Glucose decreased 24 0 Potassium decreased 16 2 Potassium increased 15 2 Sodium increased 10 <1 Bicarbonate decreased 11 <1 Creatinine increased 7 <1 Calcium increased 5 0 Triglycerides increased 3 <1 ALT=alanine aminotransferase, AST=aspartate aminotransferase. *Graded using NCI-CTC-AE v 4.0

DRUG INTERACTIONS

8.7

Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)]. 7.1

Drugs That Are Strong Inhibitors of CYP3A Enzymes In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

7.2

Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)]. Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.3

Drugs That Elevate Gastric pH Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.4

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy Pregnancy Category D Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while taking Iclusig. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis. At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/ day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

8.3

Nursing Mothers It is unknown whether ponatinib 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 ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

8.4

Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

8.5

Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6

Hepatic Impairment Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

Renal Impairment

OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally selfadministered 165 mg on cycle 1 day 2. The patient experienced fatigue and non-cardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion. In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment. Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234

For information contact: 1-855-55-ARIAD (855-552-7423) medinfo@ariad.com PB/0513/0019/US

ASCOPost.com | JULY 10, 2013

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ASCO Annual Meeting Genitourinary Oncology

Two New Genetic Tests Offer Progress in Personalized Medicine for Newly Diagnosed Prostate Cancer By Alice Goodman

t least 12 different genetic tests for prostate cancer are under development. The two tests currently available are Oncotype DX (Genomic Health, Redwood City, California) and Prolaris (Myriad Genetic Labora-

Peter R. Carroll, MD, MPH

tories, Salt Lake City). Both tests can identify which low-risk patients are “truly” at low risk and can be managed by active surveillance and which ones should seek immediate treatment.

Genomic Prostate Score The Oncotype DX prostate cancer assay can determine whether men with newly diagnosed low-risk prostate cancer (ie, Gleason score of 6) are appropriate candidates for watchful waiting or harbor more aggressive disease sugesting the need for primary treatment

Dual HER2 Targeting continued from page 23

She added that the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 trial also failed to show significant differences in pathologic complete response. “It is not clear why this is so,” she told The ASCO Post. “However, CALGB 40601 and NSABP B-41 included higher proportions of women with hormone receptor–positive disease.”

HER-enriched Subtype An exploratory analysis of tissue samples showed that “within the HER2-positive population there is considerable molecular heterogeneity,” Dr. Carey noted. “The intrinsic subtypes appear to differ in sensitivity to HER2-targeting agents, with numerically highest pathologic complete response rates among the HER2-enriched subtype.” The pathologic complete response

with surgery or radiotherapy. Recently launched by Genomic Health Inc, the Oncotype DX prostate cancer assay is similar (in the sense that it assays gene expression) to the Oncotype DX breast cancer assay used to determine whether women with node-negative early breast cancer should be treated with chemotherapy and whether women with ductal carcinoma in situ should receive radiation. Oncotype DX for prostate cancer is a biopsy-based assay of the levels of expression of 17 genes that can predict the aggressiveness of prostate cancer. A genomic prostate score ranging from 0 to 100 is derived from the prostate specimen to determine the level of risk. “The [genomic prostate score] helps assign men with newly diagnosed low-risk prostate cancer to active treatment or not. It also might be appropriate for a subset of intermediate-risk men with low-volume disease who might be assigned to active surveillance,” said H. Jeffrey Lawrence, MD, Senior Director of Medical Affairs at Genomic Health, at ASCO.

EXPERT POINT OF VIEW: ONCOTYPE DX

“P

rostate cancer is a heterogeneous disease and has not yet benefitted from personalized medicine discoveries. Anything that gets us closer to personalized medicine [for prostate cancer] is a plus,” said Michael J. Nicholas Vogelzang, MD Michael J. Morris, MD Morris, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York, when asked about the Oncotype DX prostate cancer assay. “To decide which patients are appropriate for active surveillance on a molecular basis would be great. It is fabulous to have a foothold in personalized medicine,” he added. Nicholas Vogelzang, MD, Comprehensive Cancer Centers of Las Vegas, said that he has already begun to use the Oncotype DX assay in his practice. “It has great promise. I see a lot of men with Gleason 6 scores who don’t want surgery, yet they have a tremendous amount of anxiety. This test could reassure those patients. The biggest issue from my perspective is insurance coverage,” Dr. Vogelzang commented. “This test is a great example of precision medicine. You would like to know which group of men with Gleason 6 scores should not be managed by active surveillance,” Dr. Vogelzang stated. n Disclosure: Drs. Morris and Vogelzang reported no potential conflicts of interest.

continued on page 30

rates were 75% among the HER2enriched subset, but lower for the normal-like subtype (50%), basal-like subtype (36%), and luminal A subtype (35%), and lowest of all for the luminal B subtype (29%). By treatment arm and subtype, the highest rates were achieved by HER2-enriched patients receiving trastuzumab/paclitaxel plus lapatinib (89%), followed by HER2-enriched patients receiving trastuzumab/paclitaxel alone (80%). The rates were lowest (25%) for patients with basal-like and luminal B tumors receiving only trastuzumab.

Breast-conserving Surgery A preplanned surgical endpoint was the incidence of breast-conserving therapy, reported by David W. Ollila, MD, Professor of Surgery at The University of North Carolina.2 In the combined treatment arms, 43% of women considered ineligible

for breast-conserving surgery at baseline were able to undergo breast-conserving surgery after neoadjuvant therapy. The pathologic complete response rate in this group was 43%; in patients who remained ineligible, 44% achieved a pathologic complete response.

ineligible after neoadjuvant therapy. Altogether, 76% of all patients were eligible for an attempt at breastconserving therapy after neoadjuvant therapy, and 79% of these attempts were successful, Dr. Ollila reported. “Neoadjuvant chemotherapy combined with targeted anti-HER2 treatment permits the potential for breastconserving therapy in approximately 80% of selected patients,” he said. n

Disclosure: Dr. Carey has received research funding from Genentech, Sanofi Oncology, and GlaxoSmithKline. Dr. Ollila reported no potential conflicts of interest.

David W. Ollila, MD

Of the 42% of women initially deemed eligible, 94% ultimately underwent lumpectomy; 55% of this group achieved a pathologic complete response, compared with 29% of women initially eligible but deemed

References 1. Carey LA, Berry DA, Ollila D, et al: Clinical and translational results of CALGB 40601. 2013 ASCO Annual Meeting. Abstract 500. Presented June 2, 2013. 2. Ollila DW, Berry DA, Cirrincione C, et al: Impact of neoadjuvant chemotherapy plus HER2-targeting on breast conservation rates. 2013 ASCO Annual Meeting. Abstract 501. Presented June 2, 2013.

The ASCO Post | JULY 10, 2013

PAGE 30

ASCO Annual Meeting Genetic Tests in Prostate Cancer continued from page 29

Dr. Lawrence and colleagues found that the 17-gene expression patterns that predict prostate cancer aggressiveness are similar in tumor and normal prostate tissue.1 The genomic prostate score derived from tumor-based gene expression patterns in the tumor was also associated with clinical tumor recurrence when assessed in adjacent normal prostate tissue, but the strength of the association was less robust than in tumor. The genes associated with the

Eric A. Klein, MD

strongest predictive value of the genomic prostate score in normal tissue were those representing stromal response and androgen signaling. “These results suggest the presence of an underlying field effect within the tumor-containing prostate gland that is associated with the development and presence of aggressive prostate cancer,” Dr. Lawrence stated.

Validation Study The clinical validation study of the Oncotype DX prostate cancer assay was presented at the 2013 meeting of the American Urological Association in San Diego.2 The test, developed jointly by investigators at UCSF and the Cleveland Clinic, significantly predicted the aggressiveness of disease (P = .002) beyond clinical factors (including prostate-specific antigen [PSA] level and Gleason Score obtained at biopsy. “Use of the test tripled the number of patients who were good candidates for active surveillance and identified a smaller number of patients who despite low-risk status had more aggressive disease and were candidates for immediate treatment,” stated principal investigator Peter R. Carroll, MD, MPH, Professor and Chair of the Department of Urology at the University of California (UCSF), San Francisco in a news release from Genomic Health. The percentage of patients identified as having very low risk disease

went from 5% to 10% based on PSA level and Gleason score to 26% when the genomic prostate score was factored into the assessment. These patients could be confident about active surveillance. However, about 10% of patients originally classified as low or very low risk by clinical factors were identified as having more aggressive disease when the genomic prostate score was added to PSA level and Gleason score, and these patients should be considered for immediate treatment. Dr. Carroll stated that the use of the genomic prostate score may significantly increase the use of active surveillance. “In the past, use of active surveillance has been limited to some extent by the absence of a validated genomic tool to more accurately distinguish between low- and high-risk diseases at the time of biopsy,” he added. The test is estimated to cost about $3,800. Genomic Health is in the process of building a dossier of evidence for insurers. “We are familiar with this type of dossier from experience with Oncotype DX for breast cancer, which is now reimbursed by Medicare and 90% of other insurers. We are optimistic that the same will be true for the prostate cancer assay,” said Eric A. Klein, MD, Cleveland Clinic, lead author of the study on the Oncotype DX prostate cancer test presented at the Annual Meeting.

Jack Cuzick, PhD

cine, Barts and the London School of Medicine, London, who presented the study at the ASCO Annual Meeting. He reviewed results of five retrospective studies to show the usefulness of the cell-cycle progression score. The score is calculated by measuring the average RNA expression of 31 cell-cycle progression genes normalized by the average expression of 15 housekeeping genes as quantitated by reverse transcriptase–polymerase chain reaction. “We use so many genes, because if one fails, we still have enough information for prognostic value,” he said.

Key Findings A 1-unit change in cell-cycle progression score score represents a doubling of the expression of the 31 genes. The five studies included patients undergoing transurethral resection of the

Prolaris: Retrospective Studies Like Oncotype DX, Prolaris can identify which patients are “truly” at low risk and can be managed by active surveillance, potentially reducing overtreatment of prostate cancer. Prolaris is also being marketed as a test for the postprostatectomy patient with high-risk features after surgery; it is intended to estimate the risk of tumor recurrence and to guide the adjustment of therapy accordingly. A retrospective review of studies of the Prolaris test found that the cell-cycle progression score (CCP) was able to predict prostate cancer outcomes in multiple patient cohorts and in diverse clinical settings.3 “The [cell-cycle progression score] provides independent information above and beyond traditional PSA levels and Gleason scores. Right now, it is useful in low-risk patients to determine who needs therapy and who should be assigned to active surveillance,” stated Jack Cuzick, PhD, Director of Cancer Research at the UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medi-

prostate, needle biopsy with conservative management, radical prostatectomy (two studies), and external-beam radiation therapy. The first two studies reported prostate cancer death, and the last three studies used biochemical tumor recurrence as an endpoint. The median follow-up was over 10 years. A similar distribution of cell-cycle progression scores was found in all five studies. “This shows that the distribution is largely independent of the circumstances in which the test is used,” he said. The cell-cycle progression score emerged as a significant predictor in both univariate and multivariate analyses. Dr. Cuzick added, “The predictive value of the [cell-cycle progression score] almost wiped out the predictive value of the Gleason score.” He also said, however, that the endpoints of the study are different, and this gives an indication of broad applicability, but they can’t strictly be combined. n

Disclosure: Dr. Lawrence is an employee of Genomic Health. Dr. Klein receives a consulting fee from Genomic Health but does not own stock in the company and has no other financial interest in Oncotype Dx or Genomic Health. Dr. Cuzick receives honoraria and research funding from Myriad Genetics. Dr. Carroll reported no potential conflicts of interest.

References available at www.ASCOPost.com

EXPERT POINT OF VIEW: PROLARIS

cott Tomlins, MD, PhD, a pathologist at the University of Michigan, Ann Arbor, was cautiously optimistic about this new test. “Whenever you introduce a new biomarker, you need to demonstrate its ability to impact clinical decision-making, and it needs to improve on what we currently have,” he commented. “It is unlikely that the [cellcycle progression score] will replace the [prostatespecific antigen (PSA)] value and the Gleason score, so it needs to show benefit when added to Scott Tomlins, MD, PhD models that optimally incorporate these and other parameters.” Most patients have multifocal disease, and analysis of the cores taken at biopsy may not catch the different foci. In those cases, the clinically relevant tumor focus may not be the one analyzed, he explained. Unanswered questions remain: Can these scores predict cores that are not sampled? Does incorporating this novel biomarker improve on the accuracy of currently available models that incorporate PSA values and Gleason score? “This has not been shown yet,” Dr. Tomlins cautioned. “How much does the [cell-cycle progression score] improve on the Cancer of the Prostate Risk Assessment [CAPRA, a 10-point risk-assessment score developed at the University of California, San Francisco] at diagnosis? What would doctors do if the [cell-cycle progression score] showed a lower risk? Adoption of this test will require buy-in from different sectors of the healthcare community,” he concluded. n Disclosure: Dr. Tomlins reported no potential conflicts of interest.

ASCOPost.com | JULY 10, 2013

PAGE 31

ASCO Annual Meeting Gastrointestinal Oncology

Best First-line Treatment for Advanced Colorectal Cancer Remains Unclear By Caroline Helwick

n patients with advanced colorectal cancer, it remains unclear which biologic agent added to standard chemotherapy is best, even after a headto-head comparison of two commonly used agents.

Volker Heinemann, MD, PhD

In the phase III FIRE-3 trial, conducted by the German AIO CRC Study Group, the addition of cetuximab (Erbitux) provided about a 4-month increase in overall survival, compared to bevacizumab (Avastin), but the primary endpoint—overall response rate— was not improved, according to principal investigator Volker Heinemann, MD, PhD, Professor of Medical Oncology at the University of Munich in Germany. The study was presented at an oral session by Sebastian Stintzing, MD, who is currently a postdoctoral fellow at the University of Southern California/Norris Comprehensive Cancer Center.1

Study Rationale and Design Dr. Heinemann explained the rationale at a press briefing. “So far, it’s unclear which targeted agent—ce-

tuximab or bevacizumab—should be used preferentially first-line. This is important since the drugs have different mechanisms of action and side-effect profiles. FIRE-3 aims to determine the optimal choice.” The study compared the efficacy of cetuximab vs bevacizumab when added to FOLFIRI (leucovorin, fluorouracil, irinotecan) in 592 patients with previously untreated wild-type KRAS metastatic colorectal cancer. Patients received FOLFIRI every 2 weeks plus cetuximab (400 mg/m2 on day 1, followed by 250 mg/m2 weekly) or FOLFIRI plus bevacizumab (5 mg/ kg) every 2 weeks. Median duration of treatment with all three study drugs was 4.8 months for the cetuximab combination and 5.3 months for the bevacizumab combination. The cetuximab arm received significantly fewer cycles than the bevacizumab arm (10 vs 12, P = .014). Patients were followed for a median of 33 and 39 months in the two groups, respectively.

Primary Endpoint Missed In the intent-to-treat analysis, the study did not meet its primary endpoint of an improvement in objective response rate, which was 62% with FOLFIRI/cetuximab and 58% with FOLFIRI/bevacizumab (odds ratio = 1.18; P = .183). Similarly, median progression-free survival was comparable at 10.0 and 10.3 months, respectively (hazard ratio = 1.06; P = .547). However, in the subgroup of 526

Cetuximab vs Bevacizumab in Metastatic Colorectal Cancer ■ In a head-to-head comparison of cetuximab vs bevacizumab as a first-line agent in metastatic colorectal cancer, the primary endpoint—an increase in response rate in the intent-to-treat population—was not met.

■ In the subgroups of patients who received at least three cycles of therapy

and had a post-treatment CT scan, responses were significantly improved with cetuximab.

■ Median overall survival was significantly improved with cetuximab but median progression-free survival was not.

EXPERT POINT OF VIEW

he FIRE-3 investigators did not report the use of salvage treatments, and this may be confounding the results, according to Richard Goldberg, MD, who discussed the paper at an ASCO press briefing. Dr. Goldberg is Professor of Medicine at The Ohio State University, Columbus. “The study shows a survival advantage, and the investigators are a very reputable group, so I believe their data. But I believe that within the data there are stories we have yet to understand,” he said. Richard Goldberg, MD “Today because of multiple effective drug treatments, treating advanced colon cancer is analogous to a baseball game in which we have many innings. Perhaps the first inning is the most important, but it is likely that all the innings contributed to the contest’s final outcome. In this case, different lines of therapy are analogous to different innings and all likely contributed to the overall survival,” Dr. Goldberg suggested. He advised the investigators to revisit the data and examine all subsequent lines of treatment. “This could help explain a finding that does seem a bit anomalous,” he commented. n Disclosure: Dr. Goldberg has served on data monitoring committees for Eli Lilly and Pfizer.

patients who were assessable for response—defined as having had three cycles of chemotherapy and one postbaseline CT scan—a statistically significant benefit emerged in the cetuximab arm, which had a response rate of 72.2% vs 63.1% in the bevacizumab arm (odds ratio = 1.52; P = .017). “The objective response rate favored cetuximab but did not reach the level of significance within the intent-to-treat population. However, the response rate was significantly greater by 10% with cetuximab in the assessable patients. We believe this relates to the survival benefit we saw with cetuximab,” he said. While not a primary endpoint, median overall survival was significantly longer with cetuximab, 28.7 months vs 25.0 months with bevacizumab (hazard ratio = .77; P = .017).

Deeper Tumor Shrinkage? There are indications, according to Dr. Heinemann, that cetuximabbased therapy “causes deeper tumor shrinkage” than bevacizumab. “The difference in response rates in the

assessable patients and the slightly higher rate of complete responses indicates there may be some truth to that,” he said. Another explanation may be that the sequence of anti-EGFR directed followed by anti-VEGF-directed therapy may have a beneficial effect on outcome. Data regarding treatment sequence will be presented at a later meeting this year. “Based on our findings, we believe a substantial gain in survival can be obtained when physicians offer cetuximab to patient with KRAS wild-type tumors,” Dr. Heinemann said. n

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

Reference 1. Heinemann V, von Weikersthal LF, Decker T, et al: Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE3). 2013 ASCO Annual Meeting. Abstract LBA3506. Presented June 1, 2013.

The ASCO Post | JULY 10, 2013

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JCO Spotlight Supportive Care

Updated ASCO Clinical Practice Guideline for Venous Thromboembolism Prophylaxis and Treatment By Matthew Stenger

SCO has released a new evidencebased clinical practice guideline for venous thromboembolism prophylaxis and treatment, updating the 2007 practice guideline.1 The update is based on a systematic review of literature published from December 2007 to December 2012. An Update Committee reviewed evidence to determine which of the prior recommendations required revision. The update provides recommendations about six clinical questions, as summarized below.

Six Questions Should hospitalized patients with cancer receive anticoagulation for venous thromboembolism prophylaxis? ■ Those who have active malignancy with acute medical illness or reduced mobility should receive pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications. ■ Those who have active malignancy without additional risk factors may be considered for pharmacologic thromboprophylaxis in the absence of bleeding or other con-

traindications. ■ Data are inadequate to support routine thromboprophylaxis in patients admitted for minor procedures or short chemotherapy infusion, or in patients undergoing stem cell/bone marrow transplantation. Should ambulatory patients with cancer receive anticoagulation for venous thromboembolism prophylaxis during systemic chemotherapy? ■ Routine pharmacologic thromboprophylaxis is not recommended in cancer outpatients. ■ Based on limited randomized controlled trial data, clinicians may consider low–molecular-weight heparin prophylaxis on a case-by-case basis in highly selected outpatients with solid tumors receiving chemotherapy. Consideration of such therapy should be accompanied by a discussion with the patient about the uncertainty concerning benefits and harms, as well as dose and duration of prophylaxis in this setting. ■ Patients with multiple myeloma receiving thalidomide (Thalomid)or lenalidomide (Revlimid)-based regimens with chemotherapy and/ or dexamethasone should receive

pharmacologic thromboprophylaxis with either aspirin or low–molecularweight heparin for lower-risk patients and low–molecular-weight heparin for higher-risk patients. Should patients with cancer undergoing surgery receive perioperative venous thromboembolism prophylaxis? ■ All patients with malignant disease undergoing major surgical interven-

Awareness of … disparities in access to care should be considered in the context of this clinical practice guideline and health care providers should strive to deliver the highest level of cancer care to these vulnerable populations.

■ ■

Venous Thromboembolism Expert Panela Gary H. Lyman, MD, MPH, FRCP (Edin), Co-Chair, Duke University Medical Center Anna Falanga, MD, Co-Chair, Ospedali Riuiniti Bergamo, Italy Daniel Clarke-Pearson, MD, University of North Carolina Christopher Flowers, MD, MS, Winship Cancer Institute Charles W. Francis, MD, University of Rochester Medical Center Leigh Gates, Patient Representative, University of Colorado Mohammad Jahanzeb, MD, University of Tennessee Ajay Kakkar, MD, PhD, Barts and The London School of Medicine, Thrombosis Research Institute Alok A. Khorana, MD, University of Rochester Medical Center Nicole M. Kuderer, MD, Duke University Medical Center Mark Levine, MD, PhD, McMaster University Howard A. Liebman, MD, University of Southern California David S. Mendelson, MD, Premiere Oncology Gary Edward Raskob, PhD, University of Oklahoma Health Sciences Center Paul A. Thodiyil, MD, New York Methodist Hospital David Trent, MD, PhD, Virginia Cancer Center a All members of the Expert Panel complied with ASCO policy on conflicts of interest. For full disclosures of the Panel members, visit www.JCO.ASCOPubs.org.

What is the best method for treatment of patients with cancer with established venous thromboembolism to prevent recurrence? ■ Low–molecular-weight heparin is preferred over unfractionated heparin for the initial 5 to 10 days of anticoagulation for the patient with cancer and newly diagnosed venous thromboembolism who does not have severe renal impairment (defined as creatinine clearance < 30 mL/min).

■

tion should be considered for pharmacologic thromboprophylaxis with either unfractionated heparin or low– molecular-weight heparin unless contraindicated because of active bleeding or high bleeding risk. Prophylaxis should be commenced preoperatively. Mechanical methods may be added to pharmacologic thromboprophylaxis but should not be used as monotherapy for venous thromboembolism prevention unless pharmacologic methods are contraindicated because of active bleeding or high bleeding risk. A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest-risk patients. Pharmacologic thromboprophylaxis for patients undergoing major surgery for cancer should be continued for at least 7 to 10 days. Extended prophylaxis with low–molecular-weight heparin for up to 4 weeks postoperatively should be considered for patients undergoing major abdominal or pelvic surgery who have such high-risk features as restricted mobility, obesity, history of venous thromboembolism, or additional risk factors (specified in full guideline). In lower-risk surgical settings, the decision on appropriate duration of thromboprophylaxis should be made on a case-by-case basis considering the individual patient.

■ For long-term anticoagulation, low– molecular-weight heparin for at least 6 months is preferred due to improved efficacy over vitamin K antagonists. Vitamin K antagonists are an acceptable alternative for long-term therapy if low–molecular-weight heparin is not available. ■ Anticoagulation with low–molecular-weight heparin or vitamin K antagonists beyond the initial 6 months may be considered for select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. ■ The insertion of a vena cava filter is indicated only for patients with contraindications to anticoagulant therapy (specified in full guideline). It may be considered as an adjunct to anticoagulation in patients with progression of thrombosis (recurrent venous thromboembolism or extension of existing thrombus) despite optimal therapy with low–molecular-weight heparin. ■ For patients with primary central nervous system malignancies, anticoagulation is recommended for established venous thromboembolism as for other patients with cancer. Careful monitoring is necessary to limit risk of hemorrhagic complications. ■ Use of novel oral anticoagulants for either prevention or treatment of venous thromboembolism in patients with cancer is not recommended at this time. ■ Based on panel consensus, incidental

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JCO Spotlight

pulmonary embolism and deep-vein thrombosis should be treated in the same manner as symptomatic venous thromboembolism. Treatment of splanchnic or visceral vein thrombi diagnosed incidentally should be considered on a case-by-case basis, considering potential benefits and risks of anticoagulation.

Health Disparities The panel states that rates of venous thromboembolism are higher among African Americans than among the rest of the general population. The panel also notes that minority racial/ethnic patients with cancer suffer disproportionately from comorbidities, have more substantial obstacles to receiving care, are more likely to be

Should patients with cancer receive anticoagulants in the absence of established venous thromboembolism to improve survival? ■ Anticoagulants are not recommended to improve survival in patients with cancer without venous thromboembolism. ■ Patients with cancer should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies. What is known about risk prediction and awareness of venous thromboembolism amongst patients with cancer? ■ Based on panel consensus, it is recommended that patients with cancer should be assessed for venous thromboembolism risk at the time of chemotherapy initiation and periodically thereafter. Individual risk factors, including biomarkers or cancer site, do not reliably identify patients with cancer at high risk of venous thromboembolism. In the outpatient setting, risk assessment can be conducted based on a validated risk assessment tool (see page 34). ■ Based on panel consensus, it is recommended that oncologists educate patients regarding venous thromboembolism, particularly in settings that increase risk such as major surgery, hospitalization, and systemic antineoplastic therapy.

Patient and Clinician Communication The panel emphasizes that patients are “woefully” unaware of the risk for and warning signs and symptoms of venous thromboembolism, despite the well-known association of venous thromboembolism and cancer. As stated by the authors, “Communicating with patients about both the signs and symptoms and risk of [venous thromboembolism] events is crucial. Oncologists, along with other healthcare professionals on the oncology team, should assure, at minimum, that patients have a basic recognition of [venous thromboembolism] warning signs.”

uninsured, and are at greater risk of receiving poor quality care than other Americans. As stated by the authors, “Awareness of … disparities in access to care should be considered in the context of this clinical practice guideline and health care providers should strive to deliver the highest level of cancer care to these vulnerable populations.” n

Disclosure: For full disclosures of the study authors visit JCO.ASCOPubs.org.

Reference 1. Lyman GH, Khorana AA, Kuderer NM, et al: Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 31:2189-2204, 2013.

REMEMBER 3 DISTINCT COMPONENTS IN THE VEGF-SIGNALING PATHWAY 1-3

Component 1: VEGF ligands circulating in the body1-3

Component 2: The receptors’ extracellular VEGF-binding domains1-3

Component 3: The receptors’ intracellular tyrosine kinase domains1-3

VEGF=vascular endothelial growth factor.

In an effort to improve the care of people living with cancer, Lilly Oncology remains committed to studying different VEGFsignaling events needed for angiogenesis. References: 1. Olsson AK, et al. Nat Rev Mol Cell Biol. 2006;7(5):359-371. 2. Youssoufian H, et al. Clin Cancer Res. 2007;13(suppl 18):5544s-5548s. 3. Kowanetz M, Ferrara N. Clin Cancer Res. 2006;12(17):5018-5022. OC84949

05/2013

PRINTED IN USA

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JCO Spotlight

Venous Thromboembolism in Patients with Cancer: Real-world Challenges for the Practicing Oncologist By Gary H. Lyman MD, MPH

he close association between cancer and thrombosis has been recognized now for more than 150 years.1 Not only is it now known that patients with cancer are at substan-

Gary H. Lyman MD, MPH

tially increased risk of developing venous thromboembolism, even prior to the diagnosis of cancer, but the association between coagulation factors and tumor growth and invasion and development of metastases has been unequivocally established.2 Reported rates of venous thromboembolism in patients with cancer have been increasing in recent decades, most likely reflecting improved diagnosis using sophisticated imaging techniques and more aggressive cancer diagnosis, staging, and therapeutic interventions. Indeed, patients with cancer are placed at increased risk of venous thromboembolism by several therapeutic interventions, including surgery, chemotherapy, hormonal therapy, and targeted therapeutic strategies, as well as by the frequent use of indwelling catheters and other invasive procedures. The increased risk of venous thromboembolism, the multitude of risk factors, and the greater risk of venous thromboembolism recurrence and death among patients with cancer represent considerable real-world challenges for the practicing oncologist. ASCO originally developed guidelines for venous thromboembolism specifically in patients with cancer in 2007.3 Following an extensive systematic review of the literature since publication of the original guidelines, ASCO reDr. Lyman is Professor of Medicine in the Division of Medical Oncology, Duke University School of Medicine and Duke Cancer Institute, Durham, North Carolina.

cently updated clinical practice guidelines on the treatment and prevention of venous thromboembolism in patients with cancer.4 Although several new studies in this area have added to our knowledge since the original guidelines were developed, many questions remain concerning the intimate relationship between venous thromboembolism and cancer. The updated guideline recommendations and the risks and consequences associated with venous thromboembolism in patients with cancer were discussed at a recent Education Session at the 2013 ASCO Annual Meeting and in the Education Book available online at the ASCO website.5

Hospitalized and Surgical Patients The ASCO Venous Thromboembolism Guidelines address recommended measures for the treatment and prevention of venous thromboembolism in hospitalized medical and surgical patients with cancer, as well as

prophylactic anticoagulation. Although hospitalized patients with cancer without additional risk factors may also be considered for prophylactic anticoagulation, there are inadequate data supporting routine prophylaxis in patients admitted for minor procedures or infusions of chemotherapy. The literature review identified three randomized controlled trials evaluating perioperative prophylaxis in patients undergoing major abdominal or pelvic surgery.9-11 The updated guidelines recommend perioperative prophylactic anticoagulation in patients undergoing major cancer surgery, ideally beginning preoperatively and continued for at least 7 to 10 days. Systematic reviews have been conducted of extended prophylaxis for up to 4 weeks.12-14 Based on the available evidence, extended postoperative prophylaxis for up to 4 weeks is recommended in high-risk patients undergoing major cancer surgery, and those with restricted mobility, obesity, or a history of venous thromboembolism.

Table 1: Risk Score for Predicting Outpatient Venous Thromboembolism in Patients with Cancer PATIENT CHARACTERISTICS

RISK SCORE

Site of cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, bladder, testicular)

2 1

Prechemotherapy platelet count ≥ 350,000/mm3

Hemoglobin level < 10g/dL or use of red blood cell growth factors

Prechemotherapy leukocyte count > 11,000/mm3

Body mass index ≥ 35 kg/m

High-risk score ≥ 3; Intermediate-risk score = 1–2; Low-risk score = 0. Adapted from Khorana AA, et al.22

in ambulatory patients receiving cancer therapy. Three recent randomized controlled trials of thromboprophylaxis in medically ill inpatients were identified,6-8 one of which evaluated extended prophylaxis.6 Despite limited cancer-specific data in these trials, the ASCO Guidelines continue to recommend that hospitalized patients with other major medical illnesses or reduced mobility without serious bleeding risk receive

Ambulatory Patients Nine randomized controlled trials of low–molecular-weight heparin thromboprophylaxis compared to placebo or untreated controls in ambulatory patients with advanced cancer have been reported. A meta-analysis estimated a relative risk for symptomatic venous thromboembolism of 0.47 (95% confidence interval [CI] = 0.36–0.61, P < .001) but with an absolute reduction in venous thrombo-

embolism risk of only 2.8% (95% CI = 1.8%–3.7%, P < .001).15 The most dramatic impact on the absolute risk of venous thromboembolism was observed in patients with advanced pancreatic cancer receiving specific chemotherapy.16-18 Nevertheless, due to the limitations in these trials and the small incremental benefit observed in most trials of ambulatory patients, the ASCO Guideline panel concluded that routine anticoagulation prophylaxis is not warranted. One notable exception to this recommendation relates to patients with multiple myeloma receiving thalidomide (Thalomid) or lenalidomide (Revlimid) along with chemotherapy and/or dexamethasone, where the risk of venous thromboembolism is sufficient to justify routine thromboprophylaxis.

Established and Incidental Venous Thromboembolism In patients with cancer and established venous thromboembolism, the ASCO Guidelines recommend low–molecular-weight heparins for both the initial 5 to 10 days of anticoagulation as well as for secondary prevention of recurrence for at least 6 months. Extended anticoagulation to prevent venous thromboembolism recurrence is encouraged in high-risk patients with active malignancy continuing on chemotherapy. Of importance, the risk of recurrence, bleeding, and mortality appears similar between patients with cancer who have symptomatic venous thromboembolism and those who have incidental or unsuspected venous thromboembolism.19 The ASCO Guideline panel recommends that incidental venous thromboembolism be treated the same as symptomatic venous thromboembolism, based on consensus. Although a meta-analysis of randomized controlled trials has demonstrated a significant reduction in mortality with anticoagulation in patients with cancer without a clear indication for treatment or prevention, anticoagulation for cancer treatment is not currently recommended in the updated guidelines due to the limitations of

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JCO Spotlight

the trials reported to date and concern over an increased risk for major bleeding complications.4,20

Risk Factors Finally, risk factors for venous thromboembolism in patients with cancer include patient-, disease-, and treatment-related factors. Important risk factors include such comorbid conditions as infection, pulmonary or renal disease, and obesity. Elevations in leukocyte and platelet counts, reductions in hemoglobin, and use of the erythroid stimulating factors also increase the risk of venous thromboembolism in patients with cancer. The primary site of cancer is particularly important, with highest rates of venous thromboembolism observed in patients with brain, pancreas, stomach, kidney, ovary, and lung cancers as well as hematologic malignancies including lymphoma and myeloma. The risk of venous thromboembolism is further increased in patients receiving systemic therapy, including chemotherapy, hormonal therapy, and certain targeted agents. Although the risk of arterial thrombotic events is increased with bevacizumab (Avastin), it remains unclear whether the risk of venous thromboembolism is increased after adjusting for duration on treatment.21 A risk score for cancer-associated venous thromboembolism based on five readily available clinical and laboratory parameters has been developed and validated in multiple studies (see Table).22-24 When the risk model was retrospectively evaluated in large randomized trials, the risk of venous thromboembolism among high-risk patients was significantly reduced in those randomized to thromboprophylaxis.25,26 The updated ASCO Guidelines recommend that patients with cancer

be educated about the symptoms and signs of venous thromboembolism and that venous thromboembolism risk be assessed at the time of chemotherapy initiation and periodically thereafter. n Disclosure: Dr Lyman is supported by grants from the National Cancer Institute (RC2CA148041-01) and the National Heart, Lung and Blood Institute (R01HL095109).

References 1. Rickles FR, Falanga A: Molecular basis for the relationship between thrombosis and cancer. Thromb Res 102:V215V224, 2001. 2. Falanga A, Panova-Noeva M, Russo L: Procoagulant mechanisms in tumour cells. Best Pract Res Clin Haematol 22:4960, 2009. 3. Lyman GH, Khorana AA, Falanga A, et al: American Society of Clinical Oncology guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 25:5490-5505, 2007. 4. Lyman GH, Khorana AA, Kuderer NM, et al: Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 31:2189-204, 2013. 5. Lyman GH, Khorana AA, Falanga A: Thrombosis and cancer. Am Soc Clin Oncol Educ Book 2013:337-345, 2013. 6. Hull RD, Schellong SM, Tapson VF, et al: Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: A randomized trial. Ann Intern Med 153:8-18, 2010. 7. Schellong SM, Haas S, Greinacher A, et al: An open-label comparison of the efficacy and safety of certoparin versus unfractionated heparin for the prevention of thromboembolic complications in acutely ill medical patients: CERTAIN. Expert Opin Pharmacother 11:2953-2961, 2010. 8. Riess H, Haas S, Tebbe U, et al: A randomized, double-blind study of certoparin vs. unfractionated heparin to prevent venous thromboembolic events in acutely ill, non-surgical patients: CERTIFY Study. J

New from The ASCO Post

Thromb Haemost 8:1209-1215, 2010. 9. Sakon M, Kobayashi T, Shimazui T: Efficacy and safety of enoxaparin in Japanese patients undergoing curative abdominal or pelvic cancer surgery: Results from a multicenter, randomized, open-label study. Thromb Res 125:e65-e70, 2010. 10. Kakkar AK, Agnelli G, George D, et al: The ultra-low-molecular-weight heparin semuloparin for prevention of venous thromboembolism in patients undergoing major abdominal surgery. Presented at the American Society of Hematology Annual Meeting, December 10-13, 2011. 11. Simonneau G, Laporte S, Mismetti P, et al: A randomized study comparing the efficacy and safety of nadroparin 2850 IU (0.3 mL) vs. enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism after colorectal surgery for cancer. J Thromb Haemost 4:1693-1700, 2006. 12. Akl EA, Terrenato I, Barba M, et al: Extended perioperative thromboprophylaxis in patients with cancer. A systematic review. Thromb Haemost 100:1176-1180, 2008. 13. Bottaro FJ, Elizondo MC, Doti C, et al: Efficacy of extended thrombo-prophylaxis in major abdominal surgery: What does the evidence show? A meta-analysis. Thromb Haemost 99:1104-1111, 2008. 14. Rasmussen MS, Jørgensen LN, Wille-Jørgensen P: Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev (1):CD004318, 2009. 15. Kuderer NM, Ortel TL, Khorana AA, et al: Low-molecular-weight heparin for venous thromboprophylaxis in ambulatory cancer patients: A systematic review meta-analysis of randomized controlled trials. Blood (ASH Annual Meeting Abstracts) 114:490, 2009. 16. Maraveyas A, Waters J, Roy R, et al: Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 48:1283-1292, 2012. 17. Riess H, Pelzer U, Hilbig A, et al: Rationale and design of PROSPECTCONKO 004: A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy. BMC Cancer 8:361, 2008.

18. Riess H, Pelzer U, Opitz B, et al: A prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy: Final results of the CONKO-004 trial. 2010 ASCO Annual Meeting. Abstract 4033. Presented June 4, 2010. 19. den Exter PL, Hooijer J, Dekkers OM, et al: Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: A comparison with symptomatic patients. J Clin Oncol 29:24052409, 2011. 20. Kuderer NM, Khorana AA, Lyman GH, et al: A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: Impact on survival and bleeding complications. Cancer 110:1149-1161, 2007. 21. Hurwitz HI, Saltz LB, Van Cutsem E, et al: Venous thromboembolic events with chemotherapy plus bevacizumab: A pooled analysis of patients in randomized phase II and III studies. J Clin Oncol 29:1757-1764, 2011. 22. Khorana AA, Kuderer NM, Culakova E, et al: Development and validation of a predictive model for chemotherapyassociated thrombosis. Blood 111:49024907, 2008. 23. Ay C, Dunkler D, Marosi C, et al: Prediction of venous thromboembolism in cancer patients. Blood 116:5377-5382, 2010. 24. Khorana AA, O’Connell C, Agnelli G, et al: Incidental venous thromboembolism in oncology patients. J Thromb Haemost 10:2602-2604, 2012. 25. George DJ, Agnelli G, Fisher W, et al: Venous thromboembolism (VTE) prevention with semuloparin in cancer patients initiating chemotherapy: Benefitrisk assessment by VTE risk in SAVEONCO. American Society of Hematology Annual Meeting. Abstract 206. Presented December 12, 2011. 26. Verso M, Agnelli G, Barni S, et al: A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: The Protecht score. Intern Emerg Med 7:291-292, 2012.

FOR THE TREATMENT OF PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (mCRPC) WHO HAVE PREVIOUSLY RECEIVED DOCETAXEL

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss

of consciousness could cause serious harm to themselves or others. Adverse Reactions The most common adverse drug reactions (â&#x2030;Ľ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot ďŹ&#x201A;ush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% grade 3-4) and in 6% of patients on placebo (no grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients and 2% of patients on placebo. One percent of XTANDI patients compared to 0.3% of patients on placebo died from infections or sepsis. Falls or injuries related to falls occurred in 4.6% of XTANDI patients vs 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe

Convenient, oral, once-daily administration • Dosed as four 40 mg capsules (160 mg) without food restrictions or steroid requirements. Each capsule should be swallowed whole. Patients should not chew, dissolve, or open the capsules1,2 Comparable overall rate of grade 3-4 adverse reactions • No increased overall rate of grade 3-4 adverse reactions with XTANDI vs placebo (47% vs 53%, respectively)1 37% reduced risk of death • HR = 0.63 (95% CI, 0.53-0.75); P < 0.00011 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include enzalutamide (XTANDI) with a category 1 recommendation for use following docetaxel in patients with mCRPC.3

in XTANDI patients and included nonpathologic fractures, joint injuries, and hematomas. Grade 1 or 2 hallucinations occurred in 1.6% of XTANDI patients and 0.3% of patients on placebo, with the majority on opioid-containing medications at the time of the event. Drug Interactions: Effect of Other Drugs on XTANDI Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Coadministration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If coadministration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Effect of XTANDI on Other Drugs XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is

coadministered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information. References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 2. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed March 11, 2013. 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.

Learn L earn more more a att XtandiHCP.com XtandiHCP.c com

The ASCO Post | JULY 10, 2013

PAGE 38

News Breast Cancer

Study Reports 25% of Women Donâ&#x20AC;&#x2122;t Complete Recommended Breast Cancer Treatment

ne-quarter of women who should take hormone-blocking therapies as part of their breast cancer treatment either do not start or do not

complete the 5-year course, according to a new study led by University of Michigan Comprehensive Cancer Center researchers.

For many women with hormone receptor--positive breast cancer 5 years of daily tamoxifen or an aromatase inhibitor is recommended to reduce can-

cer recurrence and increase survival. Recent studies suggest there may be even more benefit for some women to continue this treatment for 10 years.

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information. ------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel. --------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@. -------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. --------------------------------- ADVERSE REACTIONS ------------------------------Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4. 7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders Asthenic Conditionsa 9.0 44.4 9.3 Peripheral Edema 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 24.3 4.0 Arthralgia 17.3 1.8 Musculoskeletal Pain 1.3 0.3 Muscular Weakness 9.8 6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 0.0 Dizzinessb Spinal Cord 7.4 6.6 3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0 0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0 0.3 Upper Respiratory Tract Infectiond Lower Respiratory 2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0 Anxiety 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 1.0 Pollakiuria 4.8 0.0 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

ASCOPost.com | JULY 10, 2013

PAGE 39

News

A recent study of 743 women eligible for endocrine therapy found that about 11% of the study participants never initiated the tamoxifen or aromatase inhibitor therapy and 15% stopped taking treatment early. Results were published online in Breast Cancer Research and Treatment. 1 â&#x20AC;&#x153;Weâ&#x20AC;&#x2122;re doing well with women

taking endocrine therapy, but thereâ&#x20AC;&#x2122;s work to do,â&#x20AC;? says lead study author Christopher Friese, PhD, RN, Assistant Professor at the University of Michigan School of Nursing. â&#x20AC;&#x153;If guidelines begin to shift so that some women at high risk of breast cancer recurring need 10 years of endocrine therapy, then the number of women

MEDPC9886 - Xtandi Brief PI Colors: 4CP Trim/live: DO NOT PRINT Bleed: 8.625"w Ă&#x2014; 11.375"h Trim: 8.125"w Ă&#x2014; 10.875"h Output @ 100% Giant Creative Strategy

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @. -------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

who persist with treatment will likely worsen. We need to develop better ways of supporting women through this therapy.â&#x20AC;?

Side Effects A Major Deterrent The most common reason patients said they either discontinued or never started endocrine therapy was side ef-

Live: 7"w Ă&#x2014; 10"h

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8& PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\ XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ ,QF 6DQ )UDQFLVFR &$ Issued: August 2012 $ (1= %56 Rx Only ÂŠ 2012 Astellas Pharma US, Inc. XTANDIÂŽ is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

fects. Many women experience menopause-like symptoms such as hot flashes or vaginal dryness, and both types of drugs, more commonly the aromatase inhibitors, can cause joint pains. The study surveyed women in the Detroit and Los Angeles areas who were diagnosed with breast cancer and reported to Surveillance, Epidemiology and End Results tumor registries. Women were surveyed at about 9 months after their diagnosis and again about 4 years later with questions about their use of tamoxifen or any type of aromatase inhibitor. Women who expressed more worry about their cancer recurring were more likely to complete endocrine therapy, as were women who already took medication regularly. Women who reported receiving less information about endocrine therapy were less likely to begin taking it, suggesting that doctors need to address patient education before treatment starts. Women who saw a breast surgeon as their primary follow-up, rather than a medical oncologist, were also less likely to begin endocrine therapy. â&#x20AC;&#x153;It was particularly interesting that greater fear of recurrence was associated in our patient sample with greater adherence to endocrine therapy,â&#x20AC;? says senior study author Jennifer J. Griggs, MD, MPH, Professor of Internal Medicine at the University of Michigan Medical School and a medical oncologist who sees patients with breast cancer at the University of Michigan Comprehensive Cancer Center. â&#x20AC;&#x153;We donâ&#x20AC;&#x2122;t want our patients living under a cloud of fear, so we need to develop creative ways to both reassure and motivate them. This means providing better education about the importance of staying on these medications and partnering with primary care and cancer doctors to help patients manage symptoms,â&#x20AC;? Dr. Griggs said. n Disclosure: The study was funded by National Cancer Institute grants R01 CA109696, R01 CA088370, K05 CA111340; National Institute for Nursing Research grant R00 NR01570; American Cancer Society. The authors reported no potential conflicts of interest.

Reference 1. Friese CR, Pini TM, Li Y, et al: Adjuvant endocrine therapy initiation and persistence in a diverse sample of patients with breast cancer. Breast Cancer Res Treat 138(3): 931-939, 2013.

The ASCO Post | JULY 10, 2013

PAGE 40

Journal Spotlight Hematology

Genomic and Epigenomic Characterization of Acute Myeloid Leukemia By Matthew Stenger

n a study by the Cancer Genome Atlas Research Network reported in The New England Journal of Medicine, genomes of 200 adult cases of de novo acute myeloid leukemia (AML) were analyzed by whole-genome sequencing (n = 50) or whole-exome sequencing (n = 150) to identify mutations and relationships between mutation patterns and epigenetic phenotypes involved in AML pathogenesis.1 The investigators identified at least one driver mutation in nearly all samples and found that “a complex interplay of genetic events contributes to AML pathogenesis in individual patients.”

mutated in two or more samples. The significantly mutated genes included those well established as relevant to AML development (eg, DNMT3A, FLT3, NPM1, IDH1, IDH2, and CEBPA) along with some only recently implicated (eg, U2AF1, EZH2, SMC1A, SMC3). Some of the mutations commonly found in AML (eg, in DNMT3A, NPM1, CEPBA, IDH1/2, and RUNX1) were mutually exclusive of transcription-factor fusions, suggesting that these mutations may have roles in initiation of AML that are similar to the roles of fusion genes.

Small Number of Mutations

Among the 200 samples, all but one had nonsynonymous mutations in at least one of nine categories that are

AML genomes were found to contain fewer mutations than most other adult cancers. A total of 2,315 single nucleotide variants and 270 small insertions and deletions were found in the coding region of the genome, with an average of only 13 mutations per sample. Of these, an average of 5 were in genes that are recurrently mutated in AML. In three samples without recurring coding mutations, fusion events already known to initiate AML were found. Additional analysis showed that samples with MLL fusions had the smallest number of recurrent coding mutations, suggesting that MLL fusions require fewer cooperating mutations than other AML-initiating events. Similarly, lower numbers of recurring mutations were found in the group of samples containing PML-RARA fusions. Greater numbers of recurrent mutations were found in groups containing RUNX1RUNX1T1 fusions or the combination of high-risk cytogenetic profile and TP53 mutation. A total of 23 genes were significantly mutated and another 237 were

Distribution of Mutations in Gene Categories

PTPN11). Although it has been suggested that an activating mutation in a gene encoding a signaling protein might be required for AML pathogenesis, a total of only 59% of samples had mutations in a gene encoding a signaling protein. Analysis of mutual exclusivity among sets of genes revealed a number of patterns. The strongest patterns of exclusivity were exhibited by: (1) the transcription-factor fusion genes, NPM1, RUNX1, TP53, and CEPBA; (2) mutations in FLT3 and genes encoding other tyrosine kinases, serinethreonine kinases, protein tyrosine phosphatases, and RAS family proteins; and (3) mutations in ASXL1 and in genes encoding components of the cohesin complex, other myeloid transcription factors, and other

This data set will be available to provide a framework for future studies that pertain to the molecular classification of patients with AML. —The Cancer Genome Atlas Research Network

considered to be important to AML pathogenesis, including transcriptionfactor fusions in 18% of cases, the gene encoding nucleophosmin (NPM1) in 27%, tumor-suppressor genes in 16%, DNA methylation-related genes in 44%, signaling genes in 59%, chromatin-modifying genes in 30%, myeloid transcription factor genes in 22%, cohesin-complex genes in 13%, and spliceosome-complex genes in 14%. Overall, FLT3 mutations were found in 56 samples, and an additional 62 samples had mutations in genes coding other kinases, phosphatases, or RAS family proteins, although most of these genes contained mutations in only one to three samples (except for KIT, KRAS, NRAS, and

Sequencing of Acute Myeloid Leukemia ■ At least one potential driver mutation was identified in nearly all AML samples.

■ Patterns of cooperation and exclusivity suggest strong biologic relationships among several genes and gene categories.

epigenetic modifiers. The finding of mutual exclusivity within particular biologic classes—eg, genes encoding the cohesins, proteins of the spliceosome, signaling proteins, and histonemodifying proteins—suggests that one mutation in these pathways may be sufficient for AML pathogenesis.

Novel Subtype of AML? Analysis of pairwise relationships between mutations showed that the most prominent co-occurrence was among mutations in FLT3, DNMT3A, and NPM1. Samples with co-occurrence of these mutations were strongly associated with distinct clusters of mRNA expression, miRNA expression, and DNA methylation loss pattern, suggesting that the presence of mutations in these three genes represents a novel subtype of AML. Strong exclusivity was exhibited by PMLRARA, MYH-11-CBFB, and MLLcontaining fusion genes vs mutations in NPM1 and DNMT3A; and RUNX1 and TP53 mutations were strongly exclusive of FLT3 and NPM1 mutations.

Additional findings when mRNA and miRNA expression data were integrated with clinical and mutation data included the previously reported finding that differentiation states of AML samples are highly correlated with expression signatures. In addition, samples with PML-RARA fusions had distinct mRNA and miRNA signatures that were also highly correlated with a specific DNA methylation signature. All transcription-factor fusions were correlated with specific mRNA expression signatures, and PML-RARA, RUNX1-RUNX1T1, and some MLL fusions were associated with specific miRNA signatures. Notable findings on DNA methylation analysis, in addition to the observation of a characteristic signature for samples with co-occurring FLT3, DNMT3A, and NPM1 mutations, included extensive loss of DNA methylation in some samples with MLL fusions and specific patterns of gain or loss in samples with CEBPA mutations or PML-RARA, RUNX1RUNX1T1, or MYH11-CBFB fusions. The investigators noted, “This data set will be available to provide a framework for future studies that pertain to the molecular classification of patients with AML. The identification of many potentially important relationships among recurrently mutated AML genes and pathways provides a comprehensive foundation for an understanding of the genetic rules of pathogenesis.” n Disclosure: The study was funded by the National Institutes of Health.

Reference 1. The Cancer Genome Atlas Research Network: Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med May 1, 2013 (early release online).

For More on This Study Drs. Guido Marcucci and Clara Bloomfield discuss this study on page 42.

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Leading the way

The ASCO Post | JULY 10, 2013

PAGE 42

Journal Spotlight

Molecular Landscaping of Acute Myeloid Leukemia: Are We Relearning the Past or Informing the Future? By Guido Marcucci, MD, and Clara D. Bloomfield, MD

cute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease.1 This concept has been supported by more than 4 decades of studies showing distinct outcomes of subsets of patients that differ in age, disease type (primary vs secondary vs therapy-related), and cytogenetic and molecular aberrations. Indeed, both clinical and genetic features have replaced blast morphology as the basis for newer AML classifications, such as the 2008 World Health Organization2 or the European LeukemiaNet classifications.3 Of all patient characteristics at diagnosis, genetic aberrations (ie, cytogenetics and gene mutations) are among the strongest predictors for clinical outcome, are used for treatment guidance, and have allowed for a deeper understanding of the molecular mechanisms of myeloid leukemogenesis.4 However, while there has been a remarkable agreement among the results of large studies investigating the clinical impact of the recurrent cytogenetic aberrations and of the more common genetic mutations, it is striking that the outcome of patients with seemingly identical genetic “makeup” is not uniform. In fact, not all patients with favorable cytogenetic and/or genetic molecular risk achieve long-term survival, whereas a small but clinically meaningful percentage of patients remain alive despite harboring adverse cytogenetic and/or molecular aberrations. Although this may be explained by individual variations in drug metabolism and/or mechanisms of chemoresistance, it also may be a direct consequence of molecular aberrations yet to be discovered that will further segregate patients currently in the same genetic groups into different smaller molecular subsets. Should this be proven Dr. Marcucci is Professor of Medicine, Charles Austin Doan Chair of Medicine, and Associate Director of Translational Research at The Ohio State University Comprehensive Cancer Center, and Dr. Bloomfield is Distinguished University Professor, William G. Pace III Professor of Cancer Research, Cancer Scholar and Senior Advisor at The Ohio State University Comprehensive Cancer Center, Columbus.

true, virtually all AML patients may need to be approached with specific treatments tailored to their unique molecular profiles. While this is an exciting perspective, its feasibility remains to be tested, given the relatively few molecular targeting drugs available and the lack of ready information on toxicity and clinical activity of combinations of such drugs.

Cancer Genome Atlas Research Network The recent introduction of nextgeneration sequencing technology has offered a tantalizing opportunity to address these questions by scanning the entire genome in search of previously unreported genetic and epigenetic variations that offer new insights into the clinical relevance of molecular heterogeneity in AML, explain the conundrum of the different outcomes

ligible information,5 have discovered previously unknown mutations (eg, IDH1, IDH2 and DNMT3A),5,6 and have shown the temporal evolution of minor clones during the dynamics of disease relapse or treatment refractoriness.8 These results have created high expectations regarding what nextgeneration sequencing can do and how it could change our approach to leukemia patients. The CGARN study has now gone beyond its initial results and provided information that not only defines the landscape of gene and microRNA mutations but also correlates them with specific gene and microRNA expression and DNA methylation profiles in a relatively large cohort of AML patients.5 The enormous amount of data that has been generated in this project is summarized by the following key points.

The main condition for success in treating AML will be that all stakeholders involved in translational and clinical leukemia research work collaboratively to guarantee access to [individualized] therapies. —Guido Marcucci, MD, (top), and Clara D. Bloomfield, MD

of patients classified within the same cytogenetic/genetic subgroups, and ultimately may provide ground for “individualized” therapeutic approaches. Dr. Ley, leader of the recently reported Cancer Genome Atlas Research Network (CGARN) study,5 and his colleagues have pioneered the field of next-generation sequencing in AML and provided seminal observations.6-8 These investigators have shown how to deconvolute the complexity of huge amounts of bioinformatic data into biologically and clinically intel-

First, the AML genomes have been shown to harbor fewer mutations relative to most other adult cancers, with only 23 genes found to be “significantly” mutated. Second, nearly all patients had at least one nonsynonymous mutation in categories of genes that likely contribute to leukemogenesis. Third, mutations were associated with specific gene and microRNA expression and DNA methylation profiles. Fourth, patterns of cooperation and mutual exclusivity among mutations and gene categories allowed for identification of

novel molecular subsets of patients. So, could one say that we now have a new and deeper understanding of AML and that we are ready to devise “molecular-driven individualized” approaches for the vast majority of patients in the near future? To answer this question, we should consider the following points.

‘Ready for Prime Time’? First, the relatively small number of mutations identified in the analyzed patients is somewhat surprising. Even more surprising is that the majority of the 23 genes that were indicated as “significantly” mutated were already known, and very few of them were discovered through next-generation sequencing.4,5,9 Second, several of the mutations were found to be mutually exclusive and to be directly linked to specific gene, microRNA, and methylation profiles. But doesn’t this indeed confirm results that were already partly reported in previous studies? Almost a decade ago, German and Dutch groups reclassified patients into novel, clinically relevant “clusters” using a combination of cytogenetics, gene mutations, and microarray-derived gene-expression profiles.10,11 Similarly, Figueroa et al have previously reported DNA methylation profiles associated with specific mutations.12,13 We and others have demonstrated microRNA signatures that are highly associated with distinct cytogenetic aberrations and gene mutations.14-19 Could it therefore be said that our biologic and clinical knowledge of AML, albeit incomplete, was perhaps not that far from the picture that the CGARN study has now depicted? Or instead, is it true that the CGARN study has carved out previously unidentified subsets of patients, thereby leading the way to new AML classifications, risk-stratification strategies, and treatment guidelines? Fortunately, although these questions have not been addressed in the CGARN paper, the data are now available for the scientific community to find the answers. Undoubtedly, the CGARN study is an important step forward in providing an integrated “snap-shot” of the biolog-

ASCOPost.com | JULY 10, 2013

PAGE 43

Journal Spotlight

ic puzzle that is AML. However, it also requires additional steps to provide the missing pieces. In addition to in silico validation (performed using a computer simulation) of the presented data in independent cohorts of patients, it will be necessary to functionally validate these results and understand how mutations and their associated gene and microRNA epigenetic and expression profiles impact on protein expression, posttranslational modifications, and oncogenic or tumor-suppressor functions. Furthermore, while the integrated CGARN data were derived from “bulk” blasts, it may be necessary to assess which of the genetic and epigenetic changes also occur in those minute cell populations that are enriched for leukemia stem cells and may be functionally relevant for treatment resistance or disease relapse. Moreover, as it is possible that like other types of cancer, AML may be partly caused by “field defects,” the contribution of the microenvironment to the acquisition of the reported epigenetic/genetic alterations or—vice versa—how these changes affect the microenvironment needs to be dissected and the results considered for future treatment design.

Translating to the Clinic Finally, as the sequencing techniques become more affordable and broadly available and are brought

into clinical diagnostic laboratories, the wealth of knowledge from the CGARN and similar studies must be translated rapidly into the clinic. But this may not be sufficient to transform our approach to AML without eliminating other barriers. In fact, progressively smaller molecular groups of patients will be identified by next-generation sequencing assays as eligible for “individualized” therapies. Thus, the main condition for success in treating AML will be that all stakeholders involved in translational and clinical leukemia research work collaboratively to guarantee access to such therapies. Moreover, the traditional approaches to clinical trial design and drug evaluation will need to rapidly be adapted to this new biologic and clinical reality. n

Disclosure: Drs. Marcucci and Bloomfield reported no conflicts of interest.

References 1. Dombret H: Gene mutation and AML pathogenesis. Blood 118:53665367, 2011. 2. Vardiman JW, Thiele J, Arber DA, et al: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood 114:937-951, 2009. 3. Mrózek K, Marcucci G, Nicolet D, et al: Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular altera-

tions in adults with acute myeloid leukemia. J Clin Oncol 30:4515-4523, 2012. 4. Marcucci G, Haferlach T, Döhner H: Molecular genetics of adult acute myeloid leukemia: Prognostic and therapeutic implications. J Clin Oncol 29:475-486, 2011. 5. Cancer Genome Atlas Research Network: Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368:2059-2074, 2013. 6. Mardis ER, Ding L, Dooling DJ, et al: Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 361:1058-1066, 2009. 7. Ley TJ, Ding L, Walter MJ, et al: DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363:2424-2433, 2010. 8. Ding L, Ley TJ, Larson DE, et al: Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481:506-510, 2012. 9. Patel JP, Gönen M, Figueroa ME, et al: Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366:1079-1089, 2012. 10. Bullinger L, Döhner K, Bair E, et al: Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 350:16051616, 2004. 11. Valk PJ, Verhaak RG, Beijen MA, et al: Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 350:1617-1628, 2004. 12. Figueroa ME, Lugthart S, Li Y, et al: DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 19:13-27, 2010. 13. Figueroa ME, Abdel-Wahab O, Lu C, et al: Leukemic IDH1 and IDH2 muta-

tions result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553-567, 2010. 14. Jongen-Lavrencic M, Sun SM, Dijkstra MK, et al: MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood 111:5078-5085, 2008. 15. Li Z, Lu J, Sun M, et al: Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci USA 105:15535-15540, 2008. 16. Becker H, Marcucci G, Maharry K, et al: Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: A Cancer and Leukemia Group B study. J Clin Oncol 28:596-604, 2010. 17. Marcucci G, Maharry K, Wu YZ, et al: IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: A Cancer and Leukemia Group B study. J Clin Oncol 28:2348-2355, 2010. 18. Mi S, Li Z, Chen P, et al: Aberrant overexpression and function of the miR-17-92 cluster in MLL-rearranged acute leukemia. Proc Natl Acad Sci USA 107:3710-3715, 2010. 19. Mendler JH, Maharry K, Radmacher MD, et al: RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures. J Clin Oncol 30:3109-3118, 2012.

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

Mark R. Gilbert, MD, on Combination Therapies for Glioblastoma see page 1

Alice T. Shaw, MD, PhD, on Second-generation ALK Inhibitor see page 3

Lisa A. Carey, MD, on Dual HER2 Targeting in Neoadjuvant Regimen see page 23

Gary H. Lyman, MD, MPH, on Venous Thromboembolism in Patients with Cancer see page 34

Edith A. Perez, MD, on Adjuvant Trastuzumab and PTEN Status see page 63

Joyce F. Liu, MD, MPH, on Genomic Complexities of Cancer see page 72

Visit The ASCO Post online at ASCOPost.com

What if

engineering the antiBody could iMPRoVE adcc?

Immune Effector Cell

Therapeutic Antibody

Target Cell

*Based on preclinical models.

References: 1. Shields R, Lai J, Keck R, et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human FcγRIII and antibody-dependent cellular toxicity. J Biol Chemistry. 2002;277:26733-26740. 2. Ogorek C, Jordan I, Sandig V, et al. Fucose-targeted glycoengineering of pharmaceutical cell lines. IN Antibody Engineering: Methods and Protocols. Methods in Molecular Biology Biology. Vol 907. 2nd ed. Marseille, France: Humana Press; 2012. 3. Herbst R, Wang Y, Gallagher S, et al. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exper Ther Ther. 2010;335:213-222. 4. Ferrara C, Grau S, Jäger C, et al. Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose. Proc Natl Acad Sci USA. 2011;108(31):1266912674. Available at: http://www.pnas.org/content/108/31/12669.full.pdf+html. Accessed January 24, 2013. 5. Beck A, Reichert JM. Marketing approval of mogamulizumab: A triumph for glyco-engineering. MAbs. 2012;4(4):419-425.

Glycoengineering a monoclonal antibody may improve ADCC The removal of core sugar molecules via glycoengineering has been shown to improve antibody-dependent cellular cytotoxicity (ADCC) by enhancing the ability of therapeutic antibodies to activate immune effector cells.1-4

Sugar Residue

Sugar Removal

Increased Binding

SugarS MaY aY coMproMiSe iMMuNe a

gLYcoeNgiNeeriNg MaY a iNcreaSe aY

gLYcoeNgiNeeriNg couLD LeaD

eFFecTor–aNTiBoDY BiNDiNg

BiNDiNg aFFiNiTY

To iMproVeD aDcc

Based on preclinical models, the ability of an antibody to bind to immune effector cells may be compromised by the presence of certain sugar residues on the antibody’s Fc region.4

The removal of certain sugar residues via glycoengineering may result in enhanced binding affinity to immune effector cells that activate ADCC.1,3,4

Preclinical data have demonstrated that certain glycoengineered antibodies may induce a greater level of ADCC than non-glycoengineered antibodies.2,5

Glycoengineered antibodies are being studied across a panel of molecular targets5 Researchers have investigated glycoengineered antibodies directed towards a variety of molecular targets. Glycoengineered antibodies are currently being investigated in clinical trials across multiple disease states, including cancer, inflammation, and asthma.5

For more information, visit ResearchBcell.com

The ASCO Post | JULY 10, 2013

PAGE 46

In the Clinic Genitourinary Oncology

Radium-223 Dichloride for Castration-resistant Prostate Cancer with Symptomatic Bone Metastases In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication On May 15, 2013, radium Ra 223 dichloride (Xofigo) was approved for the treatment of patients with castrationresistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease.1,2 Approval was based on a doubleblind, randomized, placebo-controlled trial in which 809 patients with metastatic castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease received intravenous radium-223 dichloride 50 kBq/kg (1.35 microcurie/kg) every 4 weeks for six cycles plus best standard of care (n = 541) or placebo plus best standard of care (n = 268). Standard of care included local radiotherapy, corticosteroids, antiandrogens, estrogens, estramustine, or ketoconazole. All patients were to continue androgen-deprivation therapy. Among all patients, median age was 71 years, 94% were Caucasian, 86% had ECOG performance status of 0 or 1, 58% had received prior docetaxel, 85% had six or more bone scan lesions, 41% had received prior bisphosphonates, and 54% used opiate and 44% non-opiate pain medications. Treatment was continued until unacceptable toxicity or initiation of cytotoxic chemotherapy, other systemic

OF NOTE The active component of radium-223 dichloride is the alpha particle–emitting isotope radium-223, which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, including bone metastases. The high linear energy transfer of alpha emitters leads to a high frequency of double-strand DNA breaks in adjacent cells, resulting in an antitumor effect on bone metastases.

radioisotope treatment, hemibody external beam radiation therapy, or other investigational drug therapy. Patients with Crohn’s disease, ulcerative colitis, prior hemibody radiation, or untreated imminent spinal cord compression were excluded from the study. In patients with bone fractures, orthopedic stabilization was performed before starting or resuming treatment with radium-223 dichloride. During treatment, 83% of patients in the radium-223 dichloride group and 82% of patients in the placebo group received gonadotropin-releasing hormone agonists, and 21% and 34% of patients, respectively, received concomitant antiandrogens. Use of systemic steroids (41%) and bisphosphonates (40%) was balanced between groups. At a prespecified interim analysis, median overall survival, the primary endpoint of the trial, was significantly

double-strand DNA breaks in adjacent cells, resulting in an antitumor effect on bone metastases. The alpha particle range from radium-223 dichloride is less than 100 micrometers (less than 10 cell diameters), which limits damage to surrounding normal tissue.

How It Is Given The recommended dose of radium-223 dichloride is 50 kBq/kg (1.35 microcurie/kg) given at 4-week intervals for six injections. Safety and efficacy beyond six injections have not been studied. Determination of the volume of drug to be given involves a calculation incorporating the radioactivity concentration of the product as of a reference date and a decay correction factor to correct for physical decay of radium-223 based on number of days from the reference date. Calculated absorbed radiation doses to different organs are

Radium-223 Dichloride for Castration-resistant Prostate Cancer ■ Radium-223 dichloride (Xofigo) has been approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease.

■ The recommended dose of radium-223 dichloride is 50 kBq/kg (1.35 microcurie/kg) given at 4-week intervals for six injections.

prolonged in the radium-223 dichloride group (14.0 vs 11.2 months, hazard ratio [HR] = 0.70, P = .00185). The improvement in overall survival was supported by a delay in time to first symptomatic skeletal event in the radium-223 dichloride group (defined as external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention).

How It Works The active component of radium-223 dichloride is the alpha particle–emitting isotope radium-223 (as radium Ra 223 dichloride), which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, including bone metastases. The high linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high frequency of

provided in the drug labeling. Administration of the drug is associated with potential risks to other persons (including medical staff, caregivers, and the patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Thus, radiation protection precautions must be used.

Safety Profile The most common adverse events of any grade (≥ 10%) in patients receiving radium-223 dichloride were nausea (36% vs 35% in placebo group), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Overall, grade 3 or 4 adverse events occurred in 57% of patients receiving radium-223 dichloride and 63% of patients receiving placebo. The most common hematologic laboratory abnormalities in patients receiving radium-223 dichloride were anemia (93% vs 88%, grade 3 or 4 in 6% vs

6%), lymphocytopenia (72% vs 53%, grade 3 or 4 in 20% vs 7%), leukopenia (35% vs 10%, grade 3 or 4 in 3% vs <1%), thrombocytopenia (31% vs 22%, grade 3 or 4 in 3% vs < 1%), and neutropenia (18% vs 5%, grade 3 or 4

OF NOTE Radium-223 dichloride carries warnings/precautions for bone marrow suppression. Blood counts should be measured prior to treatment initiation and before every dose of radium-223 dichloride. in 2% vs < 1%). Bone marrow failure or ongoing pancytopenia occurred in 2% of radium-223 dichloride patients and no placebo patients. Treatment discontinuations due to adverse events occurred in 17% of radium-223 dichloride and 21% of placebo patients. The most common hematologic laboratory abnormalities leading to discontinuation in radium-223 dichloride patients were anemia (2%) and thrombocytopenia (2%). Injection site reactions were reported in 1% of radium-223 dichloride patients. Radium-223 dichloride carries warnings/precautions for bone marrow suppression. Blood counts should be measured prior to treatment initiation and before every dose of radium-223 dichloride. Treatment should be discontinued if hematologic values do not recover within 6 to 8 weeks after administration. Patients with compromised bone marrow reserve must be closely monitored. Treatment should be discontinued in patients who experience life-threatening complications despite supportive care measures. n References 1. U.S. Food & Drug Administration: Radium Ra 223 dichloride. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm352393. htm. Accessed June 20, 2013. 2. Xofigo™ (radium Ra 223 dichloride) injection prescribing information, Bayer HealthCare Pharmaceuticals Inc, May 2013. Available at http://www. accessdata.fda.gov/drugsatfda_docs/ label/2013/203971lbl.pdf. Accessed June 20, 2013.

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

The FASLODEX Story Continues… Overall Survival Update Important Safety Information About FASLODEX • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema have been reported in association with FASLODEX • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants Please see additional Important Safety Information for FASLODEX on the subsequent pages and adjacent brief summary of full Prescribing Information.

After progression following antiestrogen therapy in postmenopausal women with HR+ metastatic breast cancer…

FASLODEX 500 MG STRENGTH Prolonged Progression-Free Survival (PFS)1,* †

With FASLODEX 500 mg vs 250 mg in CONFIRM

FASLODEX 500 mg showed a

20% reduction

in relative risk of progression vs 250 mg2

Median 6.5 months with FASLODEX 500 mg vs

5.4 months with 250 mg

At minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2 • PFS was the primary endpoint 1

• FASLODEX 500 mg signifcantly increased PFS (P=0.006): median PFS 6.5 months vs 5.4 months with FASLODEX 250 mg2 • Objective response rates (ORRs)‡ were not signifcantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2 — Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261) 2 — ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

Additional Important Safety Information About FASLODEX • FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) • Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX • The most common, clinically signifcant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot fash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation * PFS is defned as the time between randomization and the earliest evidence of progression or death from any cause.2 † The CONFIRM (COmparisoN of FASLODEX In Recurrent or Metastatic Breast Cancer) trial was a randomized, double-blind, controlled phase III study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1 ‡ ORR is defned as the number of patients with complete response or partial response.2

Updat

Overaed Surviv ll Analy al s

THE FASLODEX STORY CONTINUES

Overall Survival (OS)

With FASLODEX 500 mg vs 250 mg in updated analysis in CONFIRM M22,*

FASLODEX 500 mg showed a

19% reduction

in relative risk of death vs 250 mg2

Median 26.4 months with FASLODEX 500 mg vs

22.3 months with 250 mg

At minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2,† • OS was a secondary endpoint 1 • No statistically signifcant difference in OS after a minimum duration of 50 months as no adjustments were made for multiplicity2 • In the initial OS analysis after a minimum duration of 18 months, there was no statistically signifcant difference in OS between the 2 treatment groups2

Learn more at www.FASLODEXStoryContinues.com

Additional Important Safety Information About FASLODEX • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent

Indication For FASLODEX • FASLODEX is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy Please read adjacent brief summary of full Prescribing Information. * The CONFIRM trial was a randomized, double-blind, controlled phase III study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1 † No statistically signifcant difference in OS as no adjustments were made for multiplicity.2

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

FASLODEX® (fulvestrant) Injection BRIEF SUMMARY For full Prescribing Information, see package insert. INDICATIONS AND USAGE FASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. DOSAGE AND ADMINISTRATION Recommended Dose The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter [see Clinical Studies (14) in full Prescribing Information]. Dose Modification Hepatic Impairment: A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions and Use in Specific Populations]. Administration Technique The proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged. 2. Remove perforated patient record label from syringe. 3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions refer below to the “Directions for Use of SafetyGlide™.” 4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap. 5. Twist to lock the needle to the luer connector. 6. Remove needle sheath. 7. Remove excess gas from the syringe (a small gas bubble may remain). 8. Administer intramuscularly slowly in the buttock. 9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered. 10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector. 11. Repeat steps 1 through 10 for second syringe. For additional directions for use, see Administration Technique (2.3) in full Prescribing Information. CONTRAINDICATIONS FASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX. WARNINGS AND PRECAUTIONS Blood Disorders Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use. Hepatic Impairment The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended [see Dosage and Administration]. FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations]. Use in Pregnancy Based on its mechanism of action and findings in animals, FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area. There are no adequate and well-controlled studies in pregnant women using FASLODEX. Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients). Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month. Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population Body System Number (%) of Patients and Adverse Reaction Fulvestrant 500 mg Fulvestrant 250 mg N=361 N=374 Body as a Whole Injection Site Pain 42 (11.6) 34 (9.1) Headache 28 (7.8) 25 (6.7) Back Pain 27 (7.5) 40 (10.7) Fatigue 27 (7.5) 24 (6.4) Pain in Extremity 25 (6.9) 26 (7.0) Asthenia 21 (5.8) 23 (6.1) Vascular System Hot Flash 24 (6.6) 22 (5.9) Digestive System Nausea 35 (9.7) 51 (13.6) Vomiting 22 (6.1) 21 (5.6) Anorexia 22 (6.1) 14 (3.7) Constipation 18 (5.0) 13 (3.5) Musculoskeletal System Bone Pain 34 (9.4) 28 (7.5) Arthralgia 29 (8.0) 29 (7.8) Musculoskeletal Pain 20 (5.5) 12 (3.2) Respiratory System Cough 19 (5.3) 20 (5.3) Dyspnea 16 (4.4) 19 (5.1)

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

68.3 22.7 18.9 15.4 14.4 11.8 10.9 9.9 7.1 7.1 6.4 4.5 30.3 17.7 51.5 26.0 13.0 12.5 12.3 9.0 13.7 4.5 18.2 9.0 25.5 15.8 2.8 34.3 6.9 6.9 6.4 5.7 5.0 38.5 16.1 14.9 10.4 22.2 7.3 5.0 18.2 6.1

67.6 27.0 20.3 16.8 13.2 11.6 6.6 9.0 5.0 6.4 6.4 5.7 27.9 17.3 48.0 25.3 11.8 10.6 12.8 10.9 13.5 5.0 17.7 10.2 27.9 13.7 6.1 33.8 6.6 8.5 7.6 6.9 3.8 33.6 11.6 12.3 10.4 23.4 8.0 5.2 14.9 3.5

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

Post-Marketing Experience For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions including angioedema and urticaria. Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered. Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%). DRUG INTERACTIONS There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro, drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics. Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area (BSA). Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed. Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic

girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures. Nursing Mothers It is not known if fulvestrant is excreted in human milk. Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FASLODEX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCune-Albright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8). The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry. Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26. Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known. Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died. Pharmacokinetics The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis. In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively. Geriatric Use For FASLODEX 250 mg, when tumor response was considered by age, objective responses were seen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years of age and older, who were treated with FASLODEX in Study 2 and Study 3, respectively. Hepatic Impairment FASLODEX is metabolized primarily in the liver. The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (Child-Pugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C). A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B) [see Dosage and Administration and Warnings and Precautions]. Renal Impairment Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine. OVERDOSAGE Animal studies have shown no effects other than those related directly or indirectly to antiestrogen activity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

SafetyGlide™ is a trademark of Becton Dickinson and Company. FASLODEX is a trademark of the AstraZeneca group of companies. © AstraZeneca 2013 Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, England By: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany Rev. 11/12 2543202 4/13

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Direct from ASCO

2013 Breast Cancer Symposium to Offer Expanded Meet the Professor Sessions and New Fellows, Residents, and Junior Faculty Track

s a cancer care specialist, it can be easy to become hyperfocused on your area of expertise within your subspecialty. But that’s exactly what ASCO wants its members—in all specialties—to avoid. The theme of this year’s Breast Cancer Symposium—Multidisciplinary Perspectives on Clinical Management—reflects that sentiment perfectly. The meeting, to be held in San Francisco from Saturday, September 7, to Monday, September 9, will bring together medical oncologists, radiation oncologists, surgeons, and other members of the breast-care team to discuss the latest research in order to strengthen collaborative treatment approaches.

William M. Sikov, MD, FACP

“The goal of the Symposium is to keep the members of the various specialties abreast of new data and ongoing controversies from other specialties,” explained William M. Sikov, MD, FACP, Associate Professor of Medicine at Warren Alpert Medical School of Brown University, and CoChair of this year’s Symposium.

Education across the Breast-care Team “We want to make sure, for ex-

ample, that medical oncologists are aware of important advances and unresolved questions that influence decisions being made by radiation oncologists and breast surgeons, and vice versa,” Dr. Sikov continued. “We bring experts in from each of those areas to educate attendees from their own specialty as well as those from other areas of expertise within the multidisciplinary breast-care team.” The Symposium facilitates interactive discussions about the latest treatment strategies, which treatment plans achieve optimal outcomes, and the effect of choosing one course of action over another.

Meet the Professor Offerings Doubled The popular Meet the Professor sessions have been expanded, and now there will be six instead of three. These intimate sessions feature a prominent professor who lectures for about 25 minutes on a timely topic, followed by 25 minutes of small-group discussions. The sessions are limited to 75 people and fill up fast. Attendees may request a complimentary ticket for a Meet the Professor Session during the online registration process.

Fellows to Get More Interaction The Symposium planning committees are launching a new Fellows, Residents, and Junior Faculty Track at the Symposium, offering trainees and young attendings programming geared especially to them. Meena S. Moran, MD, Associate Professor in Therapeutic Radiology at

will also be presented at the Symposium. First given in 2007, it recognizes an active clinical and/or translational researcher with a distinguished record of advancing the field of breast cancer and showing exceptional mentoring abilities. The

Meena S. Moran, MD

Yale University, Medical Director at the Backus Breast Center, and CoChair-Elect for the 2014 Breast Cancer Symposium, is this year’s Chair of the Fellows, Residents, and Junior Faculty Track. Dr. Moran has been involved with the fellows, residents, and junior faculty networking session for the last several years, which offered small group discussions with faculty geared to young physicians. But feedback showed that fellows,, residents, and junior faculty wanted more interaction, Dr. Moran said. They will now have an evening networking reception, an interactive session on how to give talks and write papers, and a Best of Journals Literature Review. In the Best of Journals Literature Review, explained Dr. Moran, “One surgeon, one radiation oncologist, and one medical oncologist will spend 20 minutes on each of the most important papers from the last year, putting them in context and explaining their medical relevance.”

Gianni Bonadonna Breast Cancer Award The ASCO Gianni Bonadonna Breast Cancer Award and Lecture

Larry Norton, MD

award provides $50,000 to a fellow in the institution of the award recipient. This year’s recipient is Larry Norton, MD, Deputy Physician-inChief for Breast Cancer Programs and Medical Director of the Evelyn H. Lauder Breast Center at Memorial Sloan-Kettering Cancer Center. In addition, he is the founding incumbent of the Norna S. Sarofim Chair of Clinical Oncology and a Professor of Medicine in the Weill Medical College of Cornell University. Dr. Norton has dedicated his life to the eradication of cancer through participation in medical care, laboratory and clinical research, advocacy, and government. For more information about the 2013 Breast Cancer Symposium and to register, please visit breastcasym.org. n © 2013. American Society of Clinical Oncology. All rights reserved.

Business Summit Fosters Innovative Solutions to Oncology Market Challenges

o provide a forum for key cancer stakeholders to join with business, finance, and legal thought leaders to explore the future course for oncology, ASCO is co-hosting the seventh annual Cancer Center Business Summit on October 24 and 25 in Chicago, Illinois. De-

signed as a resource for the business side of oncology, the event, themed “Transforming Oncology Through Innovation,” features presentations and panels that address an array of issues affecting practice, including value-based payment models and federal payment reform, oncologist-

hospital relationships, emerging business models, and market strategies in cancer care. According to Sandra M. Swain, MD, FACP, ASCO Immediate Past President and Medical Director of Washington Cancer Institute MedStar Washington Hospital Center,

“Today’s market and government reform dynamics require innovative solutions to drive care quality improvements while reducing costs. To help meet those demands, the Cancer Center Business Summit allows industry leaders to collaborate in decontinued on page 53

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Direct from ASCO

Institute Initiatives Help Oncologists Integrate Evidence-based Guidelines in Practice

uilding on ASCO’s longstanding commitment to drive quality, value, and accountability in cancer care, the Institute for Quality’s initiatives provide oncologists with resources to ensure that every patient receives the highest level of cancer care. Established in 2011, the Institute for Quality oversees the development of clinical practice guidelines; the Quality Oncology Practice Initiative (QOPI); the QOPI Certification Program (QCP); CancerLinQ, ASCO’s newly developed rapid learning system; and other quality initiatives and partnerships. Since issuing its first practice guideline in 1994, the organization’s expert panels have issued more than 30 guidelines and guideline updates, four provisional clinical opinions, and two guideline endorsements.

Quality Oncology Practice Initiative To spur the integration of such

guidelines into clinical practice, in 2006, ASCO developed QOPI—a program that gives oncology practices quality measurement and improvement tools. Participating practices that meet the highest standards of care may receive a 3-year certification. More than 750 practices have registered in QOPI since its launch, and nearly 140 practices have been certified since QCP was established in 2010. Other quality-related initiatives housed within the Institute for Quality include ASCO’s leadership in the development of quality measures for the Centers for Medicare & Medicaid Services’ Physician Quality Reporting System; collaborations with other organizations to establish quality measures for safe chemotherapy administration and breast and colorectal cancer care; and other partnerships aiming to drive quality improvements.

New CancerLinQ Prototype The latest addition to the Institute for Quality is CancerLinQ—a tool that builds on all of the other quality initiatives, harnessing technological advances to connect oncology practices, measure quality and performance, and provide physicians with decision support in real time. The system will aggregate clinical data that is currently housed in disparate medical record systems that lack interoperability. This multiphase initiative is in the first stage, which involves the development of a breast cancer-specific prototype. ASCO President Clifford A. Hudis, MD, FACP, noted that, because a relatively small number of adults with cancer participate in clinical trials, the majority of data collected in care delivery remains underutilized, contributing little to advance understanding and spur treatment innovations. CancerLinQ has “transformative potential,” he said, to facilitate

Clifford A. Hudis, MD, FACP

the development of guidelines for the vast, often unstudied aspects of cancer care and to inform the further evolution of existing guidelines. Although the Institute for Quality is the organization’s center for explicitly quality-related initiatives, “all of the efforts within ASCO can ultimately be tracked back to the goal of cancer care quality improvement, which is at the core of ASCO’s mission,” said Dr. Hudis. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO Issues Progress Report on Blueprint for Cancer Research

SCO has released a Progress Report on the gains made toward achieving goals set forth in its landmark 2011 report, Blueprint for Transforming Clinical and Translational Cancer Research. The ASCO Blueprint laid out an innovative roadmap for the clinical research system to capitalize on the new understanding of cancer biology.

Examples of Progress Since issuing the Blueprint report, ASCO and other major partners have made important strides in achieving the Blueprint’s vision. Examples include: ■ ASCO has initiated efforts to develop recommendations on clinically meaningful outcomes for clinical trials to ensure that new cancer therapies offer meaningful improvements in patient survival and quality of life

■ FDA has adopted its breakthrough therapy initiative to prioritize and streamline development of highly promising new therapies ■ NCI took actions to strengthen the Cooperative Group Program, which will revitalize federally-funded clinical research ■ ASCO completed the CancerLinQ prototype, the first step toward fulfilling the Society’s commitment to develop a “rapid learning system” for cancer care The Blueprint and Progress Reports can be downloaded at www .cancer progress.net/bluepr int .html.

Be Counted in Oncology Practice Census ASCO is continuing its efforts to assess and monitor the state of oncology practices and respond to its rapid-

ly changing environment. The ASCO National Oncology Census will help the Society maintain its full picture of the oncology landscape for 2013. More than 600 U.S. oncology practices representing more than 5,000 individual oncologists participated in the 2012 census, the preliminary results of which were published in the Journal of Oncology Practice.1 In 2013, ASCO is seeking full participation to ensure that the collected data is representative of the entire oncology community in the United States across the spectrum of practice settings—community practices, hospitals, government, and academic institutions. The survey instrument has been significantly streamlined mini-

mizing the time required to answer the survey questions. To learn more about the 2013 ASCO National Oncology Census, visit www.asco.org/census. To take the survey now, visit www.asco .org/2013-asco-national-oncologycensus. (Survey respondents may use their ASCO ID or log in as a guest.) n © 2013. American Society of Clinical Oncology. All rights reserved. Reference 1. Forte GJ, Hanley A, Hagerty K, et al: American Society of Clinical Oncology National Census of Oncology Practices: Preliminary report. J Oncol Pract 9:9-19, 2013.

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Direct from ASCO

Business Summit continued from page 51

veloping sustainable business models for high-quality cancer care delivery.”

of oncology from the current payment and care delivery systems to the target value-based systems will benefit from attending the Summit.” He noted that the event will identify resources to help navigate the rapidly changing business landscape and

provide a window into peers’ efforts to prepare for and transform the future of cancer care delivery. B:8.25”

For More Information T:7.5”

For the latest information on the S:6.75” 2013 Cancer Center Business Sum-

mit, visit www.cancerbusinesssummit. com to register, view the agenda, and learn more about the event hosts, advisory board, speakers, and sponsors. n © 2013. American Society of Clinical Oncology. All rights reserved.

INVESTIGATIONAL PHASE 3 TRIALS CURRENTLY ACCRUING Allen Lichter, MD

2013 Program Highlights ASCO CEO Allen Lichter, MD, will deliver the opening remarks, painting a picture of the future of oncology. The next session will address health plan payers’ market dynamics, setting the stage for four case studies of paired provider-payer initiatives in care process and payment redesign. The case studies will highlight project results, lessons learned, and plans for the future. Another theme featured proximately in the program is the evolution of data analytics in oncology, aiming to provide attendees with the information and resources needed to extract the full value from clinical and financial data in anticipation of likely payment bundling in the near future. Other sessions will address topics such as academic medical center and community oncology alignment, mobile technology innovations in health care, the development of oncology-specific accountable care organizations and oncology medical homes, oncology standards and measures in value-based payment systems, options for oncology practice integration that preserve private practice, alternative oncology payment arrangements, issues in valuing oncology transactions, emerging business models in genomics and precision medicine, and strategies and structures for radiation therapy programmatic success.

Cabozantinib phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases KEY ELIGIBILITY CRITERIA • Diagnosis of CRPC • Presence of bone metastases • Prior treatment with docetaxel • Prior treatment with abiraterone and/or MDV3100 (enzalutamide) • No limit to the number of prior therapies

COMET-1

COMET-2

PRIMARY ENDPOINT

Overall Survival

Confirmed Pain Response CRPC (N=246)

CRPC (N=960) • Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies

Cabozantinib 60 mg QD Randomization Prednisone

• Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies • Pain related to bone metastases

Cabozantinib 60 mg QD Randomization

Target Audience According to Ronald Barkley, MS, JD, President of Cancer Center Business Development Group and co-founder of the Cancer Center Business Summit, “Stakeholders in cancer care delivery who are seeking to be part of the transformation

Randomized, double-blind, controlled trial

Mitoxantrone + Prednisone

The ASCO Post | JULY 10, 2013

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Direct from ASCO

New International Innovation Grant Directly Supports Research Projects in Developing Countries

he Conquer Cancer Foundation and ASCO International have just launched a new research funding opportunity, the Conquer Cancer Foundation of ASCO International Innovation Grant, which directly supports research being conducted by investigators in low- and middle-income countries.

mental agencies in low- and middleincome countries. The principal

grant application. Past recipients of the ASCO/Conquer Cancer Foun-

Potential Applicants Needed

Advancing Cancer Control Worldwide The new grant will fund hypothesis-driven research for projects that can generate new knowledge about how to advance cancer control in low- and middle-income countries. It is anticipated that novel approaches proposed for this grant will differ from what would be considered standard practice within high-income settings. The International Innovation Grant will support proposals that have the potential to reduce the cancer burden in local communities, while also being potentially transferrable to other low- and middle-income countries. Grantees will be expected to disseminate the knowledge gained from their research. The International Innovation Grant is a 1-year grant for up to $20,000 that will be awarded to notfor-profit organizations or govern-

who meet the eligibility criteria. The deadline to submit a letter of intent is August 1, 2013.

investigator of the research project must be a resident of the low- or middle-income country who is affiliated with the grantee organization and must be an ASCO member or apply for ASCO membership at the time of

ASCO Answers Guides to Breast, Colorectal, Prostate, and Lung Cancer Now Available to Order

dation International Development and Education Award (IDEA) and Long-term International Fellowship (LIFe) awards are particularly encouraged to apply as principal investigators, but the grants are open to all

The International Innovation Grant is part of ASCO International, an ambitious expansion of new programs, initiatives, and research opportunities that will increase awareness, improve practice, and foster innovation in cancer care around the world. Please help us reach potential applicants by sharing this information with colleagues in your international network and directing them to www.conquercancerfoundation .org/innovation for more information. At least two grants will be awarded in 2014, which are being generously supported by the Conquer Cancer Foundation Mission Endowment and by ASCO, but additional support is needed to help continue this program into the future. You can help improve cancer care—in all parts of the world—by making a gift at www .conquercancerfoundation.org/ donate. Together, we can make a global difference. n © 2013. American Society of Clinical Oncology. All rights reserved.

Save the Date Best of ASCO 2013

he ASCO Answers guides to cancer are designed to help patients newly diagnosed with cancer understand their disease and treatment options. These comprehensive, patientfriendly booklets contain trusted information about diagnosis, treatment, side effects, and the psychosocial effects of cancer. They also provide space for patients to record details about their diagnosis and treatment

plan, a feature that allows patients to easily go back and find the most pertinent information when needed. Each guide can be purchased from the ASCO University Bookstore at www.cancer.net/estore, with a 20% discount for ASCO members and free shipping. n © 2013. American Society of Clinical Oncology. All rights reserved.

Best of ASCO® Chicago August 9-10, 2013 Best of ASCO® Los Angeles August 16-17, 2013 Best of ASCO® Boston August 23-24, 2013 For more information, visit boa.asco.org

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Dermatologic Events in Oncology Melanomas Induced by BRAF Inhibitors By Ashfaq A. Marghoob, MD, and Sarah Yagerman, BS

he realization that targeted blockade of specific components of the MAP kinase pathway can be used to treat melanoma is considered by many to be one of the watershed moments in melanoma therapeutics. The resultant use of vemurafenib (Zelboraf ) for the treatment of a subset of metastatic melanomas harboring the BRAF V600E mutation continues to be embraced with much enthusiasm by patients, physicians, and researchers. However, this enthusiasm is somewhat mitigated by the observation that responses to BRAF inhibitor therapy are often not durable. Moreover, targeted therapy has the potential to paradoxically unmask the expression of other driver mutations, leading to a heightened risk for developing other cancers such as squamous cell carcinomas and second primary melanomas. Therefore, patients receiving vemurafenib therapy will likely benefit from periodic cutaneous surveillance examinations aimed at detecting and treating any second primary melanomas (as well as squamous cell carcinomas), while these neoplasms are thin and more easily curable. Research and clinical observations have revealed that melanomas and nevi that harbor the BRAF V600E mutation involute when the patient is given vemurafenib. While the new and darkening/enlarging nevi and the new melanomas developing in these individuals are BRAF wild-type, they do harbor other driver mutations such as in NRAS (Fig. 1) that may paradoxically activate the very same pathway targeted by vemurafenib, leading to unchecked proliferation. Given the paucity of targeted therapies for advanced BRAF wild-type melanomas, it behooves the clinician to diagnose these second primary malignancies as early as possible, while they are potentially amenable to cure via surgical excision. Dr. Marghoob is Clinical Associate Professor in the Dermatology Service and Ms. Yagerman is a Clinical Research Fellow in Dermatology at Memorial Sloan-Kettering Cancer Center, New York.

Since patients with a previous melanoma are at increased risk for developing subsequent primary melanomas, many experts recommend lifelong surveillance examinations performed at least every 6 to 12 months. â&#x20AC;&#x201D; Ashfaq A. Marghoob, MD, (top), and Sarah Yagerman, BS

A more formal evaluation to determine the degree of volatility of melanocytic lesions in patients on BRAF inhibitors is currently underway at multiple institutions. At Memorial Sloan-Kettering, we sequentially followed patients receiving vemurafenib with photographic

images. Average photographic follow-up was 261 days (nÂ =Â 21). The average number of combined new and changing melanocytic lesions per patient was 13.1, 16.4, 9.5, and 6.1 for the upper back, lower back, chest, and abdomen, respectively. Of all new and changing lesions, 38

Mario E. Lacouture, MD

Dermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, an Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan-Kettering Cancer Center, New York. He is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments and the author of many publications, including the recently published Skin Care Guide for People Living With Cancer. The series is intended to offer oncologists guidance in recognizing and treating the skin toxicities associated with anticancer agents. were biopsied, revealing 31 benign melanocytic lesions and 7 melanomas (18% of lesions biopsied).

Management Recommendations Fig. 1: (a) Clinical image of a melanoma that developed on the back of a patient on BRAF inhibitor, that is NRAS mutated. (b) Dermoscopic image allowing for the visualization of subsurface structures.

Fig. 2: Baseline photos of a patient on vemurafenib before (a) and after (b) initiation of treatment. Arrow indicates a growing and darkening dysplastic nevus. Note other nevi are also changed.

Patients on BRAF inhibitor therapy would benefit from periodic skin surveillance examinations. One proposal suggests skin examinations be performed at baseline, week 4, and every 12 weeks following initiation of therapy. Although not mandatory, obtaining photographs of the entire cutaneous surface can facilitate identifying new or changing lesions on subsequent examinations (Fig. 2). Additional evaluation of all new and changing lesions with dermoscopy can further increase the sensitivity and specificity for melanoma detection. It is important to be aware that many nevi in these individuals will demonstrate clinical, dermoscopic, and histologic features of dysplastic nevi. The biologic potential of continued on page 59

Can you tell which patient has ALK-positive NSCLC? Molecular testing is increasingly important in lung cancer In a study of 420 patients with adenocarcinoma non-small cell lung cancer (NSCLC), more than 50% of tumors tested positive for a predictive biomarker.1 About 3% to 5% of patients with advanced NSCLC harbor a genetic alteration known as the anaplastic lymphoma kinase (ALK) fusion gene.2-9 The ALK fusion gene (a fusion between ALK and other genes such as EML4) is believed to be a key oncogenic driver that contributes to cell proliferation and tumor survival.6,10-12

Approval of the first ALK inhibitor is a compelling reason to test patients for the ALK fusion gene XALKORI® (crizotinib)—the first ALK inhibitor—may offer antitumor activity for patients with locally advanced or metastatic ALK-positive NSCLC. As an inhibitor of the ALK receptor tyrosine kinase, XALKORI is believed to block growth and survival mechanisms in tumor cell lines, potentially leading to regression or stabilization of tumors.7 Testing is necessary to identify patients for whom XALKORI may be appropriate. An FDA-approved test must be used to determine which patients have ALK-positive NSCLC.

Clinical characteristics should not be used to determine which patients to test13 In XALKORI registration studies, the ALK fusion gene was identified in patients who varied by age, race, gender, and performance status. While the ALK fusion gene was identified more frequently in never-smokers, it was also seen in former and current smokers. In addition, the ALK fusion gene was identified more frequently in patients with adenocarcinoma but occurred in all histologic types. Thus, simultaneous testing for all clinically relevant biomarkers—including ALK—prior to treatment initiation may help guide

therapeutic decisions.14

References: 1. Johnson BE, Kris MG, Kwiatkowski D, et al. Clinical characteristics of planned 1000 patients with adenocarcinoma of lung (ACL) undergoing genomic characterization in the US Lung Cancer Mutation Consortium (LCMC). 14th World Conference on Lung Cancer. July 3-7, 2011; Amsterdam, the Netherlands. Abstract O16.01. 2. Garber K. ALK, lung cancer, and personalized therapy: portent of the future? J Natl Cancer Inst. 2010;102:672-675. 3. Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008;14:6618-6624. 4. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-567. 5. Palmer RH, Vernersson E, Grabbe C, Hallberg B. Anaplastic lymphoma kinase: signalling in development and disease. Biochem J. 2009;420:345-361. 6. Mossé YP, Wood A, Maris JM. Inhibition of ALK signaling for cancer therapy. Clin Cancer Res. 2009;15:5609-5614. 7. Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46:1773-1780. 8. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14:4275-4283. 9. Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009;115:1723-1733. 10. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non–small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253. 11. Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8:11-23. 12. Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A. 2008;105:19893-19897. 13. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer V.2.2013. © 2013 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed January 22, 2013. To view the most recent and complete version of the guideline, go online to http://www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 14. Pérez-Soler R. Individualized therapy in non-small cell lung cancer: future versus current clinical practice. Oncogene. 2009;28(suppl 1):S38-S45.

Not without testing. The National Comprehensive Cancer Network® (NCCN®) recommends that all patients with advanced or metastatic NSCLC determined by histology to be nonsquamous or NOS undergo EGFR and ALK testing13 • EGFR and ALK testing is also recommended in patients with squamous cell carcinoma if they never smoked and if small biopsy specimens were used to assess histology

XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

SELECTED SAFETY INFORMATION Drug-induced hepatotoxicity with fatal outcome has occurred. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. XALKORI has been associated with severe, life-threatening or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes and permanently discontinue XALKORI in patients with treatment-related pneumonitis. Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI.

Please see additional Important Safety Information on the next page and accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com.

XALKORI® (crizotinib) is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

IMPORTANT SAFETY INFORMATION Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome has occurred. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. Pneumonitis: XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes and permanently discontinue XALKORI in patients with treatmentrelated pneumonitis. QT Interval Prolongation: QTc prolongation has been observed. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI for grade 4 QTc prolongation. XALKORI should be withheld for grade 3 QTc prolongation until recovery to ≤ grade 1. Permanently discontinue XALKORI if grade 3 QTc prolongation recurs. ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. If the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. Adverse Reactions: Among the 397 patients for whom information on deaths and serious adverse reactions is available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4). Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). The most common adverse reactions (≥25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia. • Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia were reported in 159 (62%) patients in clinical trials. Consider ophthalmological evaluation, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment. Advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder. • Neuropathy attributed to study drug was reported in 34 (13%) patients. Grade 2 motor neuropathy and grade 3 peripheral neuropathy were reported in 1 patient each. • Bradycardia was reported in 12 (5%) patients treated with XALKORI. All of these cases were grade 1 or 2 in severity. • Complex renal cysts were reported in 2 (1%) patients treated with XALKORI. There were no reports of abnormal urinalyses or renal impairment in these cases. Grade 3 or 4 laboratory abnormalities of neutropenia, thrombocytopenia, and lymphopenia were observed in 5.2%, 0.4%, and 11.4% of patients, respectively. Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue XALKORI. Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment. Renal Impairment: No starting dose adjustment is needed for patients with mild and moderate renal impairment. No data are available for patients with end-stage renal disease. Use caution in patients with severe renal impairment or patients with end-stage renal disease. XALKORI is a registered trademark of Pfizer Inc.

Please see accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com.

CRI550916-01

Printed in USA/March 2013

ASCOPost.com | JULY 10, 2013

PAGE 59

Dermatologic Events in Oncology Melanomas Induced by BRAF Inhibitors continued from page 55

these “atypical” nevi remains to be elucidated. That said, many issues remain unresolved, including the advantages of intermittent dosing, the optimal frequency of surveillance skin examinations, even after thera-

py, and optimal frequency of examination after cessation of therapy. Since patients with a previous melanoma are at increased risk for developing subsequent primary melanomas, many experts recommend lifelong surveillance examinations performed at least every 6 to 12 months. In addition, these patients

XALKORI® (crizotinib) capsules Brief Summary of Prescribing Information

ADVERSE REACTIONS Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). Among the 255 patients for whom data on Grade 1-4 adverse reactions are available, median exposure to study drug was 5.1 months in Study A and 7.8 months in Study B. Dosing interruptions occurred in 36% and 45% of patients in Studies A and B, and lasted >2 weeks in 13% and 19% of all patients. Dose reductions occurred in 44% and 29% of patients. The rates of treatment-related adverse events resulting in permanent discontinuation were 6% in Study A and 3% in Study B. The most common adverse reactions (≥ 25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia. Among the 397 patients for whom information on deaths and serious adverse reactions is available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4). Respiratory causes of death included pneumonia (2), hypoxia (2), ARDS (1), dyspnea (1), pneumonitis (1), empyema (1), and pulmonary hemorrhage (1). Other causes of deaths included septic shock, DIC, cardiovascular event, and death due to unknown cause (1 each). Serious adverse events in ≥2% of patients included pneumonia, dyspnea, and pulmonary embolism. Table 3 lists the common adverse reactions on Studies A and B in patients receiving XALKORI. Table 3: Adverse Reactions in ≥ 10% of Patients with Locally Advanced or Metastatic ALK-Positive NSCLC on Studies A and B1

EYE DISORDERS

Vision Disorder2

Treatment Emergent (N=255) All Grades Grades 3/4 n (%) n (%)

Treatment Related (N=255) All Grades Grades 3/4 n (%) n (%)

163 (64%)

0 (0)

159 (62%)

0 (0)

145 (57%) 124 (49%) 116 (45%) 98 (38%) 51 (20%) 40 (16%) 27 (11%)

2 (<1%) 1 (<1%) 3 (1%) 2 (<1%) 3 (1%) 1 (<1%) 1 (<1%)

136 (53%) 109 (43%) 101 (40%) 69 (27%) 29 (11%) 20 (8%) 15 (6%)

0 0 0 1 (<1%) 0 0 1 (<1%)

97 (38%) 80 (31%) 30 (12%) 30 (12%)

2 (<1%) 6 (2%) 1 (<1%) 1 (<1%)

72 (28%) 51 (20%) 3 (1%) 2 (<1%)

0 4 (2%) 0 0

GASTROINTESTINAL DISORDERS

Nausea Diarrhea Vomiting Constipation Esophageal Disorder3 Abdominal Pain4 Stomatitis5 GENERAL DISORDERS

Edema6 Fatigue Chest Pain/Discomfort7 Fever INFECTIONS AND INFESTATIONS

Upper Respiratory Infection8 INVESTIGATIONS

Alanine Aminotransferase Increased Aspartate Aminotransferase Increased METABOLISM AND NUTRITION

Decreased Appetite MUSCULOSKELETAL

Arthralgia Back Pain

50 (20%)

1 (<1%)

4 (2%)

38 (15%) 29 (11%)

17 (7%) 7 (3%)

34 (13%) 24 (9%)

14 (5%) 5 (2%)

69 (27%)

3 (1%)

49 (19%)

29 (11%) 28 (11%)

3 (1%) 0

4 (2%) 2 (<1%)

0 0

60 (24%) 58 (23%) 34 (13%) 33 (13%)

0 1 (<1%) 1 (<1%) 0

42 (16%) 34 (13%) 10 (4%) 30 (12%)

0 1 (<1%) 0 0

NERVOUS SYSTEM DISORDERS

Dizziness9 Neuropathy10 Headache Dysgeusia PSYCHIATRIC DISORDERS

Insomnia

RESPIRATORY DISORDERS

Dyspnea Cough

SKIN DISORDERS

Rash

Study A used CTCAE v4.0, and Study B used CTCAE v3.0. Includes diplopia, photopsia, photophobia, vision blurred, visual field defect, visual impairment, vitreous floaters, visual brightness, and visual acuity reduced. Includes dyspepsia, dysphagia, epigastric discomfort/pain/burning, esophagitis, esophageal obstruction/pain/spasm/ulcer, gastroesophageal reflux, odynophagia, and reflux esophagitis. 4 Includes abdominal discomfort, abdominal pain, abdominal pain upper, and abdominal tenderness. 5 Includes mouth ulceration, glossodynia, glossitis, cheilitis, mucosal inflammation, oropharyngeal pain/discomfort, oral pain, and stomatitis. 6 Includes edema, edema localized, and peripheral edema. 7 Includes chest pain, chest discomfort, and musculoskeletal chest pain. 8 Includes nasopharyngitis, rhinitis, pharyngitis, and upper respiratory tract infection. 9 Includes balance disorder, dizziness, and presyncope. 10 Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, paresthesia, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensory neuropathy. 2

CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome has occurred. These cases have occurred during XALKORI treatment in <1% of patients in clinical trials. Concurrent elevations in ALT >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal, with normal alkaline phosphatase, occurred in <1% of patients in clinical trials. Elevation in ALT >5 times the upper limit of normal occurred in 7% of patients in Study A and in 4% of patients in Study B. These laboratory findings were generally asymptomatic and reversible upon dosing interruption. Patients usually resumed treatment at a lower dose without recurrence; however, 3 patients from Study A (2%) and 1 patient from Study B (<1%) required permanent discontinuation from treatment. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Pneumonitis: XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients across Studies A and B. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes of pneumonitis, and permanently discontinue XALKORI in patients diagnosed with treatment-related pneumonitis. QT Interval Prolongation: QTc prolongation has been observed. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI in patients who develop Grade 4 QTc prolongation. Withhold XALKORI in patients who develop Grade 3 QTc prolongation until recovery to ≤ Grade 1, then resume XALKORI at 200 mg twice daily. In case of recurrence of Grade 3 QTc prolongation, withhold XALKORI until recovery to ≤ Grade 1, then resume XALKORI at 250 mg once daily. Permanently discontinue XALKORI if Grade 3 QTc prolongation recurs. ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for treatment with XALKORI. Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using XALKORI. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

30 (12%)

8 (3%)

57 (22%) 54 (21%)

16 (6%) 3 (1%)

5 (2%) 9 (4%)

3 (1%) 0

41 (16%)

25 (10%)

Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia, were reported in 159 (62%) patients in clinical trials. These events generally started within two weeks of drug administration. Consider ophthalmological evaluation, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment. Advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder. Neuropathy as defined in Table 3 and attributed to study drug by the investigator was reported in 34 (13%) patients. While most events were Grade 1, Grade 2 motor neuropathy and Grade 3 peripheral neuropathy were reported in 1 patient each. Dizziness and dysgeusia were also very commonly reported in these studies, but were all Grade 1 or 2 in severity. Bradycardia occurred in 12 (5%) patients treated with XALKORI. All of these cases were Grade 1 or 2 in severity. Complex renal cysts occurred in 2 (1%) patients treated with XALKORI. There were no reports of abnormal urinalyses or renal impairment in these cases. Laboratory Abnormalities: Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 5.2%, 0.4%, and 11.4% of patients, respectively. DRUG INTERACTIONS Drugs That May Increase Crizotinib Plasma Concentrations: Coadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations. Avoid concomitant use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib. Exercise caution with concomitant use of moderate CYP3A inhibitors. Drugs That May Decrease Crizotinib Plasma Concentrations: Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations. Avoid concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital phenytoin, rifabutin, rifampin, and St. John’s Wort. Drugs Whose Plasma Concentrations May Be Altered By Crizotinib: Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Avoid coadministration of crizotinib with CYP3A substrates with narrow therapeutic indices, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. USE IN SPECIFIC POPULATIONS Pregnancy Category D: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies of XALKORI in pregnant women. Advise women of childbearing potential to avoid becoming pregnant while receiving XALKORI. Women of childbearing potential who are receiving this drug, or partners of women of childbearing potential receiving this drug, should use adequate contraceptive methods during therapy and for ≥90 days after completing therapy. If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Nursing Mothers: It is not known whether XALKORI 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 XALKORI, consider 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 XALKORI in pediatric patients has not been established. Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 10 times the AUC in adult patients at the recommended human dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatic Use: Clinical studies of XALKORI did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Of the 136 patients in Study A, 19 (14%) were ≥65 years. Of the 119 patients in Study B, 16 (13%) were ≥65 years. Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Clinical studies excluded patients with AST or ALT >2.5 x ULN, or >5 x ULN, if due to liver metastases. Patients with total bilirubin >1.5 x ULN were also excluded. Therefore, use caution in patients with hepatic impairment. Renal Impairment: No starting dose adjustment is needed for patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) and moderate renal impairment (CLcr 30 to 60 mL/min), as steady-state trough concentrations in these two groups were similar to those in patients with normal renal function (CLcr >90 mL/min) in Study B. The potential need for starting dose adjustment in patients with severe renal impairment cannot be determined, as clinical and pharmacokinetic data were available for only one patient. In addition, no data are available for patients with end-stage renal disease. Therefore, use caution in patients with severe renal impairment (CLcr <30 mL/min) or patients with end-stage renal disease. OVERDOSAGE There have been no known cases of XALKORI overdose. Treatment of overdose with XALKORI should consist of general supportive measures. There is no antidote for XALKORI. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with crizotinib have not been conducted. Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures, in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat bone marrow micronucleus assays. Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. No specific studies with crizotinib have been conducted function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given ≥50 mg/kg/day for 28 days (>3 times the AUC at the recommended human dose). Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day (approximately 10 times the recommended human daily dose on a mg/m2 basis) for 3 days. PATIENT COUNSELING INFORMATION Hepatotoxicity: Inform patients that symptoms of weakness, fatigue, anorexia, nausea, vomiting, abdominal pain (especially RUQ abdominal pain), jaundice, dark urine, generalized pruritus, and bleeding diathesis, especially in combination with fever and rash, should be reported immediately. Gastrointestinal Effects: Inform patients that nausea, diarrhea, vomiting, and constipation are the most commonly reported gastrointestinal adverse events occurring in patients who received XALKORI. Supportive care for gastrointestinal adverse events requiring treatment may include standard anti-emetic and/or anti-diarrheal or laxative medications. Visual Effects: Inform patients that visual changes such as perceived flashes of light, blurry vision, light sensitivity, and floaters are commonly reported adverse events. These events began most commonly during the first two weeks of treatment. Advise patients to report flashes or floaters to their physicians. Effects on Ability to Drive and Use Machines: No studies on the effect of XALKORI on the ability to drive and use machines have been performed. However, advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder, dizziness, or fatigue while taking XALKORI. Concomitant Medications: Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Instructions for Taking XALKORI: Advise patients to take XALKORI exactly as prescribed, not to change their dose or to stop taking XALKORI unless they are told to do so by their doctor. Take XALKORI with or without food. Swallow XALKORI capsules whole. Advise patients to keep XALKORI in the original container. Do not crush, dissolve, or open capsules. Inform patients to avoid grapefruit or grapefruit juice while taking XALKORI. If a patient misses a dose, advise the patient to take it as soon as remembered unless it is less than 6 hours until the next dose, in which case, advise the patient not to take the missed dose. Advise patients not to take two doses at the same time to make up for a missed dose. Pregnancy and Nursing: Inform patients of childbearing potential to use adequate contraceptive methods during therapy and for ≥90 days after completing therapy. Advise patients to inform their doctor if they or their partners are pregnant or think they may be pregnant. Also advise patients not to breastfeed while taking XALKORI. Rx Only April 2012

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Disclosure: Dr. Marghoob and Ms. Yagerman reported no potential conflicts of interest.

INDICATIONS AND USAGE XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI. DOSAGE AND ADMINISTRATION Recommended Dosing: The recommended dose and schedule of XALKORI is 250 mg taken orally twice daily. Continue treatment as long as the patient is deriving clinical benefit from therapy. XALKORI may be taken with or without food. Swallow capsules whole. If a dose of XALKORI is missed, make up that dose unless the next dose is due within 6 hours. Dose Modification: Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary, then reduce the dose of XALKORI to 200 mg taken orally twice daily. If further dose reduction is necessary, then reduce the dosage to 250 mg taken orally once daily based on individual safety and tolerability.

Adverse Event

should be instructed on the importance of protecting their skin from exposure to ultraviolet radiation and educated on the benefits of monthly skin self-examination looking for any new or changing lesions. n

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

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PAGE 60

Journal Spotlight Breast Cancer

Measurement of Circulating Tumor DNA Shows Promise in Monitoring Metastatic Breast Cancer By Matthew Stenger

anagement of metastatic breast cancer requires monitoring of tumor burden to assess response to treatment, and there is a need for biomarkers that can measure tumor burden with high sensitivity and specificity. Assays measuring serum cancer antigen (CA) 15-3 and circulating tumor cells have been reported to have sensitivities of approximately 60% to 70%. As reported in The New England Journal of Medicine, a proof-of-concept study performed by Sarah-Jane Dawson, FRACP, PhD, of the University of Cambridge and the Cancer Research UK Cambridge Institute,

and colleagues has shown that circulating tumor DNA is “an informative, inherently specific, and highly sensitive” biomarker of metastatic breast cancer.1 In this study, the investigators used targeted sequencing to identify somatic genetic alterations in TP53 and PIK3CA, the two genes that are noted to be mutated in up to 50% of all patients with metastatic breast cancer. In a selected number of the remaining individuals, the investigators undertook whole-genome sequencing to identify mutations in other genes or structural variants that were unique to the tumor. They then designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens using digital polymerase chain

Our expanding knowledge of the genetic mechanisms underpinning breast cancer now provides a framework to better stratify patients. —Sarah-Jane Dawson, FRACP, PhD, and colleagues

reaction or targeted deep sequencing. CA 15-3 levels and circulating tumor cell numbers were measured at the same time points. Computed tomography (CT) imaging of tumors was compared with assays for circulating tumor DNA,

EXPERT POINT OF VIEW for individual patients may require very intensive and costly sequencing strategies or may remain elusive. Although the investigators found that mutations in PIK3CA and TP53 were common (found in 25 of the 52 patients), there is no single locus in these genes Marc Lippman, MD C. Kent Osborne, MD that is commonly mutated. n editorial by Marc Lippman, “Therefore, very substantial sequencMD, Leonard M. Miller School ing will be required for probe design; of Medicine, University of Miami, and a standard ‘panel’ is unlikely to work C. Kent Osborne, MD, Breast Center, for all patients,” Drs. Lippman and OsBaylor College of Medicine, Houston,1 borne wrote. accompanied the study by Dawson and colleagues. These authors com- Additional Concerns The commentators also pointed out mented that the study’s key findings— that variation in the level of circulating that the number of patients with an obtumor DNA was reasonably correlated jective response of circulating tumor with response to treatment and signifi- DNA to treatment was limited, and cantly associated with prognosis—are that the attempt to compare usefulness positive and encouraging. However, of this measure with the more standard they described a number of practical biomarkers was “more encouraging limitations facing clinical application than definitive.” They continued, “And of circulating tumor DNA measure- of course, many patients have readily measurable lesions that are effecment. First, mutations or structural vari- tively and cheaply assessed by means ants that could be measured and fol- of physical examination or imaging. In lowed were identified in only about an era of financial stressors on clinical 60% of the original group of 52 patents care, the cost-effectiveness of such new investigated. Since all patients with methods will require rigorous study.” Drs. Lippman and Osborne obbreast cancer have mutations in their DNA, development of specific probes served that despite such concerns

and limitations, there is considerable potential for assays measuring circulating tumor DNA. Noting that some patients with complete pathologic remissions on adjuvant therapy nevertheless eventually relapse, they posited that “assays of circulating tumor DNA, which has an impressive dynamic range, could more reliably predict patients who might not need further therapy or identify those with localized cancer who would be adequately treated by lumpectomy alone.” Further, the apparent high sensitivity of the assay suggests potential usefulness in screening for recurrence in asymptomatic patients with early-stage disease. They concluded, “the new study provides proof of the concept that circulating tumor DNA represents a sensitive biomarker of tumor burden. Demonstration that the method can be used to take better care of patients with metastatic breast or other cancers in a cost-effective manner awaits further studies, which are clearly warranted.” n

Disclosure: Drs. Lippman and Osborne reported no potential conflicts of interest.

Reference 1. Lippman M, Osborne CK: Circulating tumor DNA—ready for prime time? N Engl J Med 368:1249-1250, 2013.

CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. The 30 women were those from a group of 52 in whom genomic alterations (point mutations [in PIK3CA or TP53] or structural variants) could be identified. Overall, 22 of the 30 had mutations (in PIK3CA or TP53), 3 had mutations and structural variants, and 5 had structural variants only.

Relative Sensitivity Overall, circulating tumor DNA was detected in 29 (97%) of 30 women and 115 (82%) of 141 plasma samples. The median level of circulating tumor DNA across samples was 150 amplifiable copies/mL (interquartile range, 9–720 copies/mL). Data comparing CA 15-3 and circulating tumor DNA levels were available for 114 serial time points for 27 patients. CA 15-3 levels were elevated (> 32.4 U/mL) at one or more time points in 78% of women (21/27) and 62% of samples (71/114), whereas circulating tumor DNA was detected in 96% of women (26/27) and 82% of samples (94/114). Of the 43 samples without elevated CA 15-3 levels, 27 (63%) had measurable levels of circulating tumor DNA. Analysis using a modified bootstrapping method showed that the sensitivity of circulating tumor DNA was 85% vs 59% for CA 15-3, with a median difference in sensitivity of 26% (P < .002). Data comparing circulating tumor cells and circulating tumor DNA levels were available for 126 time points for all 30 women. Circulating tumor cells were detected (≥ 1 cell/7.5 mL) at one or more time points in 87% of women (26/30), with elevated counts (≥ 5 cells/7.5 mL) identified in 60% continued on page 62

NOW ENROLLING

ACUTE LYMPHOBLASTIC LEUKEMIA

INO-VATE ALL INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy A randomized, phase 3 trial in patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) This is a 2-armed, randomized, open-label, phase 3 study designed to evaluate the hematologic remission rate (CR + CRi) with inotuzumab ozogamicin compared with investigators’ choice of FLAG, cytarabine combined with mitoxantrone, or HIDAC.

Selected inclusion criteria • Relapsed or refractory CD22-positive ALL due to receive salvage 1 or salvage 2 therapy • Ph+ ALL patients must have failed treatment with at least 1 second-generation tyrosine kinase inhibitor • Bone marrow involvement with ≥5% lymphoblasts • Aged 18 years or older • ECOG performance status 0-2 • Adequate liver function

Selected exclusion criteria • Isolated extramedullary relapse, Burkitt’s lymphoma or mixed-lineage leukemia, or active central nervous system leukemia • Active heart disease • Prior chemotherapy ≤2 weeks prior to randomization and/or patients not recovered from acute toxicity • Prior treatment with monoclonal antibodies ≤6 weeks before randomization • Prior allogeneic hematopoietic stem cell transplant ≤4 months before randomization • Peripheral lymphoblasts >10,000/µL

Reference: ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01564784. Accessed April 3, 2012.

Inotuzumab ozogamicin is an investigational compound. This information is current as of August 14, 2012.

STW00067B

April 2012

Learn more about INO-VATE (B1931022) For more information about this trial, please visit www.clinicaltrials.gov (NCT01564784) or call: 1-877-369-9753 in the United States and Canada (toll-free) or +1-646-277-4066 outside the United States

The ASCO Post | JULY 10, 2013

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Journal Spotlight

Monitoring Metastatic Breast Cancer continued from page 60

of women, and in 37% of samples (46/126). By comparison, circulating tumor DNA was detected in 97% of women (29/30) and 84% of samples (106/126). Of the 50 samples in which circulating tumor cells were not detected, circulating tumor DNA was detected in 33 (66%). On the modified bootstrapping method, sensitivities were 90% for circulating tumor DNA vs 67% for circulating tumor cells, with a median difference in sensitivity of 27% (P < .002). At the median, the number of amplifiable copies of circulating tumor DNA was 133 times the number of circulating tumor cells and exhibited a greater dynamic range.

Tumor Monitoring The performance of the biomarkers was compared with computed tomography (CT) in 20 patients with measurable disease in whom biomarker data were available at three or more time points over 100 days of follow-up. Circulating tumor DNA was detected in 95% of these women with fluctuations in levels generally correlating with treatment responses observed on CT. Similar correlations were observed in 10 (50%) of the women who had

elevated circulating tumor cell counts (≥ 5 cells/7.5 mL), with the lower counts in the remainder of the group being uninformative with regard to treatment response. Women with high levels of CA 15-3 also had fluctuations corresponding to CT responses, but with a small dynamic range; no consistent serial changes in CA 15-3 levels were observed in the 8 (42%) of 19 patients with levels of 50 U/mL or lower.

culating tumor DNA levels increased at an average of 5 months (range, 2–9 months) before detection of progressive disease on imaging. In two women, increased levels of circulating tumor DNA did not reflect CT-detected progressive disease.

Prognostic Utility Proportional hazards analysis showed that increased levels of cir-

Circulating Tumor DNA ■ Fluctuations in circulating tumor DNA levels corresponded with changes in tumor burden detected on CT, and increasing levels were significantly correlated with poorer prognosis.

■ Circulating tumor DNA levels frequently provided an early indication of progressive disease.

Progressive disease was documented by CT in 19 of 20 women during followup. Increases in circulating tumor DNA levels reflected progressive disease in 17 (89%) of the 19, with levels increasing by a factor of 505 from the lowest point prior to establishment of progressive disease. By comparison, the numbers of circulating tumor cells increased in 7 (37%) of the 19 women and CA 15-3 levels increased in 9 (50%) of 18. Circulating tumor DNA levels provided an early measure of treatment failure. In 10 of the 19 patients, cir-

culating tumor DNA (P < .001) and increased numbers of circulating tumor cells (P = .03), but not increasing CA 15-3 15-3 levels, were significantly significantly associated with poorer overall survival. Increasing circulating tumor DNA levels and increasing numbers of circulating tumor cells were associated with increasing relative hazard values, indicating that absolute levels of each biomarker provided prognostic information. As stated by the investigators, “In the detection of metastatic breast cancer, circulating tumor DNA shows superior

sensitivity to that of other circulating biomarkers and has a greater dynamic range that correlates with changes in tumor burden. Circulating tumor DNA often provides the earliest measure of treatment response, as has been supported by recent analyses of circulating tumor DNA in other solid cancers.” The investigators concluded: Our expanding knowledge of the genetic mechanisms underpinning breast cancer now provides a framework to better stratify patients. The analysis of circulating tumor DNA represents a unique opportunity to integrate this knowledge into the clinical arena. Although the acquisition of tumor-tissue specimens will continue to be important, the use of biopsy specimens is limited, since such material may not capture tumor heterogeneity; in addition, repeated biopsy is impractical. Circulating tumor DNA represents a ‘liquid biopsy’ alternative, allowing for sensitive and specific serial sampling to be performed during the course of treatment. n Disclosure: Dr. Dawson reported receiving grant support from Australian NHMRC. For a complete list of other study authors’ potential conflicts of interest, visit www.nejm.org.

Reference 1. Dawson S-J, Tsui DWY, Murtaza M, et al: Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368:1199-1209, 2013.

Thoracic Oncology

News

Immunohistochemistry Effectively Detects ALK Rearrangement in Non-small Cell Lung Cancer Study

LK rearrangement has been demonstrated to be a potent oncogenic driver and a promising therapeutic target in non-small cell lung cancer. It defines a distinct molecular subset of NSCLC, in particular adenocarcinoma that can benefit by the treatment of ALK-inhibitors. Development of robust and reliable laboratory tests for predictive biomarkers is essential to select appropriate patients for targeted therapy. Researchers from the Chinese University of Hong King evaluated the practical usefulness of immunohistochemistry to detect ALK expression as a reliable detection

method of ALK rearrangement in lung adenocarcinoma. A study published this month in the Journal of Thoracic Oncology concluded that immunohistochemistry can effectively detect ALK rearrangement in lung cancer and could provide a reliable and cost-effective diagnostic approach in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy. 1

ALK Immunohistochemistry Researchers tested 373 lung adenocarcinomas for ALK rearrangement by immunohistochemistry

and fluorescent in situ hybridization. They concluded that, “[Immunohistochemistry] would be served as an effective and rapid detection method in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy,” the researchers said. Immunohistochemistry is a less complex and less costly technology than fluorescent in situ hybridization. In addition, their research demonstrated that some ALK immunohistochemistry-positive but fluores-

cent in situ hybridization-negative lung cancers did harbor the translocation events as confirmed by RT-PCR. Thus, this subgroup of patients should also benefit from ALK inhibitory therapy. Further clinical trials are required to address the predictive value of ALK immunohistochemistry in these patients. n Reference 1. To KF, Tong J, Yeung K, et al: Detection of ALK rearrangement by immunohistochemistry in lung adenocarcinoma and the identification of a novel EML4-ALK variant. J Thorac Oncol 8(7):883-891, 2013.

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JCO Spotlight Breast Cancer

Outcomes with Adjuvant Trastuzumab in HER2-positive Breast Cancer Not Affected by PTEN Status By Matthew Stenger

TEN is a negative regulator of PI3K/AKT signaling. PI3K/ AKT signaling can be activated by HER2, and it has been hypothesized that alteration in this pathway may affect sensitivity to trastuzumab (Herceptin). Preclinical data and some of the limited available clinical data suggest that loss or inactivation of PTEN, which has been reported in a significant proportion of HER2positive breast cancers, may result in reduced sensitivity to trastuzumab. In an analysis reported in Journal of Clinical Oncology, Edith A. Perez, MD, Deputy Director at Large, Mayo Clinic Cancer Center, and Group Vice Chair, Alliance for Clinical Trials in Oncology, Mayo Clinic, Jacksonville, Florida, and colleagues found that disease-free survival among patients with early-stage breast cancer receiving adjuvant trastuzumab in the North Central Cancer Treatment Group N9831 trial did not significantly differ according to PTEN status.1

Study Details In the N9831 trial, women with early-stage HER2-positive breast cancer received doxorubicin and cyclophosphamide followed by weekly paclitaxel (control group) or the same regimen followed by 1 year of sequential trastuzumab or concurrent trastuzumab (started on

the same day as paclitaxel). Patents receiving trastuzumab had significantly better disease-free survival and overall survival compared with the control group, and patients receiving concurrent trastuzumab had significantly better disease-free survival than those receiving sequential trastuzumab. The current analysis of the effect of PTEN status included 1,802 of the 3,505 patients registered in N9831, with reasons for exclusion consisting of absence of HER2-positivity on central pathology review, withdrawal before starting therapy, failure to meet eligibility criteria, no consent for future translational analysis, withdrawn consent/loss to follow-up, no or inadequate tumor tissue, and technical failure. Clinic pathologic characteristics and outcomes in the 1,802 patients from the three treatment groups included in the analysis (601 in control group, 650 in sequential trastuzumab group, and 551 in concurrent trastuzumab group) were similar to excluded patients in the three treatment groups. To determine PTEN status, the intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections with three cores per block (n = 1,286) or in whole tissue sections (n = 516) using standard immunohistochemistry (IHC). Tu-

Notes from the Lead Investigator By Edith A. Perez, MD

e conducted this study to clarify a hypothesis that had been generated from preclinical work and small clinical datasets. One additional background point that should be made is that although not all previously reported small datasets had demonstrated a relationship between PTEN expression and outcome, most summaries of these data mentioned just the positive associations. So, our study has provided definite data that will be helpful to the overall field. It was very important Edith A. Perez, MD that we had a large set of tumors, long follow-up, blinded analysis, and various cutoffs for negativity that yielded consistent information. n Dr. Perez is Deputy Director at Large, Mayo Clinic Cancer Center, and Group Vice Chair, Alliance for Clinical Trials in Oncology, Mayo Clinic, Jacksonville, Florida.

mors were considered PTEN-positive if any core or whole tissue section had any invasive cells with IHC ≥ 1� staining. In the primary analysis, outcomes were assessed according to PTEN-negative status defined

sequential trastuzumab (HR = 0.81, P = .27), or concurrent trastuzumab (HR = 1.40, P = .20) groups. For the concurrent trastuzumab group compared with the control group, hazard ratios for disease-free

Adjuvant Trastuzumab and PTEN Status ■ No significant differences in disease-free survival were found within the chemotherapy alone, chemotherapy plus sequential trastuzumab, or chemotherapy plus concurrent trastuzumab groups for patients with PTEN-positive vs PTEN-negative tumors.

■ Concurrent trastuzumab was associated with significantly better diseasefree survival compared with chemotherapy alone among all patients, independent of tumor PTEN protein expression.

as IHC 0 staining; outcomes were also assessed according to PTENnegative status defined as IHC 0–1 staining.

Characteristics of PTEN-positive Cases Of 1,802 patients, 1,342 (74%) had PTEN-positive tumors (≥ 1� staining) and 460 (26%) had PTENnegative tumors (0 cytoplasmic staining). Of those with PTEN-positive tumors, 650 had 1� staining, 523 had 2� staining, and 169 had 3� staining. Patients with PTEN-positive tumors defined as ≥ 1� staining had a lower rate of hormone receptor positivity (45% vs 55%, P < .001) and a higher rate of nodal positivity (87% vs 83%, P = .04) compared with PTEN-negative patients. However, when PTEN positivity was defined as 2–3� staining, patients with PTEN-positive tumors had a higher rate of hormone receptor positivity (60% vs 48%, P < .001) but still had a higher rate of nodal positivity (90% vs 83%, P < .001).

Disease-free Survival Outcomes Median follow-up of patients in the analysis was 6.0 years. There were no significant differences in disease-free survival between patients with PTEN-positive vs PTENnegative tumors defined as IHC 0 staining among all patients (hazard ratio [HR] = 0.96, P = .70) or within the control (HR = 0.92, P = .64),

survival were 0.65 (P = .003) for those with PTEN-positive tumors and 0.47 (P = .005; P = .16 .16 for interaction) for those with PTEN-negative tumors defined as IHC 0. For the sequential trastuzumab group compared with the control group, hazard ratios were 0.70 (P = .009) for those with PTEN-positive tumors and 0.85 (P = .44; P = .47 for interaction) for those with PTENnegative tumors. For the concurrent trastuzumab group compared with the sequential group, hazard ratios were 0.90 (P = .49) for those with PTEN-positive tumors and 0.56 (P = .04; P = .08 for interaction) for those with PTEN-negative tumors. When PTEN-negativity was defined as IHC 0–1 staining, there were no significant differences in diseasefree survival for PTEN-positive vs PTEN-negative patients among all patients (HR = 0.96, P = .70) .70) or within the control (HR = 0.87, P = .38), sequential trastuzumab (HR = 0.79, P = .19), or concurrent trastuzumab (HR = 1.27, P = .25) groups. For the concurrent trastuzumab group compared with the control group, hazard ratios for diseasefree survival were 0.70 (P = .08) for those with PTEN-positive tumors and 0.50 (P < .001; P = .17 for interaction) for those with PTENnegative tumors. For the sequential trastuzumab group compared with the control group, hazard ratios were 0.68 (P = .04) for those with PTENpositive tumors and 0.78 (P = .08; continued on page 64

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Journal Spotlight

Adjuvant Trastuzumab continued from page 63

P = .61 for interaction) for those with PTEN-negative tumors. For the concurrent trastuzumab group compared with the sequential group, hazard ratios were 1.01 (P = .95) for those with PTEN-positive tumors and 0.66 (P = .02; P = .10 .10 for interaction) for those with PTEN-negative tumors.

Benefit of Trastuzumab Independent of PTEN Status As summarized by the investigators, “In contrast to the hypothesis that PTEN loss is correlated with poor prognosis and decreased survival, our carefully conducted study demonstrated a lack of correlation of PTEN expression with outcome of N9831 patients. The disease-free survival of patients within each treatment arm was not significantly different between patents with PTENpositive and PTEN-negative tumors. We observed a benefit of concurrent trastuzumab compared with chemotherapy alone in all patients, independent of tumor PTEN expression.” They further noted, “Our results in the adjuvant setting appear to conflict with a somewhat general consensus that PTEN loss correlates with trastuzumab resistance, although it is important to note that previously available correlative data have been inconsistent as well.” The investigators concluded, “Overall, the N3981 data indicate that PTEN protein expression alone (independent of cut point) is not significantly associated with prognosis or with differential benefit to concurrent trastuzumab. Importantly, the conflicting results obtained between this study in the adjuvant setting and some (not all) of the reported small studies in the metastatic and neoad-

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juvant settings highlight the need for accurate validation of biomarkers in large patient groups….” The investigators are continuing protein expression and whole-genome expression profiling studies in tumors from patients in the N9831 trial to examine associations between combinations of markers and

disease-free survival. By doing so, they hope to improve understanding of the effects of signaling pathway alterations on outcomes with adjuvant trastuzumab and chemotherapy. n

Disclosure: Dr. Perez has received research funding from Genentech and S:6.75” GlaxoSmithKline. For full disclosures of all study authors, see jco.ascopubs.org.

Reference 1. Perez EA, Dueck AC, McCullough AE, et al: Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early-stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. J Clin Oncol 31:2115-2122, 2013.

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

COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. 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: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and 1 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. 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. 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. 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 (modified JNC criteria stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo, respectively). 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: 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.

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FDA Update

Investigational New Drug Application Filed for CFI-400945 nvestigators from Princess Margaret Cancer Centre in Toronto and the University of California, Los Angeles, have submitted an Investigational New Drug (IND) application for CFI400945, a novel drug candidate target-

ing the enzyme PLK4, which plays a crucial role in cell division. The news was announced at a press briefing by TakS:6.75” Mak, MD, OC, PhD, DSc (Hon), FRSC, FRS, Director of The Campbell Family Institute

for Breast Cancer Research at Princess Margaret Cancer Centre, and Dennis J. Slamon, MD, PhD, Director of Clinical/Translational Research at UCLA’s Jonsson Comprehensive Cancer Center.

In lab studies, the agent has been shown to effectively inhibit the growth of human breast and ovarian cancers, as well as colorectal, glioblastoma, lung, melanoma, pancreatic, and prostate cancers. n

PROD

COMETRIQ™ demonstrated significant efficacy in a phase 3 trial (N=330) in metastatic MTC patients with radiographically confirmed disease progression.*

median

months

11.2

ED AE/AS AD

4.0

COMETRIQ™ (n=219)

Progression-free survival (PFS)

> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) > COMETRIQ™ demonstrated a greater than 2.5-fold increase in median PFS vs placebo —Median PFS was 11.2 months with COMETRIQ™ vs 4.0 months with placebo > Partial response rate was 27% with COMETRIQ™ vs 0% with placebo (P<0.0001) —Median duration of objective response was 14.7 months (95% CI: 11.1, 19.3) > Adverse reactions occurring in ≥25% of patients treated with COMETRIQ™ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, 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 ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia

TC QC PG

Adverse Reactions: 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, 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. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo.

B:11.25”

S:9.75”

Please see brief summary of full Prescribing Information on next page.

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SIGNOFF

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit fda.gov/medwatch or call 1-800-FDA-1088.

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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 (≥ 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. Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, 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 (<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.

T:10.25”

*Results of the international, multicenter, randomized, double-blind EXAM study in patients (N=330) with progressive, metastatic MTC. Primary endpoint: PFS; secondary endpoints: objective response rate and overall survival (OS). OS data are not yet mature.

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The ASCO Post | JULY 10, 2013

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FDA Update

FDA Approves Denosumab to Treat Giant Cell Tumor of the Bone

he U.S. Food and Drug Administration (FDA) has expanded the approved use of denosumab (Xgeva) to treat adults and some adolescents with giant cell tumor of the bone, a rare and usually noncancer-

ous tumor. Denosumab, which was granted orphan product designation, was reviewed under the FDA’s priority review program. The agent was previously approved in 2010 for the prevention of skeletal-related events

in patients with bone metastases from solid tumors. Giant cell tumor of the bone generally occurs in adults between the ages of 20 and 40 years. In most cases, the tumor does not spread to other

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; 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 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% in 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%) of 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 medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity 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

parts of the body but destroys normal bone as it grows, causing pain, limited range of motion, and bone fractures. Rarely, giant cell tumor of the bone can transform into a cancerous tumor and spread to the lungs.

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

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FDA Update

Denosumab is a monoclonal antibody that binds to RANKL, a protein essential for maintenance of healthy bone and that is also present in giant cell tumor of the bone. The agent is intended for patients who have unresectable giant cell tumor of the bone or for whom surgery is likely to result in severe morbidity, such as loss of

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 All Grade Grades 3-4 Grades 3-4 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 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. 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

limbs or joint removal. Denosumab should only be used in adolescents whose bones have matured. “Today’s approval of [denosumab] provides a needed treatment option for patients with giant cell tumor of the bone who are not surgical candidates or who would otherwise have to undergo extensive, life-altering

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ Placebo HYPERTENSION, JNC1 STAGE N=2113 (%) N=1073 (%) Normal: Grade 0: Systolic 4 15 < 120 mmHg and Diastolic < 80 mmHg Pre-hypertension: Systolic 34 54 ≥ 120 mmHg or Diastolic ≥ 80 mmHg Stage 1: Systolic ≥ 140 mmHg 46 25 or Diastolic ≥ 90 mmHg Stage 2: Systolic ≥ 160 mmHg 15 5 or Diastolic ≥ 100 mmHg Malignant: Diastolic 0 0 ≥ 120 mmHg 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 1

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 singledose 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 singledose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentin, 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

surgery,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research.

bone were established in two clinical trials that enrolled a total of 305 adult or adolescent patients. All patients had confirmed cases of giant cell tumor of the bone that were recurrent,

Safety and Effectiveness The safety and effectiveness of denosumab for giant cell tumor of the

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. Distributed by Exelixis, Inc. 12/2012 © 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 12/12 [24523]

unresectable, or where surgery would result in severe morbidity. Of the 187 patients whose tumors could be measured, 47 patients had their tumors reduce in size after an average of 3 months. Over an average follow-up duration of 20 months, regrowth of giant cell tumor of the bone occurred in three patients whose tumors originally became smaller during treatment. Common side effects included arthralgia, headache, nausea, fatigue, back pain, and extremity pain. The most common serious side effects were osteonecrosis of the jaw and osteomyelitis. Women of reproductive potential should use highly effective contraception while taking denosumab because of potential fetal harm. n

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In the Clinic Thoracic Oncology

Erlotinib in First-line Treatment of Metastatic NSCLC with EGFR Exon 19 Deletion or Exon 21 (L858R) Substitution By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication On May 14, 2013, erlotinib (Tarceva) was approved for first-line treatment of metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.1,2 This indication for erlotinib was approved concurrently with the cobas EGFR Mutation Test, a companion diagnostic test for patient selection. (Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at http://www.

OF NOTE Erlotinib inhibits EGFR kinase activity, preventing autophosphorylation of tyrosine residues associated with the receptor and inhibiting downstream signaling. In some tumor cells, signaling through EGFR plays a role in tumor cell survival and proliferation irrespective of mutation status. fda.gov/CompanionDiagnostics.) The safety and efficacy of erlotinib have not been evaluated in first-line treatment of metastatic NSCLC with EGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution. Erlotinib is not recommended for use in combination with platinum-based chemotherapy.

Pivotal Trial Approval was based on a randomized, multicenter, open-label European trial comparing oral erlotinib (150 mg/d; n = 86) vs platinum-based doublet chemotherapy (n = 88) = 88) 88) in patients with metastatic NSCLC whose tumors had EGFR exon 19 deletions or exon 21 (L858R) substitution mutations determined by a clinical trial

assay. Tumor samples from 134 patients (69 erlotinib patients and 65 chemotherapy patients) were tested retrospectively by the cobas EGFR Mutation Test. Patents had a median age of 65 years. The majority of the patients were female (72%), Caucasian (99%), never-smokers (69%), had adenocarcinoma histology (93%), and had ECOG performance status of 1 (53%). On the clinical trial assay, 66% of patients had exon 19 deletions and 34% had the exon 21 L858R substitution. Regimens in the chemotherapy group consisted of cisplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin plus gemcitabine, and carboplatin plus docetaxel. Median investigator-assessed progression-free survival—the primary endpoint—was 10.4 months in the erlotinib arm and 5.2 months in the platinum-based chemotherapy arm (hazard ratio = 0.34, P < .001). Progression-free survival outcomes were similar on independent review committee analysis and according to cobas EGFR Mutation Test results. A protocol-specified analysis of overall survival conducted at the time of the final analysis of progression-free survival showed no statistically significant difference between the erlotinib and chemotherapy groups (median, 22.9 vs 19.5 months). At the time of the data cutoff, at least one subsequent treatment had been given to 84% of patients in the chemotherapy group (an EGFR tyrosine kinase inhibitor in 97% of these patients) and to 66% of patients in the erlotinib group. Objective response rates were 65% in the erlotinib group and 16% in the chemotherapy group.

How It Works Erlotinib reversibly inhibits the kinase activity of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thus inhibiting downstream signaling. EGFR is expressed on the cell surface of both normal and cancer cells. In some tumor cells, signaling through this receptor plays a role in tumor cell survival and proliferation irrespective of EGFR mutation sta-

Expanded Indications for Erlotinib in Lung Cancer ■ Erlotinib (Tarceva) was approved for first-line treatment of metastatic

non–small cell lung cancer with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test.

■ Erlotinib is given at 150 mg once daily, at least 1 hour before or 2 hours after food, until disease progression or unacceptable toxicity.

tus. The binding affinity of erlotinib for EGFR exon 19 deletions and exon 21 L858R mutations is higher than its affinity for the wild-type receptor. Inhibition of other tyrosine kinase receptors by erlotinib has not been fully characterized.

How It Is Given The recommended daily dose of erlotinib is 150 mg at least 1 hour before or 2 hours after food. Treatment should continue until disease progression or unacceptable toxicity. Erlotinib should be discontinued for interstitial lung disease, severe hepatic toxicity that does not improve significantly within 3 weeks, gastrointestinal perforation, severe bullous, blistering, or exfoliating skin conditions, and corneal perforation or severe ulceration. It should be withheld during diagnostic evaluation for possible interstitial lung disease and for severe (grade 3 or 4) renal toxicity, total bilirubin levels greater than three times the upper limit of normal, or transaminases greater than five times upper limit of normal in patients without preexisting hepatic impairment, doubling of bilirubin or tripling of transaminase values in patients with preexisting hepatic impairment or biliary obstruction, persistent severe diarrhea,

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

severe rash, keratitis of grade 3 or 4 or grade 2 lasting more than 2 weeks, and acute/worsening ocular disorders such as eye pain. The erlotinib dose should be reduced (in 50-mg decrements) if severe adverse reactions occur with concomitant use of a strong CYP3A4 inhibitor (eg, carbamazepine, dexamethasone, phenobarbital). or an

OF NOTE The most frequent adverse events associated with erlotinib therapy are rash, diarrhea, cough, and dyspnea. inhibitor of both CYP3A4 and CYP1A2 (eg, ciprofloxacin) and when restarting therapy after resolution of dose-limiting toxicity. The dose should be increased (in 50-mg increments) for concomitant use with CYP3A4 inducers (eg, carbamazepine, dexamethasone, and ethosuximide) and for concurrent cigarette smoking. Concomitant use of erlotinib and proton pump inhibitors should be avoided. Erlotinib should be given 10 hours after or at least 2 hours before dosing of H2-receptor antagonists and several hours before or after an antacid. During erlotinib treatment, patients should be watched for new or progressive pulmonary symptoms (eg, dyspnea, cough, and fever). Patients should undergo monitoring of liver function and renal function as well as electrolytes, particularly if there is risk of dehydration. International normalized ratio (INR) should be monitored in patients taking warfarin or other coumarin-derivative anticoagulants. Women of reproductive potential should be advised of potential risk to the fetus and to use highly effective contraception. continued on page 69

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News Cancer Prevention

Study Shows HPV Vaccine Reduced Rate of Infection in Teenage Girls by 56% By Jo Cavallo

new government study investigating the prevalence of human papillomavirus (HPV) infections in females aged 14 to 59 before and after the introduction in 2006 of the HPV vaccine found that the rate of the HPV infection dropped by 56%, decreasing from 11.5% in 2006 to 5.1% in 2010 among female teenagers aged 14 to 19. Despite the success of the vaccine, only 32% of teenage girls aged 13 to 17 received the recommended three doses in 2010 and 49% received only one dose. The study, conducted by the Centers for Disease Control and Prevention and published recently in The Journal of Infectious Diseases,1 analyzed data from the National Health and Nutrition Examination Survey (NHANES) to compare prevalence of certain types of HPV in females before the start of the HPV vaccination program (2003-2006) with the rate of infection after the vaccine was introduced (2007-2010). Study researchers used the Linear Array HPV Assay in cervicovaginal swab samples taken from girls and women aged 14 to 59 to determine infection prevalence. About 79 million Americans, most in their late teens and early 20s, are infected with HPV, and each year about 14 million become infected. According to CDC figures, each year about 19,000 cancers caused by HPV occur in women, with cervical cancer the most common, and about 8,000 cancers caused by HPV occur

Erlotinib continued from page 68

Safety Profile

In the trial supporting approval, the most frequent adverse events of any grade occurring in at least 5% more patients in the erlotinib group were rash (85% vs 2% in chemotherapy group), diarrhea (62% vs 21%), cough (48% vs 40%), and dyspnea (45% vs 30%). The most frequent grade 3 or 4

each year in men, with throat cancer the most common.

Wake-up Call to the Nation CDC Director Tom Frieden, MD, MPH, issued a statement saying: “This report shows that HPV vaccine works well, and the report should be a wake-up call to our nation to protect the next generation by increasing

every year we delay doing so, another 4,400 girls will develop cervical cancer in their lifetimes.” In addition to the unexpected effectiveness of the partial dosage of the HPV vaccine, another possible explanation for the sharp decline in HPV prevalence may be herd immunity, in which people who are vaccinated reduce the overall prevalence of the virus

HPV Vaccine Reduces HPV Infection Rate in Girls

study from the Centers for Disease Control and Prevention (CDC) looking at the prevalence of HPV infections in girls before and after the introduction of the HPV vaccine in 2006 found a significant reduction of 56% in infections among female teenagers aged 14 to 19. About 79 million Americans, most in their late teens and early 20s, are infected with HPV, and each year about 14 million become infected. The CDC recommends that routine HPV vaccinations of three shots over 6 months begin at age 11 to 12 for both boys and girls. The vaccine is also recommended for older teens and young adults who were not vaccinated when they were younger. n HPV vaccination rates. Unfortunately, only one-third of girls aged 13 to 17 have been fully vaccinated with HPV vaccine. Countries such as Rwanda have vaccinated more than 80% of their teen girls. Our low vaccination rates represent 50,000 preventable tragedies—50,000 girls alive today will develop cervical cancer over their lifetime that would [be] prevented if we reach 80% vaccination rates. For adverse events in the erlotinib group were rash (14% vs 0%), dyspnea (8% vs 4%), and diarrhea (5% vs 1%). Adverse events caused dose interruptions or reductions in 37% of erlotinib patients and discontinuation in 14%. The most frequent adverse events leading to dose modification were rash (13%), diarrhea (10%), and asthenia (4%). Erlotinib carries warnings/precautions for interstitial lung disease, renal

fordable Care Act calls for insurance providers to cover the full cost of the HPV vaccine, eliminating one of the potential reasons for low vaccination rates, parental opposition to the vaccine is growing. According to a study published in Pediatrics,2 in 2010, 44% of parents said they had no intention of vaccinating their daughters, up from 40% in 2008, because their daughters were “not sexually active” and they had concerns about the vaccine’s safety.

HPV Vaccine Recommendations The CDC recommends that routine HPV vaccinations of three shots over 6 months begin at age 11 to 12 for both boys and girls. The vaccine is also recommended for older teens and young adults who were not vaccinated when they were younger. n

Although a provision in the Af-

References 1. Markowitz LE, Hariri S, Lin S, et al: Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003–2010. J Infect Dis. June 19, 2013 (early release online). 2. Darden P, Thompson DM, Roberts JR, et al: Reasons for Not Vaccinating Adolescents: National Immunization Survey of Teens, 2008–2010. Pediatrics. March 18, 2013. (early release online).

failure, hepatotoxicity with or without hepatic impairment including hepatic failure and hepatorenal syndrome, gastrointestinal perforation, bullous and exfoliative skin disorders, ocular disorders, hemorrhage in patients taking warfarin, and embryo-fetal toxicity. Risk of myocardial infarction, cerebrovascular accident, and microangiopathic hemolytic anemia is increased in patients receiving erlotinib for pancreatic cancer. n

References 1. U.S. Food and Drug Administration: Erlotinib. Available at http://www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm352317.htm. Accessed May 31, 2013. ® 2. TARCEVA (erlotinib) prescribing information, Astellas Pharma US, Inc, and Genentech, Inc, May 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021743s018lbl.pdf. Accessed May 31, 2013.

in the general population, thereby decreasing the chances that unvaccinated people would be exposed to someone who is infected, according to study lead author Lauri E. Markowitz, MD, the team leader in Epidemiology Research in the Division of Sexually Transmitted Disease Prevention at the CDC.

Growing Parental Resistance

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Journal Spotlight Gynecologic Oncology

Integrated Genomic Characterization of Endometrial Carcinomas Suggests New Classification Scheme By Matthew Stenger

s recently reported in Nature, investigators in The Cancer Genome Atlas Research Network performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas, including 307 endometrioid and 66 serous or mixed histology cases, using array- and sequencing-based techniques.1 Their findings indicate that endometrial cancers can be classified into at least four subtypes on the basis of molecular characteristics. Moreover, they found that a significant proportion of high-grade endometrioid tumors share a molecular phenotype with uterine serous tumors, and that uterine serous tumors share molecular characteristics with ovarian serous and basal-like breast carcinomas.

Somatic Copy Number Alteration Investigation of somatic copy number alterations in the endometrial carcinomas indicated that most of the serous (94%) and mixed histology (62%) cases clustered with a small proportion (12%) of endometrioid tumors in a group characterized by extremely high rates of somatic copy number alteration. This group was also characterized by frequent TP53 mutations (90%), low rate of microsatellite instability (6%), and a lower rate of PTEN mutations than in other endometrioid tumors (11% vs 84%). Tumors in this “serous-like” cluster were associated with significantly worse progression-free survival than tumors in the other three somatic copy number alteration clusters, which contained almost exclusively endometrioid tumors (97%).

Classification into Four Groups With a combination of somatic nucleotide substitutions, microsatellite instability status, and somatic copy number alteration, the endometrial tumors could be classified into four groups: (1) an ultramutated group with unusually high mutation frequencies despite microsatellite stability, and

a unique nucleotide change spectrum (POLE group); (2) a hypermutated group of tumors with microsatellite instability, most with MLH1 promoter methylation (microsatellite instability group); (3) a lower mutation frequency group, including most of the microsatellite-stable cancers (copy number–low group); and (4) the group consisting primarily of serous-like cancers with extensive copy number alteration and low mutation frequencies (copy number–high group). The ultramutated group (7% of tumors) was characterized by an increased somatic transversion frequency, with all the tumors having mutations in the exonuclease domain of the POLE gene (involved in nuclear DNA replication and repair). Surprisingly, this group was associated with favorable progression-free survival, as the tumor cells possibly continued to accumulate unrepaired somatic muta-

gen/progesterone receptor levels. In addition to the high frequency of TP53 mutations, these tumors also had a high frequency of FBXW7 and PPP2R1A mutations, a profile previously reported as common in uterine serous but not endometrioid cancers.

Shared Features across Cancer Types Additional analyses showed similar molecular features among uterine serous carcinomas, high-grade serous ovarian carcinomas, and basal-like breast carcinomas, including similar focal somatic copy number alteration and gene expression patterns. These three subtypes share a high frequency of TP53 mutations (84%–91%) and low frequency of PTEN mutations (1%–2%), although the uterine serous cancers were found to have higher frequencies of FBXW7, PPP2R1A, PIK3CA, and ARID1A mutations than the

Classification of Endometrial Carcinomas ■ Approximately 25% of high-grade endometrioid tumors share molecular

characteristics with uterine serous tumors, and uterine serous tumors share molecular characteristics with ovarian serous tumors and basal-like breast carcinomas.

■ “Clinicians should carefully consider treating copy-number-altered endometrioid patients with chemotherapy rather than adjuvant radiotherapy and formally test such hypotheses in clinical trials.”

tions. Novel recurrent mutations were identified at codons 286 and 411 of POLE in most of these tumors. The microsatellite instability endometrioid tumors had a mutation frequency approximately 10-fold greater than microsatellite-stable endometrioid tumors and few copy number alterations. The microsatellite stable, copy number–low group had a high frequency of CTNNB1 mutations (52%), with this gene being the only one with a higher mutation frequency than in the microsatellite unstable cases. The copy number–high group contained most of the serous cases and approximately 25% of the grade 3 endometrioid cases. In addition to increased somatic copy number alterations, frequent TP53 mutations, and infrequent PTEN mutations, this group was characterized by few DNA methylation changes and low estro-

high-grade serous ovarian carcinomas or basal- like breast tumors. As noted by the investigators, despite the greater frequency of mutations in uterine serous carcinomas, the shared molecular characteristics of these three tumor subtypes suggest “new opportunities for overlapping treatment paradigms.” Overall, the investigators found that endometrial cancers have more frequent mutations in the PI3K/AKT pathway than any other tumor type they have studied thus far. Most endometrioid tumors had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, KRAS, and newly described mutations in ARID5B (SWI/SNF [SWItch/Sucrose NonFermentable] chromatin remodeling complex gene). In addition to the finding of mo-

lecular similarities among uterine serous, ovarian serous, and basal-like breast cancers, the investigators noted that the endometrioid tumors shared similarities with colorectal cancers— eg, frequent microsatellite instability, POLE alteration correlated with ultrahigh mutation frequency, and frequent activation of WNT/CTNNB1 signaling—although the endometrioid cancers are also characterized by KRAS and CTNNB1 mutations and a distinct mechanism of pathway activation. For the serous-like tumors delineated on the basis of somatic copy number alterations, the investigators identified alterations that may be candidates for therapeutic targeting, including amplifications of ERBB2, FGFR1, and FGFR3 and LRP1B deletion, an alteration recently associated with resistance to liposomal doxorubicin in serous ovarian cancer.

Clinical Implications The investigators note that earlystage type I endometrioid tumors are often treated with adjuvant radiotherapy and that similarly staged type II serous tumors are treated with chemotherapy. The findings indicate a similar molecular phenotype among roughly 25% of the high-grade endometrioid tumors and the uterine serous carcinomas, which “suggest that genomicbased classification may lead to improved management of these patients.” In this regard, the investigators concluded, “Clinicians should carefully consider treating copy-number-altered endometrioid patients with chemotherapy rather than adjuvant radiotherapy and formally test such hypotheses in clinical trials. Furthermore, the marked molecular differences between endometrioid and serous-like tumors suggest that they warrant separate clinical trials to develop the personalized treatment paradigms that have improved outcomes in other tumor types, such as breast cancer.” n

Disclosure: The study was supported by the National Institutes of Health.

Reference 1. The Cancer Genome Atlas Research Network: Integrated genomic characterization of endometrial carcinoma. Nature 497:67-72, 2013.

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Journal Spotlight

Learning to Negotiate the Genomic Complexities of Cancer By Joyce F. Liu, MD, MPH

he Cancer Genome Atlas (TCGA) Research Network recently reported the results of an integrated analysis of the genomic features of 373 endometrial carcinomas.1 This report joins previously published results of similar analyses in ovarian, breast, and colorectal cancers, squamous cell carcinoma of the lung, and glioblastoma as well as, most recently, acute myeloid leukemia.2-6 This ongoing project—a multicenter collaborative effort spearheaded by the National Cancer Institute and National Human Genome Research Institute—is planned to ultimately genomically characterize over 20 cancers, and all data generated from these efforts is publically available through a data portal at http://cancergenome.nih.gov/. As the data from these analyses become available, they provide valuable insight into each of the target cancers, and will also serve as roadmaps as we learn to negotiate the genomic complexities of each of these diseases.

Validation and New Insights The TCGA report on endometrial carcinoma both substantiates some of the clinical differences previously observed between endometrial cancer subtypes and provides new insights into their molecular nature. For example, serous carcinomas of the endometrium, which have been described to have a clinically different course from endometrioid endometrial cancers, indeed form a distinct molecular subtype with significantly worse outcomes, with the overwhelming majority (94%) of serous carcinomas demonstrating high copy number alterations, as well as mutations in TP53 (> 90%). Interestingly, about a quarter of high-grade (grade 3) endometrioid endometrial cancers also fall into this “serous-like” category, a molecular profile that shares similarities with that of high-grade ovarian carcinomas and triple-negative breast cancers. Dr. Liu is Instructor in Medicine at Harvard Medical School and Dana-Farber Cancer Institute, Boston.

TCGA also provides greater insight into the spectrum of type I endometrial cancers, separating the non–serouslike tumors into three additional clusters—an ultramutated group with POLE mutations, a hypermethylated group with microsatellite instability, and a copy number–low group. Additionally, the analysis reinforces some of the previously described molecular findings in endometrial cancers, such

chemotherapy to these patients as we do for serous cancers? Can we improve clinical outcomes by treating patients with specific pathway alterations with drugs that target the relevant pathway? Although TCGA provides molecular evidence to support such efforts, the link between molecular characterization and clinical outcome is not yet clear. For example, attempts to link targeted therapy responses to pathway

The data made available by TCGA represent fantastic opportunities for exploration and deeper understanding of the molecular drivers of cancer. It is now time to translate these into clinical significance. —Joyce F. Liu, MD, MPH

as a high rate of PI3K/AKT pathway alterations, including mutations in PTEN and PIK3CA, as well as mutations in genes such as ARID1A and KRAS, and also describes novel mutations in genes such as ARID5B. Frequent activation of the WNT/ CTNNB1 signaling pathway was also observed, with a characteristic exclusivity between KRAS and CTNNB1 mutations suggesting that alternative mechanisms of WNT signaling activation are present in endometrioid endometrial cancers compared to other tumors, such as colon cancer.

Questions and Challenges The findings from this study provide us with a wealth of information about the molecular spectrum of endometrial cancer. As with other TCGA studies, the real questions and challenges as we move forward will lie in how we apply this knowledge. These data suggest many promising pathways for exploration, including potential novel therapies and new approaches to therapy. For example, should we identify the subset of “serous-like” endometrioid cancers and recommend adjuvant

alterations have not been easily interpreted in endometrial cancer. Janku et al reported on a cohort of 140 patients with breast, cervical, endometrial, or ovarian cancer referred to the Clinical Center for Targeted Therapy at The University of Texas MD Anderson Cancer Center.7 Patients on study were analyzed for PIK3CA, KRAS, NRAS, and BRAF mutations; 25 were found to have PIK3CA mutations and, of these, 23 were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. A 30% partial response rate was observed in these patients, compared to 10% in 70 patients with wild-type PIK3CA treated on the same protocols (P = .04). In contrast, in a phase II study of the AKT-1/2/3 inhibitor MK-2206 in endometrial cancer, Myers et al reported no clear correlation between PIK3CA mutation and clinical response.8

Translation to Clinical Practice These results highlight the challenges that lie ahead as we seek to integrate the growing stream of genomic and molecular information into clinical practice. Even a potential biomarker

that seems relatively straightforward, such as PIK3CA mutation, may not prove to be so in the setting of multiple interacting pathways and escape mechanisms. The data made available by TCGA represent fantastic opportunities for exploration and deeper understanding of the molecular drivers of cancer. It is now time to translate these into clinical significance. As we analyze the data from TCGA analysis of endometrial cancer, it is therefore even more imperative that we incorporate molecular analyses into our clinical trials, to better determine how these molecular subtypes should influence our treatment strategies. n Disclosure: Dr. Liu reported no potential conflicts of interest.

References 1. Cancer Genome Atlas Research Network: Integrated genomic characterization of endometrial carcinoma. Nature 497:6773, 2013. 2. Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma. Nature 474:609-615, 2011. 3. Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 490:61-70, 2012. 4. Cancer Genome Atlas Research Network: Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519-525, 2012. 5. Cancer Genome Atlas Research Network: Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061-1068, 2008. 6. Cancer Genome Atlas Research Network: Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368:2059-2074, 2013. 7. Janku F, Wheler JJ, Westin SN, et al: PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 30:777-782, 2012. 8. Myers AP, Broaddus R, Makker V, et al: Phase II, two-stage, two-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer (EC). J Clin Oncol 31(suppl):Abstract 5524, 2013.

Bristol-Myers Squibb is leading the way in Immuno-Oncology What if we take a different approach to fight cancer by harnessing the potential of the immune system? Immuno-Oncology is a rapidly evolving field of research that focuses on working directly on the immune system in the fight against cancer.1 As our understanding of how cancer evades the immune system continues to evolve, the potential of Immuno-Oncology continues to drive our research efforts. At Bristol-Myers Squibb, we are committed to researching and developing innovative new treatments that can help patients in their fight against cancer. Visit us at BMSimmunooncology.com. References: 1. DeVita VT Jr, Rosenberg SA. N Engl J Med. 2012;366:2207-2214.

ÂŠ2013 Bristol-Myers Squibb Company.

ONCUS13UB01103-01-01

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Journal Spotlight Gastrointestinal Oncology

SEER Analysis Shows Increased Survival with Surgery and Radiation Therapy in Metastatic Gastric Cancer By Matthew Stenger

Surveillance, Epidemiology, and End Results (SEER) database analysis reported by Ravi Shridhar, MD, PhD, and colleagues in Cancer indicates that patients receiving surgery and radiation therapy for metastatic gastric cancer have prolonged survival compared with those receiving either alone or neither surgery nor radiotherapy.1

Analysis Details In the study, the Moffitt Cancer Center investigators queried the SEER 2004 to 2008 data set to identify patients aged 18 years or older with stage IV (M1) gastric cancer who did or did not undergo surgery or radiotherapy. Patients had to have histologic subtypes of adenocarcinoma (not otherwise specified [NOS], intestinaltype, mucinous or mucin-producing, mixed cell or with mixed subtypes, in adenoma or polyp, and with neuroendocrine differentiation) or carcinoma (NOS, diffuse type, or signet ring cell). Patients receiving radiotherapy had received postoperative or preoperative external-beam radiotherapy and were excluded if they had received intraoperative radiotherapy. All surgical patients had some form of gastrectomy with or without lymph node dissection. Patients with survival of less than 3 months were excluded from the analysis; of 3,337 such patients, 2,750 received neither surgery nor radiotherapy, 241 received radiotherapy alone, 330 received surgery alone, and 16 received both. Data not included in the database included comorbidities, performance status, surgical margin status, postoperative complications, type of lymphadenectomy, chemotherapy, and radiotherapy field design and dose. Of the initial 8,978 patients identi-

fied in the SEER database, 5,072 remained in the analysis after exclusion based on histology and survival of less than 3 months. Of these, 3,069 patients received neither surgery nor radiotherapy (no surgery/no radiotherapy group), 806 received radiotherapy alone, 957 received surgery alone, and 240 received both (surgery/ radiotherapy group). There were significant

that surgery was associated with a significant 43.5% reduction in risk for mortality (hazard ratio [HR] = 0.565 vs no surgery, P < .0001) and radiotherapy with a significant 11.8% reduction (HR = 0.882 vs no radiotherapy, P = .042). Increasing age (HR = 1.01 as a continuous variable, P < .0001), T4 tumors (HR = 1.18 vs T1, P = .021), N3 nodes (HR = 1.27

Although … limitations may confound the results, our findings do elucidate a possible association between surgery and radiation therapy and improved survival for metastatic gastric cancer patients. —Ravi Shridhar, MD, PhD, and colleagues

differences across these four groups in mean age, sex, year of diagnosis, type of metastases, tumor location, tumor histology, T stage, N stage, and tumor grade.

Increased Survival with Surgery/Radiotherapy Median and 2-year overall survival durations were 16 months and 31.7% in the surgery/radiotherapy group, 10 months and 18.2% in the surgery-alone group, 8 months and 8.9% in the radiotherapy-alone group, and 7 months and 8.2% in the no surgery/no radiotherapy group (overall P < .00001). Kaplan-Meier analysis showed that survival curves for each of the groups differed significantly from each other. When patients with survival of less than 3 months were included in the analysis, the differences among groups remained significant. Multivariate analysis of overall survival including all patients showed

Surgery and Radiotherapy in Advanced Gastric Cancer ■ In the SEER database analysis, patients with metastatic gastric cancer

who received both surgery and radiotherapy had a median survival of 16 months and 2-year survival of 31.7%.

■ On multivariate analyses, surgery and radiotherapy were each associated

with a significant reduction in risk for death among all patients, and radiation therapy was associated with a significant reduction in risk among patients undergoing surgery.

vs N0, P = .024), signet ring histology (HR = 1.22 vs adenocarcinoma NOS, P = .002), and peritoneal carcinomatosis (HR = for peritoneal metastasis 1.33 vs nodal metastasis, P < .0001; HR = 1.40 for peritoneal and nodes vs nodes, P < .0001) were associated with significantly increased risk of mortality. Sex, tumor grade, and tumor location were not predictive of mortality.

Reduced Mortality with Surgery plus Radiotherapy Multivariate analysis among all patients undergoing surgery showed that radiotherapy was associated with a significant 26.7% reduction in risk for mortality (HR = = 0.733 vs no radiotherapy, P = .004), whereas increasing age, removal of less than 15 nodes (HR = 1.24 vs ≥ 15 nodes, P = .022), tumor stage (T2, T3, and T4 vs T1), nodal stage (N2 and N3 vs N1), signet ring histology, and peritoneal carcinomatosis were associated with significantly increased risk of mortality. Sex, tumor location, and tumor grade were not predictive of mortality. Among patients not undergoing surgical resection, radiotherapy had no significant effect on mortality. Increasing age was associated with increased risk, and there was a trend for increased risk with signet ring histology. Sex, tumor stage, nodal stage, tumor location, histology, tumor grade, and peritoneal

carcinomatosis were not predictive. The authors noted that there have been few reports on the role of locoregional therapy in metastatic gastric cancer, with available data from small series suggesting a survival benefit with palliative resection and no evidence of a survival benefit of radiotherapy. In addition to suggesting a significant survival benefit of surgery and radiotherapy in this setting, the SEER analysis suggests that patients with metastatic disease may benefit from removal of 15 or more nodes, a strategy that has been associated with a survival benefit in the nonmetastatic setting.

Limitations of Analysis The authors acknowledged that the analysis has a number of limitations, including the absence of data on performance status, nutritional status, systemic chemotherapy, resection margin status, extent of lymphadenectomy, whether resection was complete or not, use of concurrent chemotherapy with radiotherapy, and radiotherapy field design, technique, and dose. They noted, “[I]t is impossible to fully understand from SEER why some people may have received surgery and/or radiation therapy as part of their treatment management. It is possible that healthier patients, hence better prognosis patients, received these locoregional treatments. However, despite these inherent biases, SEER documents the real world outcomes of these patients. Although these limitations may confound the results, our findings do elucidate a possible association between surgery and radiation therapy and improved survival for metastatic gastric cancer patients…. [The findings] warrant…prospective clinical trials addressing the role of locoregional treatment in well-defined patient cohorts with metastatic gastric cancer.” Two trials are currently examining the role of palliative surgery in stage IV gastric cancer. The phase III III REGATTA trial in Japan and Korea is examining use of palliative surgery followed by chemotherapy. In a phase II/III trial continued on page 75

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News Genitourinary Oncology

Progression of Renal Cell Carcinoma Linked to Shifts in Tumor Metabolism

nvestigators in The Cancer Genome Atlas (TCGA) Research Network have uncovered a connection between how tumor cells use energy from metabolic processes and the aggressiveness of the most common form of kidney cancer, clear cell renal cell carcinoma. Their findings demonstrate that normal metabolism is altered in clear cell renal cell carcinoma tumor cells, and involves a metabolic shift that correlates with tumor stage and severity in some cases. The scientists also found mutations in a pathway that may cause increased aggressiveness in this cancer. Taken together, the findings may offer new insight into underlying disease mechanisms and potential treatments as well as an understanding of how some cancer cells can shift from using normal metabolic pathways to alternative pathways, thereby providing a growth advantage to tumor cells

Study Details The scientists used data generated by TCGA, a collaborative effort funded by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI). The results of this study were published online June 23, 2013, in Nature.1 In the study, scientists examined nearly 450 clear cell renal cell carcinoma tumors and matched each with a normal sample from the same patient. When they looked at the amounts of specific proteins expressed in cancer cells, they found that low levels of AMPK, a protein essential to cell metabolism, and high levels of acetyl-CoA

SEER Analysis continued from page 74

in Japan, patients with a partial or complete response to S-1 and docetaxel or cisplatin are to be randomly assigned to either continued chemotherapy or surgical resection followed by additional chemotherapy. n

Disclosure: The authors of the study reported no potential conflicts of interest.

Reference 1. Shridhar R, Almhanna K, Hoffe SE, et al: Increased survival associated with surgery and radiation therapy in metastatic gastric cancer: A Surveillance, Epidemiology, and End Results database analysis. Cancer January 29, 2013 (early release online).

carboxylase were associated with worse patient outcomes. “Earlier findings from the characterization of other types of cancers have given us important clues as to how to design better therapies for these

cancers,” said NCI Director Harold Varmus, MD. “The new results from the TCGA analysis of clear cell renal cell carcinomas provide an explanation for how mutations in certain genes can alter chromosome chemistry to pro-

duce changes in enzyme levels that affect cell metabolism in ways correlated with clinical outcomes. These findings will stimulate some novel ideas about therapies for other lethal cancers.” continued on page 76

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News

Renal Cell Carcinoma continued from page 75

Shifts in PI3K Pathway In addition to the connection between metabolic shift and tumor aggressiveness, TCGA Research Network scientists discovered that, in some cases, the metabolic shift may be caused by changes in the PI3K cellular

Harold Varmus, MD

pathway, which helps regulate cell metabolism. The investigators observed a number of changes in PI3K pathway genes and its regulators in tumor cells, including DNA mutations in proteincoding areas and other changes affecting gene expression. They found such alterations in the PI3K pathway—or its partner pathways, AKT and mTOR—

in 29% of tumor samples. The effects of these changes show the importance of the PI3K/AKT/mTOR pathways. For example, researchers found a decrease in factors that activate tumor-suppressor genes. At the same time, factors activating genes that inhibit the PI3K pathway were blocked. Both of these changes promote activity in the PI3K/AKT/mTOR pathways. The results suggest the pathways’ potential as therapeutic targets with inhibitor drugs.

Potential for Novel Therapies W. Marston Linehan, MD, Chief of the NCI Urologic Oncology Branch and one of the study’s leaders, sees several implications from the results. “The finding of a metabolic shift in the aggressive tumors could provide the foundation for the development of a number of novel approaches to therapy for patients with advanced kidney cancer,” said Linehan. New therapies are especially important since advanced kidney cancer is often resistant to chemotherapy. The TCGA data offer insights into various global processes occurring in kidney cancer and can show how different tumor pathways intersect. “The molecular analysis of this disease impacts understanding of all cancers through furthering insights into the role of metabolic perturbation in malignancy,” said Richard A. Gibbs, PhD, another lead investigator in the project and Director of the Human Genome Sequencing Center at Baylor College of Medicine, Houston. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. The Cancer Genome Atlas Network: Integrative analysis of genomic and molecular alterations in clear cell renal cell carcinoma. Nature. June 23, 2013 (early release online).

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

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Perspective Genitourinary Oncology

Results of AXIS Trial Indicate a Significant Improvement over Historical Survival Data in Renal Cell Carcinoma By Janice Dutcher, MD

he phase III open-label AXIS trial comparing axitinib (Inlyta) vs sorafenib (Nexavar) as secondline treatment for metastatic renal cell carcinoma has shown a significant difference in median progression-free survival (8.3 months in the axitinib group vs 5.7 months in the sorafenib group; hazard ration [HR] = 0.656, P < .0001), which is sustained in the 2013 report of long-term follow-up.1 (See page 71 of the June 10, 2013, issue of The ASCO Post for prior coverage of the AXIS trial.) However, neither the initial report2 nor the updated report1 was able to demonstrate a statistically significant difference in median overall survival between the two arms.

in clinical reports and textbooks during the decades prior to the development of the antiangiogenic targeted therapies for renal cell carcinoma. Granted, in this study of patients treated in second line, the population is a bit skewed by entering patients who are still eligible for a clinical trial after progressing on their first-line therapy. However, by the Memorial Sloan-Kettering Cancer Center definition of risk group, this study of over 700 patients showed

Dr. Dutcher is Associate Director, Cancer Research Foundation, and Immediate Past-Chair of the ECOG-ACRIN Renal Cancer Subcommittee.

In the AXIS trial, patients who were treated with axitinib had improved progression-free survival compared with sorafenib whether their prior therapy was a cytokine or another antiangiogenic agent, demonstrating some ability to respond again to inhibition of angiogenesis with a subsequent agent after a “treatment break.” Additionally, those with the longest duration of progression-

We and our patients should be grateful that we can safely sequence these agents and provide continued treatment after study drugs are discontinued, leading to prolonged survival for both groups.

‘Triumphant Results’ for New Treatments Rather than comparing survival in the two arms, it is important to look at the absolute survival numbers for both. In fact, both arms have generated median survivals of nearly 2 years (20.1 months in the axitinib group and 19.2 months in the sorafenib group; HR = 0.969, P = .374). This is actually a triumphant result for these new treatments for renal cell carcinoma, with the numerical median survivals amounting to a doubling of the historical median survival for patients with renal cell carcinoma as described

Difference in Survival Less Surprising, More Promising

—Janice Dutcher, MD

264 patients with intermediate risk characteristics, and 201 and 238 patients with favorable and poor risk characteristics, respectively. So, again, the average and median risk remains intermediate, with a historical survival on therapy of 10 months. In this particular trial, the survival improvement over historical data appears to reflect the development of multiple active therapies, including cytokines, antiangiogenic tyrosine kinase inhibitors, and mTOR inhibitors, which are now being used in sequence, and which all appear to have an additional level of activity against renal cell carcinoma when used in a sequential fashion.

free survival on their first agent had the longest progression-free survival with either axitinib or sorafenib— again demonstrating continued sensitivity to antiangiogenic therapy in some patients. Thus, having no difference in survival between the two arms of the AXIS trial is less surprising and more promising than might appear at first glance—patients were treated with active agents on both arms, and more than half of patients on each arm went on to subsequent therapy, also with active agents. Additionally, the learning curve for managing patients on antiangiogenic agents has improved and patients are able to

stay on such agents with adequate management of toxicity for longer periods of time, thereby adding to drug-related benefit. Finally, the study pointed out an as yet hypothetical but potentially important concept: that the development of hypertension may be a biomarker of prolonged survival in patients treated with antiangiogenic tyrosine kinase inhibitors. Prospective analysis of this hypothesis is warranted in future studies. Overall, the expectation of demonstrating a survival difference when comparing new antiangiogenic agents in renal cell carcinoma in this era of multiple active, commercially available agents may be unrealistic. We and our patients should be grateful that we can safely sequence these agents and provide continued treatment after study drugs are discontinued, leading to prolonged survival for both groups. n

Disclosure: Dr. Dutcher is a speaker for Pfizer, Novartis, Prometheus, and GlaxoSmithKline, an advisor for Pfizer, Prometheus, and Novartis, and serves on Data Safety and Monitoring Committees for Bristol-Myers Squibb and Merck.

References 1. Motzer RJ, Escudier B, Tomczak P, et al: Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: Overall survival analysis and updated results from a randomized phase 3 trial. Lancet Oncol 14:552-562, 2013. 2. Rini BI, Escudier B, Tomczak P, et al: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomized phase 3 trial. Lancet 378:1931-1939, 2011.

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2013

2013 Oncology Meetings July

August

WIN 2013 Symposium: Personalized Cancer Therapy: From Innovation to Implementation July 10-12 • Paris, France For more information: www.winsymposium.org

Best of ASCO® Chicago August 9-10 • Chicago, Illinois For more information: boa.asco.org

12th International Congress on the Future of Breast Cancer July 18-20 • Huntington Beach, California For more information: www.gotoper.com/conferences Georgia Society of Clinical Oncology Debates and Didactics in Hematology and Oncology July 24 • Sea Island, Georgia For more information: www.gasco.us/meetings.php Indiana Oncology Society Fall Membership Conference July 25 • Indianapolis, Indiana For more information: www.accc-cancer.org/ossn_network/ IN/INevents.asp 14th International Lung Cancer Congress July 25-27 • Huntington Beach, California For more information: www.gotoper.com/conferences Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org

Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences Second Annual 2013 World Cutaneous Malignancies Congress July 26-28 • San Diego, California For more information: www.cutaneousmalignancies.com

South Carolina Oncology Society Fall 2013 Membership Conference August 9-10 • Charleston, South Carolina For more information: www.scosonline.com Hematology and Medical Oncology Best Practices August 15-22 • Arlington, Virginia For more information: www.gwumc.edu/cehp/ hemoncbestpractices/ Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org North Carolina Oncology Association Fall Membership Conference August 24 • Greensboro, North Carolina For more information: www.ncoa-northcarolina.com 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

September Georgia Society of Clinical Oncology 2013 GASCO Annual Meeting September 6 • Atlanta, Georgia For more information: www.gasco.us

SGI Summit Turkey 2013: Innovations in Obstetrics and Gynecology September 6-8 • Istanbul, Turkey For more information: www.sgiturkey2013.org/ Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org

Minnesota Society of Clinical Oncology - MSCO Fall Membership Conference September 10 • Minneapolis, Minnesota For more information: www.msco-minnesota.com 2013 Interscience Conference on Antimicrobial Agents and Chemotherapy September 10-13 • Denver, Colorado For more informaton: www.icaac.org Rocky Mountain Oncology Society Fall Membership Conference September 12 • Denver, Colorado For more information: www.rmos-colorado.com 9th Scientific Meeting of the Australasian Society for Breast Disease September 12-14 • Cairns, Queensland, Australia For more information: www.asbd.org.au International Liver Cancer Association Seventh Annual Conference September 13-15 • Washington, DC For more information: www.ilca2013.org/ Inflammation, Microbiota, and Cancer September 19-20 • Bethesda, Maryland For more information: ncifrederick.cancer.gov/events/ microbiota/agenda.asp

Continuum Cancer Centers of New York Conference on Quality of Care in Oncology September 20 • New York, New York For more information: www.chpnet. org/cme

Tennessee Oncology Practice Society 2013 Membership Conference September 20 • Nashville, Tennessee For more information www.tops-tennessee.com

Michigan Society of Hematology and Oncology Annual Meeting September 20-21 • Traverse City, Michigan For more information: www.msho.org

NCCN 8th Annual Congress: Hematologic Malignancies September 20-21, 2013 New York, New York For more information: www.nccn.org

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13 Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences

Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences

2013 ASH State-of-the-Art Symposium September 27-28 • Chicago, Illinois For more information: www.hematology.org continued on page 84

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

LIGHTING A WAY FORWARD

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. Please see additional Important Safety Information on adjacent pages. Please see Brief Summary of Prescribing Information, including BOXED WARNING, for VOTRIENT on adjacent pages.

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

VOTRIENT demonstrated significant improvement in PFS in a Phase 3 trial1 PFS in overall study population (N=369)1

1.6 MONTHS 4.6 MONTHS

Proportion progression-free

1.0

Median PFS

VOTRIENT (n=246 ) Placebo (n=123)

Median PFS

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

0.8

• VOTRIENT provided a 65% reduced risk of progression or death compared with placebo (HR 0.35; 95% CI 0.26-0.48; P<0.001)1 • The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or GIST has not been demonstrated1

0.6 0.4 0.2 0.0 0

Months

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

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

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

• Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound 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.

Please see Brief Summary of Prescribing Information, including BOXED WARNING, for VOTRIENT on adjacent pages.

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In soft tissue sarcoma, a dose decrease or increase should be in 200 mg steps based on individual tolerability • In patients taking VOTRIENT, dose modifications, interruptions, and discontinuations may be required for hepatic impairment, drug interactions, and following adverse events • In the advanced STS clinical trial, 58% of patients on VOTRIENT required a dose interruption; 38% of patients on VOTRIENT had their dose reduced • 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 • For additional information on dosing modifications based on drug interactions, please see Section 2.2 of accompanying Brief Summary

T:14”

B:14.25”

S:13”

• Hypothyroidism: Hypothyroidism was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider interruption or discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. • Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. • 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.

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

• Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs 0% in the placebo group). • 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. 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. 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.

The most common adverse reactions (≥20%) in patients who received VOTRIENT versus placebo were fatigue (65% vs 48%), diarrhea (59% vs 15%), nausea (56% vs 22%), decreased weight (48% vs 15%), hypertension (42% vs 6%), decreased appetite (40% vs 19%), hair color changes (39% vs 2%), vomiting (33% vs 11%), tumor pain (29% vs 21%), dysgeusia (28% vs 3%), headache (23% vs 8%), musculoskeletal pain (23% vs 20%), myalgia (23% vs 9%), gastrointestinal pain (23% vs 9%), and dyspnea (20% vs 17%). Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in patients receiving VOTRIENT versus placebo included increases in AST (51% vs 22%), ALT (46% vs 18%), glucose (45% vs 35%), alkaline phosphatase (32% vs 23%), total bilirubin (29% vs 7%), and potassium (16% vs 11%); decreases in albumin (34% vs 21%) and sodium (31% vs 20%); and leukopenia (44% vs 15%), lymphocytopenia (43% vs 36%), thrombocytopenia (36% vs 6%), and neutropenia (33% vs 7%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Data on file. GlaxoSmithKline, 2011.

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. • Adverse Reactions in the Randomized STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption, 38% of patients on VOTRIENT had their dose reduced, and 14% of patients who received VOTRIENT discontinued therapy due to adverse reactions.

VOTRIENT.com/HCP GSKSource.com

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In STS, a decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. 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. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized STS trial, ALT >3 X ULN was reported in 18% and 5% of the VOTRIENT and placebo groups, respectively. ALT >8 X ULN was reported in 5% and 2% of the VOTRIENT and placebo groups, respectively. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (4/240) of patients on VOTRIENT and <1% (1/123) on placebo. Four-tenths percent (0.4%) of patients (1/240) in the randomized STS trial died of hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the randomized STS trial, 0.2% (1/240) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 123 patients who received placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the randomized STS trial, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared to baseline or a decline in LVEF of ≥10% compared to baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements,

myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thrombotic 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 thrombotic 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 including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 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. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: 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)]. 5.10 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. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 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. 5.14 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. 5.15 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)]. 5.16 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 thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Fourteen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

Adverse Reactions Fatigue

VOTRIENT

Placebo

(N=240)

(N=123)

All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 % % % % % % 65

Diarrhea

Nausea

Weight decreased

Hypertension

Appetite decreased

Hair color changes

Vomiting

Tumor pain

Dysgeusia

Headache

Musculoskeletal pain

Myalgia

Gastrointestinal pain

Dyspnea

Exfoliative rash

Cough

Peripheral edema

Mucositis

Alopecia

Dizziness

Skin disorderb

Skin hypopigmentation

Stomatitis

Chest pain

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

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo

Parameters Hematologic Leukopenia Lymphocytopenia Thrombocytopenia Neutropenia Chemistry AST increased ALT increased Glucose increased Albumin decreased

VOTRIENT Placebo (N=240) (N=123) All Grade Grade All Grade Grade Gradesa 3 4 Gradesa 3 4 % % % % % % 4 43 3 3

41 10 63 34

0 0 1 0

1 36 6 7

50 9 0 0

0 2 0 0

5 4 45

15 68 <1

3 2 0

2 1 35

22 82 2

0 1 0

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B:14.25”

S:13”

Alkaline phosphatase 3 23 0 2 31 0 increased Sodium decreased 3 14 0 2 03 0 Total bilirubin 2 9 1 0 7 2 0 increased Potassium increased 1 61 0 1 10 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 STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. 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. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)] 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. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. 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. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 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]. 7.3 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. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.16)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile

animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.15)]. 8.5 Geriatric Use: In the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT >ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/ moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/ day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration

of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

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2013

2013 Oncology Meetings continued from page 78

ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu 28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston, Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

October The 2nd International Multidisciplinary Forum on Palliative Care (IMFPC 2013) October 3-6 • Sofia, Bulgaria For more information: www.imfpc.org Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences Second Annual Conference Global Biomarkers Consortium October 4-6 • Boston, Massachusetts For more information: www.globalbiomarkersconsortium. com

9th International Symposium on Hodgkin Lymphoma October 12-15, 2013 • Cologne, Germany For more information: www.hodgkinsymposium.org/ International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/About+ASCO/ International+Affairs/International+Cli nical+Trials+Workshops 4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in 18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org

Virginia Association of Hematologists and Oncologists Fall Membership Conference October 11 • Virginia Beach, Virginia For more information: www.vah-o.org 4th International Breast Cancer Prevention Symposium: Genes, the Environment, and Breast Cancer Risks October 11-13 • Beirut, Lebanon For more information: www.purdue.edu/breastcancer/ Merrill J. Egorin Workshop in Cancer Therapeutics and Drug Development October 11-14 • Leesburg, Virginia For more information: www.cancereducationconsortium. org/programs_paaw.html

Illinois Medical Oncology Society 2013 Membership Conference October 25 • Itasca, Illinois For more information: www.imos-illinois.com 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

November Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org Multidisciplinary Symposium on Head and Neck Cancer November 2 • Chicago, Illinois For more information: www.gotoper.com/conferences EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de 9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/ Diagnostic Development Tutorial November 5-7 • Brussels, Belgium For more information: www.markersincancer.eu

Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas For more information: www.mdanderson.org/conferences

SITC Workshop on Personalized Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013

51st Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www2.convention.co.jp/jsco2013/

SITC Primer on Tumor Immunology and Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013

Advanced Breast Cancer Second International Consensus Conference November 7-9 • Lisbon, Portugal For more information: www.abc-lisbon.org/ International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw 11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro New York Lung Cancer Symposium November 9 • New York, New York For more information: www.gotoper.com/conferences Academy of Oncology Nurse Navigators 4th Annual Navigation and Survivorship Conference November 14-17 • Memphis, Tennessee For more information: aonnonline.org/conference African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

December 55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org 36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org

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Awards Geriatric Oncology

American Geriatrics Society Presents Diane E. Meier, MD, the 2013 Edward Henderson Award

he American Geriatrics Society (AGS) presented Diane E. Meier, MD, the 2013 Edward Henderson Award in recognition of her many invaluable contributions to the field of geriatrics. Dr. Meier received the award and delivered the Henderson State-ofthe-Art Lecture during AGS’ Annual Scientific Meeting held recently. Dr. Meier’s Henderson Lecture, Palliative Care: Transforming the Care of Serious Illness, examined how palliative

Diane E. Meier, MD

medicine and geriatrics have developed an evidence base, demonstrating models of care delivery that have improved care quality and reduced costs. She discussed the challenges in improving access to these proven care delivery models to all persons in need. “We are thrilled to present Dr. Meier with the 2013 Henderson Award,” said AGS President James Pacala, MD. “Dr. Meier has devoted her career to increasing the availability of quality palliative care services in hospitals and other health-care settings for people facing serious illnesses, and for their

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family caregivers.” Dr. Meier is the Director of the Center to Advance Palliative Care (CAPC) at the Icahn School of Medicine at

Mount Sinai in New York City, and the Catherine Gaisman Professor of Medical Ethics and Professor of Geriatrics and Palliative Medicine at Mount Si-

nai. Under her leadership, the number of palliative care programs in American hospitals has more than doubled in the last 5 years. n

Trebananib (AMG 386) Phase III Clinical Trials in Ovarian Cancer

Trials Now Enrolling

TRINOVA-2: A Phase 3, Randomized, Double-Blind Trial of Pegylated Liposomal Doxorubicin (PLD) Plus Trebananib (AMG 386) or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

TRINOVA-3: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Trebananib (AMG 386) With Paclitaxel and Carboplatin as First-Line Treatment of Women With FIGO Stage III-IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Primary Endpoint: • Progression-free survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

Key Secondary Endpoint: • Overall survival (OS) Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

R A N D O M I Z A T I O N

Trebananib15 mg/kg IV QW + PLD 50 mg/m2 IV Q4W

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + PLD 50 mg/m2 IV Q4W

R A N D O M I Z A T I O N

Trebananib IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Trebananib IV QW Monotherapy

ENDPOINTS

Primary

PFS 2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Key Secondary

Placebo IV QW Monotherapy

*Subjects with FIGO stage IIIC or IV disease undergoing planned interval debulking surgery (IDS) will receive 3 cycles of therapy prior to IDS and 3 cycles of therapy following IDS

Trebananib is an investigational agent that has not been approved by regulatory agencies for the use under investigation for this trial.

Key Inclusion Criteria: • Subjects must have had one to three prior chemotherapeutic regimens • Radiographically documented disease progression either on or following the last dose of prior chemotherapeutic regimen • ECOG performance status of 0 or 1

Key Inclusion Criteria: • FIGO Stages III-IV epithelial ovarian, primary peritoneal or fallopian tube cancer with an indication for first-line treatment with paclitaxel and carboplatin • No prior use of any anticancer therapy or experimental therapy for epithelial ovarian, primary peritoneal or fallopian tube cancer • ECOG performance status of 0 or 1

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • EudraCT 2009-017946-30 • www.ClinicalTrials.gov (NCT01281254)

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • EudraCT 2011-001112-53 • www.ClinicalTrials.gov (NCT01493505)

@ASCOPost

The ASCO Post | JULY 10, 2013

PAGE 86

Announcements

AMA Announces 2013-2014 Board of Trustees; Names Oncologist Barbara McAneny, MD, Chair-elect

he American Medical Association (AMA) recently introduced the 21 members of its Board of Trustees for the coming year fol-

lowing elections held during the Annual Meeting of the AMA House of Delegates. The new Chair of the AMA Board of Trustees is David O. Barbe,

MD, MHA, a Family Medicine physician from Mountain Grove, Missouri. Barbara L. McAneny, MD, a Medical Oncologist/Hematologist from Albu-

2014 ASCO Special Awards Nomination Period Open ASCO’s Special Awards are the Society’s highest and most prestigious awards. Including time-honored awards such as: • American Cancer Society Award and Lecture • B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology

• Humanitarian Award • Partners in Progress Award • Pediatric Oncology Award and Lecture • Public Service Award

• David A. Karnofsky Memorial Award and Lecture

• Science of Oncology Award and Lecture

• Distinguished Achievement Award

• NEW this year: Excellence in Teaching Award

• Gianni Bonadonna Breast Cancer Award and Lecture

• Special Recognition Award

To find out more about these awards, including the criteria and how to make a nomination, please visit asco.org/specialawards.

Nomination period closes August 12, 2013. Individuals may be nominated for more than one award as long as they meet the criteria for each. Nominating an individual requires answering a few questions concerning the nominee’s qualifications for that particular ASCO award. If you have any questions or need assistance, please contact specialawards@asco.org.

querque, New Mexico, was chosen as Chair-elect.

Leadership Experience Dr. McAneny’s medical leadership experience includes serving as President of the New Mexico Medical Society and the New Mexico Chapter of the

Barbara L. McAneny, MD

American College of Physicians. She previously served on ASCO’s Board of Directors and the Practicing Physicians’ Advisory Council (PPAC), a congressionally designated physician committee that advises Health and Human Services on Medicare. Dr. McAneny is cofounder of her multi-disciplinary oncology practice and manages the New Mexico Cancer Center. In New Mexico, she has been involved in medical liability reform, helping to maintain New Mexico’s cap on non-economic damages. She also helped to pass New Mexico’s Dee Johnson Clean Indoor Air Act and direct monetary tobacco settlements toward prevention efforts. She also chairs the Albuquerque Emergency Medical Service Authority.

Executive Officers The other executive officers on the AMA Board of Trustees for 2013-2014 are listed below: Susan R. Bailey, MD, an Allergist, Immunologist and Pediatrician from Fort Worth, Texas, was re-elected Vice Speaker. Andrew W. Gurman, MD, an Orthopedic Surgeon from Hollidaysburg, Pennsylvania., was re-elected Speaker. Carl A. Sirio, MD, a Citical Care Physician and Internist from Pittsburgh, Pennsylvania, was named Secretary. Steven J. Stack, MD, an Emergency Medicine Physician from Lexington, Kentucky, assumed the office of Immediate Past Chair. n

ASCOPost.com | JULY 10, 2013

PAGE 87

News Pediatric Oncology

Molecular Imaging Improves Care in Pediatric Glioma

he amino acid imaging agent, O-(2-[18F]-fluoroethyl)-L-tyrosine (F-18 FET), may improve upon standard magnetic resonance imaging (MRI) and its diagnostic benefit for imaging pediatric gliomas when conventional MRI is not sufficient, said researchers at the Society of Nuclear Medicine and Molecular Imaging’s

provide information about either glucose or the cellular metabolism of amino acids. Amino acid PET imaging has been shown to be better for detection of neoplastic tissue and treatment monitoring in cases of brain cancer than glucose imaging. In general, the brain requires more glucose than the body’s other tissues and organs, mak-

F-18 FET is complementary and can potentially improve diagnosis and treatment of pediatric brain tumors. —Veronika Dunkl, MD

2013 Annual Meeting.1 The imaging agent helps by providing information about tumor metabolism and extent of cancer in children diagnosed with glioma, the researchers said. Brain cancer imaging is often conducted with conventional MRI, but there are some limitations. Glioma accounts for approximately 80% of all invasive brain tumors. Conventional MRI can sometimes over- or underestimate the extent of these tumors and the exact shape of their outlying margins. Positron-emission tomography (PET) provides information about physiological functions rather than structures of the brain, and can be performed with a variety of imaging agents that bind to specific cellular systems to image gliomas. Two of the main types of brain imaging agents used for this purpose

ing brain scans less defined than others due to this increase in overall cellular metabolism, whereas areas of increased amino acid activity show up clearly on scans as a visual “hot spot.” This study1 focused on F-18 FET and its diagnostic benefit for imaging pediatric gliomas when conventional MRI was not able to obtain a clear image.

PET and F-18 FET “Tumors in younger patients show a greater variety in both type and size, and in many cases the tumors are located near critical brain structures that prohibit surgical removal,” said Veronika Dunkl, MD, a Research Scientist at the Institute of Neuroscience and Medicine, Forschungszentrum Jülich, in Jülich, Germany. “In patients with brain tumors, contrast-enhanced structural MRI is currently the diagnostic

method of choice. However, in youths with newly diagnosed cerebral lesions thought to be brain tumors, MRI’s ability to identify neoplastic tissue or tumor progression and recurrence after treatment is limited. F-18 FET is complementary and can potentially improve diagnosis and treatment of pediatric brain tumors,” Dr. Dunkl said. Pediatric brain imaging with PET and F-18 FET can be used not only to evaluate extent of tumors but also to help doctors plan for biopsy, surgery, and radiation therapies and track response to therapy and recurrence of tumors after completion of a treatment cycle. F-18 FET is also unique from other amino acid PET agents because the production of the drug can be centrally located and distributed by a radiopharmacy, whereas other amino acid–based PET agents must be produced by an on-site cyclotron—a massive particle accelerator that bombards particles with a target used to radiolabel the agent’s molecular compound. For F-18 FET, it is the amino acid tyrosine that allows brain cells to signal each other. The greater logistical ease of F-18 FET is due to its radioactive half-life of approximately 110 minutes, whereas many other isotopes have a half-life of only about 20 minutes and must be administered for patient imaging almost immediately.

Highly Effective Technique For this study, 15 young patients suspected of glioma cerebral cancer

via MRI screening underwent PET imaging with the guidance of F-18 FET. The investigators found the molecular imaging technique to be about 87% effective for detecting and differentiating brain lesions in children and young adults. Specifically, the method was able to pinpoint 11 out of 12 brain lesions correctly as tumors and 2 out of 3 as a nontumorous growth. Repeated PET imaging (17 scans) for seven more pediatric patients provided meaningful information about cancer progression or remission. F-18 FET imaging was able to detect residual tumor and tumor progression in 5 out of 6 scans, and in 11 scans in which the cancer had been eradicated, for a 94 percent rate of accuracy. “Results of the present study may improve the clinical management of this vulnerable patient population significantly, especially when a decision for further treatment is difficult or impossible on the basis of conventional MRI alone,” said Dr. Dunkl. n Reference 1. Dunkl V, Stoffels G, Fink G, et al: The use of dynamic O-(2-[18F] fluoroethyl)-L-tyrosine-PET in the clinical evaluation of brain tumors in children and young adults. Society of Nuclear Medicine and Molecular Imaging (SNMMI) 60th Annual Meeting, June 8–12, 2013, Vancouver, British Columbia. Scientific Paper 474.

Gary L. Dillehay, MD, Is New President, Society of Nuclear Medicine and Molecular Imaging

he Society of Nuclear Medicine and Molecular Imaging (SNMMI) recently announced the appointment of Gary L. Dillehay, MD, FACNM, FACR, to 2013-2014 President, SNMMI, during the Society’s Annual Meeting in Vancouver. Dr. Dillehay is Professor of Radiology at Northwestern Memorial Hospital in Chicago. “Implementing SNMMI’s newly approved strategic plan will be a main focus over the next 6 months as I begin my term as president,” said Dr. Dillehay. “Our major goals for this 3-year plan include advancing the development and

Gary L. Dillehay, MD

approval of new technologies; facilitating the availability and clinical utilization of these technologies; increasing the appropriate use of radionuclide

therapy; promoting quality, value and safety; and supporting and enhancing the professional workforce and environment for nuclear medicine and molecular imaging professionals.” In addition, Dr. Dillehay has made it a priority to maintain strong working relationships with SNMMI’s sister organizations in the imaging community, in particular international groups, such as the International Atomic Energy Agency, the European Association of Nuclear Medicine, as well as those involved with the Nuclear Medicine Global Initiative. Other priorities in-

clude advocating for adequate and appropriate reimbursement and providing development and leadership opportunities for residents, young physicians and scientists through an SNMMI Leadership Academy. Dr. Dillehay has served as Professor of Radiology at the Northwestern University Feinberg School of Medicine since 2006. Prior to that, he was Professor of Radiology at Loyola Stritch School of Medicine. Dr. Dillehay is certified by the American Board of Radiology and the American Board of Nuclear Medicine. n

The ASCO Post | JULY 10, 2013

PAGE 88

Health-care Policy

Accountable Care Organizations May Be at Risk for New Medical Liabilities By Jo Cavallo

he promotion of accountable care organizations, a crucial element in the Affordable Care Act, may result in liability risks, said H. Benjamin Harvey, MD, JD, a radiologist in the Department of Radiology at Massachusetts General Hospital, and I. Glenn Cohen, JD, Assistant Professor of Law at Harvard Law School, in a Viewpoint they published recently in the Journal of the American Medical Association ( JAMA).1 The authors pointed out that the health-care delivery and payment

model system of accountable care organizations is designed to limit risking medical costs while improving quality of care by agreeing to share the financial risk of health-care overspending with third-party payers, such as Medicare. These sharedrisk arrangements are now spreading to private insurance markets, “where they aim to dismantle the volumedriven fee-for-service revenue model,” said the authors.

Litigation Concerns The concern is that accountable

Accountable Care Organizations and Medical Liabilities ■ Accountable care organizations may be facing the same types of lawsuits managed care organizations encountered in the 1990s, when they were accused of prioritizing their financial success over the health and wellbeing of their members.

■ The threat of potential litigation may be mitigated by purchasing managed care errors and omissions insurance and employing self-help remedies, such as matching institutional care to published patient care guidelines or evidence-based medicine.

■ These solutions, as well as possible Congressional intervention to broaden the protections available to managed care organizations in the Employee Retirement Income Security Act, would balance cost savings and highquality patient care while reducing the threat of liability.

care organizations may face the same types of litigation that managed care organizations encountered in the 1990s when lawsuits were filed by their members alleging that managed care organizations negligently prioritized their financial success over the health and well-being of their members. Managed care organizations received some immunity against such lawsuits in 2004, when the Supreme Court recognized federal preemption (ie, that federal law blocked enforcement) of these claims for employer-provided health insurance plans that are subject to the requirements in the Employee Retirement Income Security Act (ERISA). ERISA provided managed care organizations some protection against liability by preventing second-guessing of their motivations in medical coverage decisions. However, the authors said that accountable care organizations will encounter the same type of suspicion as they try to contain health-care costs while providing good patient care, but will not have the benefit of ERISA protection since they are not covered by the law.

Balancing Cost Savings and Effective Patient Care According to the authors, accountable care organizations can protect themselves from potential liability by purchasing managed care errors and omissions insurance and enacting self-help remedies, such as matching institutional care algorithms used for hospital admissions to published patient care guidelines or evidence-based medical studies, which would link accountable care organization policies to established standards of care. Lobbying Congress for protection from too much liability by broadening the requirements in ERISA to include accountable care organizations could also be helpful, they wrote. These measures could mitigate the threat of an uncertain liability environment while balancing cost savings with the most effective patient care, the authors concluded. n Reference 1. Harvey HB, Cohen IG: The looming threat of liability for accountable care organizations and what to do about it. JAMA. June 17, 2013 (early release online).

FDA Update

Newly Approved Drugs and Indications

DA has approved the following new drugs and/or indications in 2013: • Denosumab (Xgeva subcutaneous injection) for giant cell tumor of bone • Lenalidomide (Revlimid capsules) for relapsed/refractory mantle cell lymphoma FDA approved • Trametinib (Mekinist tablets) for unresectable or metastatic melanoma with BRAF V600E or V600K mutation • Dabrafenib (Tafinlar capsules) for unresectable or metastatic

Visit

•

melanoma with BRAF V600E mutation Radium Ra 223 dichloride (Xofigo injection) for castrationresistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. Erlotinib (Tarceva) for first-line treatment of metastatic nonsmall cell lung cancer patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. This indication for erlotinib was approved concurrently with the cobas EGFR Mutation Test, a com-

•

panion diagnostic test for patient selection. Ado-trastuzumab emtansine (Kadcyla injection) for single-

•

agent treatment of HER2-positive, metastatic breast cancer previously treated by trastuzumab and a taxane, separately or in combination. Pomalidomide (Pomalyst cap-

sules) for multiple myeloma patients who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy. Bevacizumab (Avastin) for use in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy for metastatic colorectal cancer that has progressed on a first-line bevacizumab-containing regimen. n

website at ASCOPost.com

This is the biologic medicine That the patient counts on That the nurse trusts That the pharmacist has confidence in That the doctor relies on Because it was manufactured knowing the patient’s treatment depends on it. Building confidence in the quality and supply of biologic medicines starts with a deeper understanding of how these medicines are made. After all, there’s so much at stake.

That’s why manufacturing matters. Learn more at

buildingbiologics.com

The ASCO Post | JULY 10, 2013

PAGE 90

Announcements

Big Ten Universities Join Together in Cancer Research Consortium

eaders from cancer centers affiliated with the “Big Ten” universities joined together in launching the Big Ten Cancer Research Consortium on June 1 in Chicago. The group is uniting to transform cancer research through collaborative on-

transform cancer research through collaborative oncology trials, we will be able to leverage the scientific and clinical expertise of the Big Ten Universities. The consortium will benefit patients because researchers will work together to turn ideas into

This is a rare opportunity for the universities to work together as part of a regional team science initiative to advance cancer research. —Patrick J. Loehrer Sr, MD

cology trials that leverage the scientific and clinical expertise of the Big Ten universities. “Tremendous strengths exist in the cancer centers of the Big Ten,” said Patrick J. Loehrer Sr, MD, Director of the Indiana University Melvin and Bren Simon Cancer Center. “This is a rare opportunity for the universities to work together as part of a regional team science initiative to advance cancer research. The advantage of this, particularly during a time of austerity for research, is that we can build upon the strengths of the institutions and fortify some

potential new treatments. I view this as the beginning of a broad spectrum of potential research, training and care initiatives that will benefit our patients and society.”

Maha Hussain, MD, FACP

The clinical trials that will be developed will be linked to molecular diagnostics, enabling researchers to understand what drives the cancers to grow and what might be done to stop them from growing.

Powerful Collaboration Steven T. Rosen, MD

of the shortcomings. This allows us to be lean, efficient but, most importantly, collaborative.” Steven T. Rosen, MD, Director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, added “By uniting to

Also, the consortium forms a powerful collaboration because of the impact each university already has made in cancer research and the solid research infrastructure already in place at each university. The consortium also leverages geographical locations and existing relationships among the cancer centers. “For research to be truly impact-

Big Tena Cancer Research Consortium ■ Indiana University (Indiana University Melvin and Bren Simon Cancer Center) ■ Northwestern University (Robert H. Lurie Comprehensive Cancer Center) ■ Penn State University (Penn State Hershey Cancer Institute) ■ Purdue University (Purdue University Center for Cancer Research) ■ Rutgers University (The Cancer Institute of New Jersey) ■ University of Illinois (University of Illinois Cancer Center) ■ University of Iowa (Holden Comprehensive Cancer Center) ■ University of Michigan (University of Michigan Comprehensive Cancer Center) ■ University of Minnesota (Masonic Cancer Center) ■ University of Nebraska (Fred & Pamela Buffett Cancer Center) ■ University of Wisconsin (Carbone Comprehensive Cancer Center) The Big Ten Conference is an association of universities whose member institutions share a common mission of research, graduate, professional, and undergraduate teaching and public service. Founded in 1896, the Big Ten has sustained a comprehensive set of shared practices and policies that enforce the priority of academics in studentathletes’ lives and emphasize the values of integrity, fairness and competitiveness..

ful, we must work together,” said Maha Hussain, MD, FACP, Associate Director of Clinical Research at the University of Michigan Comprehensive Cancer Center. “Collaborating with other institutions gives us another opportunity for a broader and deeper brain trust while allowing implementation of novel ideas in a more representative patient population. The synergy, the collaboration, the implementation all are aimed at one ultimate goal—making a real difference for patients.” The Big Ten Cancer Research Consortium will collaborate with and mentor future research leaders with the goal of improving the lives of all cancer patients. The Consortium will provide junior faculty and fellows the opportunity to write, conduct, and complete trials, which would not normally be done at a single institution or on a national level for young investigators. “A critical byproduct of the Big Ten Cancer Research Consortium will be the creation of a new arena

for junior faculty cancer researchers to design and lead potential practice-

Noah Hahn, MD

changing cancer studies,” said Noah Hahn, MD, Executive Officer of the consortium, Associate Professor of Medicine at IU School of Medicine and a researcher at the IU Simon Cancer Center. “Opportunities for junior faculty to lead clinical trials have been evaporating in recent years, but the consortium aims to intentionally promote junior faculty participation and leadership in all trials under appropriate senior faculty guidance and mentorship in an effort to address those decreasing opportunities.” n

MULTIPLE MYELOMA

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GIVES UP.

BUT NEITHER

DO WE. There is no cure for multiple myeloma. That’s why we’ve dedicated ourselves to three guiding principles: a relentless commitment to scientific advances, a persistent focus on patient needs, and a progressive approach to collaboration. Celgene has put these beliefs into practice for more than 15 years. And we’re not done yet.

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The ASCO Post | JULY 10, 2013

PAGE 92

ASCO State Affiliates Focus on the Society of Rhode Island Clinical Oncologists By Jo Cavallo

and the changing dynamic of oncology care in Rhode Island.

ASCO Relationship

Joseph DiBenedetto, Jr, MD, FASCO

ounded in 1994, just 1 year after ASCO launched the State/Regional Affiliate Program, the Society of Rhode Island Clinical Oncologists is one of ASCO’s oldest state affiliates. Like many other ASCO affiliates, the Providence-based group is facing a myriad of challenges, including ensuring continued patient access to high-quality oncology care in an environment of rising health-care costs and decreasing Medicare reimbursements as well as addressing the needs of Society members serving in solo community practices, community hospital-based practices, and academic institutions. The ASCO Post talked with Joseph DiBenedetto, Jr, MD, FASCO, President of the Society of Rhode Island Clinical Oncologists, about the challenges his Society faces

Why is it important for your Society to be an ASCO state affiliate? ASCO provides us with a number of resources we would not have on our own, including guidance on Medicare and private insurance reimbursement issues, information on national legislation and how it may affect oncologists and patients in our state, continuing medical education materials, and government activism. ASCO also offers

By fostering camaraderie among Society members and improving communication, we find that members do not hesitate to consult with each other regarding treatment for a specific patient, and that is making a difference in improving care. —Joseph DiBenedetto, Jr, MD, FASCO

helpful workshop seminars in billing and coding and other office management concerns.

Professional Challenges What professional challenges does your organization face? When we started our Society 20 years ago, our greatest challenge was

Fast Facts about the Society of Rhode Island Clinical Oncologists ■ ■ ■ ■

in bridging the dichotomy between academic and community oncologists. Today, our greatest challenge is the change in the economic landscape of the community oncologist in private practice, which is resulting in many community oncologists closing their practices and working for community-based hospitals instead. So oncologists are becoming employed by hospitals, and their salaries are based on what these hospitals can afford to pay for their services. As a Society, we have to stay relevant

Founded in 1994 President: Joseph DiBenedetto, Jr, MD, FASCO 25 members Mission: to promote excellence in oncology care through continued professional education; advocate for patients to ensure their access and reimbursement for medical care; continue the highest professional standards of oncology care; and research and exchange information, experiences, and ideas leading to improvements in oncology care

■ The Society holds two to three meetings a year to discuss relevant

state and national issues that affect patient oncology care, such as the Affordable Care Act, specialty pharmacy issues, 340B Drug Pricing Program, and changes in Medicare reimbursements.

to all the oncologists we serve, whether they are in the academic, private, or hospital-based setting, and make sure that their needs are being met. It is a big challenge to overcome, and we are looking to ASCO to provide us with the tools and learning modules to make sure our message stays relevant to all oncologists, as we provide the support our members need and maintain their interest in our group.

Early Successes What were some of your early successes? We were the second state in the country to pass legislation requiring state-regulated health insurers to cover off-label use of FDA-approved drugs for oncology treatment. We were quite proud of this accomplishment. We have also worked with health-care insurers to decrease the higher copayments for outpatient care so patients could receive chemotherapy and supportive care drugs

without incurring a severe financial strain. We also met with the medical directors of health-care carriers in our state regarding patient and physician reimbursement issues and have worked with the director of our J14 Medicare Administrative Contractor [for Rhode Island, Maine, New Hampshire, Massachusetts, and Vermont] to ensure the maintenance of high-quality patient care. The Society serves on the Carrier Advisory Committee of the Centers for Medicare & Medicaid Services (CMS), and when there are oncology questions on coverage, we provide assistance as needed.

Quality of Care How has your Society helped oncologists improve the quality of care for their patients? Being part of the Society of Rhode Island Clinical Oncologists provides members with a venue to exchange ideas about patient care and fosters camaraderie and better communication among oncologists throughout the state. Having a Society allows us to bridge our differences regardless of our type of practice. We don’t see ourselves in competition. We see each other as colleagues, and that is something our Society has fostered. The organization has been a conduit for exchange of ideas, all to benefit the patient. For example, I’m in a group practice, so it’s easy for me to consult with other oncologists immediately. But some oncologists are more isolated in solo practices and don’t have ready access to colleagues. By fostering camaraderie among Society members and improving communication, we find that members do not hesitate to consult with each other regarding treatment for a specific patient, and that is making a difference in improving care. n

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

NOW ENROLLING A Phase 2 Trial of Rindopepimut in Patients With Relapsed EGFRvIII-Positive Glioblastoma • Rindopepimut is an investigational therapeutic vaccine. It is thought to target EGFRvIII, a constitutively activated deletion mutant that is found only in tumors. About a third of glioblastoma patients express EGFRvIII, and its presence has been linked to poor long-term survival1-3 • ReACT is a phase 2 study being conducted in the United States that will evaluate if rindopepimut is effective in extending progression-free survival (PFS) in patients with relapsed EGFRvIII-expressing glioblastoma, when added to standard bevacizumab

1:1 Randomization

Blinded Rindopepimut Group 1 Bevacizumab Naïve (n=70)

1st or 2nd relapse EGFRvIII-positive glioblastoma

Bevacizumab Blinded KLH Control

Bevacizumab

Treat until tumor progression, intolerance, or withdrawal of consent

Rindopepimut

Group 2 Bevacizumab Refractory

Bevacizumab

(n=25)

KLH=keyhole limpet hemocyanin.

N=95

Key Inclusion Criteria

Key Exclusion Criteria

• Previous treatment must include surgery (biopsy, partial resection, or full surgical resection), conventional radiation therapy, and temozolomide

• Presence of diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease

• First or second relapse of glioblastoma. Patients enrolling into group 2 must have progressed while receiving bevacizumab

• Clinically significant increased intracranial pressure, uncontrolled seizures, or requirement for immediate palliative treatment

• Documented EGFRvIII-positive tumor status. A tumor sample from either the initial diagnosis or more recent relapse will be acceptable. Only patients with the EGFRvIII mutation can participate in the trial

• History, presence, or suspicion of metastatic disease

Key Trial Endpoints • Primary: PFS rate at 6 months (PFS 6) • Secondary: Objective response rate, overall PFS, and overall survival

For more information visit www.celldextherapeutics.com, www.clinicaltrials.gov/show/NCT01498328, or e-mail info@celldextherapeutics.com. 1. Pelloski CE et al. J Clin Oncol. 2007;25(16):2288-2294. 2. Sampson JH et al. J Clin Oncol. 2010;28(31): 4722-4729. 3. Sampson JH et al. Neuro Oncol. 2011;13(3):324-333. ©2013 Celldex Therapeutics, Inc.

J2A

7/13

The ASCO Post | JULY 10, 2013

PAGE 94

In the News Melanoma

‘Spectacular’ Results with Immunotherapies in Melanoma Galvanize the Oncology Community By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

uch of the news about immunotherapy that came out of the 2013 ASCO Annual Meeting focused on agents that target immune system checkpoints and block pathways for receptors that suppress T-cell activity. This approach is more direct than other immunotherapeutic strategies and, at least for now, seems to hold the most promise. “It is simple, it is relatively nontoxic, and it is well defined, which is not the case with many of the other immunotherapies. And it seems to work really well,” Kim A. Margolin, MD, told The ASCO Post. Dr. Margo-

lin, whose clinical expertise is in immunotherapy for treating melanoma and kidney cancer, is Professor of Medical Oncology at the University of Washington, a member of the Fred Hutchinson Cancer Research Center, and a physician with the Seattle Cancer Care Alliance. Results of trials using these immunotherapeutic agents in patients with melanoma and some other cancers have shown improved treatment outcomes, but survival data so far are limited. “There are survival results, but they are relatively short, which is a consequence of having results that are so spectacular that you are compelled to present them so early,” Dr. Margolin stated. She pointed out that in many cases, these “are the results of phase I studies, and that’s pretty amazing, to have such promising results in phase I that you make a huge splash, not only at a meeting, but in The New England Journal of Medicine.”1

Expect Questions about Programmed Death Receptors

n today’s high-tech, sci-fi–loving culture, “programmed death receptor” seems like a term apt to stir up public interest, particularly when those receptors are being “targeted” by “agents.” In this case, however, the agents are antibodies that target programmed death 1 (PD-1) receptor and disable its hold on or interference with the immune system. They are getting attention at scientific meetings and in the press because studies in patients with advanced melanoma have shown that these agents are effective. Although these agents are still investigational, “I suspect that for melanoma, we will soon see one of the PD-1 antibodies cleared by the FDA for use through an expanded access program,” Kim A. Margolin, MD, said in an interview with The ASCO Post. Dr. Margolin is Professor of Medical Oncology at the University of Washington, a member of the Fred Hutchinson Cancer Research Center, and a physician with the Seattle Cancer Care Alliance.

Immunotherapy Boom “I think it is super-important to recognize that immunotherapy does not just belong to the worlds of melanoma and renal cancer,” Dr. Margolin said, acknowledging that others have also stated this position. “The field is really branching out, and tumors that we never thought were likely to be immunoresponsive, for example, because they are so fast-growing, are now also being studied with this strategy.” As examples, she listed soft-tissue sarcomas, osteosarcomas, breast cancer, gastrointestinal cancers, and a variety of hematologic malignancies. While this approach is still in beginning stages for some of these cancers, they are all now being targeted by various types of immunotherapy. “This modality is just exploding,” she commented. n Disclosure: Dr. Margolin receives research support from Bristol-Myers Squibb.

Objective Response Rate One of the phase I studies found the combination of ipilimumab (Yervoy) and nivolumab produced an objective response rate of 40% in patients with previously treated stage III/IV melanoma.1,2 Ipilimumab is a monoclonal antibody that blocks cytotoxic

at least 30% by RECIST criteria. The median overall survival across all doses was 16.8 months, which the investigators noted “compares favorably with historical data.” 3 “A very interesting thing is that responses don’t necessarily have to be maintained by continuing the drug,” re-

There are survival results, but they are relatively short, which is a consequence of having results that are so spectacular that you are compelled to present them so early. — Kim A. Margolin, MD

T-lymphocyte–associated antigen 4 (CTLA-4) and has been approved by the FDA for the treatment of unresectable or metastatic melanoma. The investigational drug nivolumab is an antibody that blocks programmed death 1 (PD-1) receptor. “Responses were durable, although longer follow-up is needed in some cohorts,” the investigators wrote in The New England Journal of Medicine.1 “The effect of the combination regimen on long-term survival remains to be defined.” “There are other combinations that also have either checkpoint blockers together or a combination of checkpoint blockers with other immunostimulants—like cytokines, vaccines, or other accessory molecules like CD137—that have promise,” Dr. Margolin said, but haven’t come as far as the combination of ipilimumab and nivolumab. “Of course, that is in great part because the same company makes nivolumab and ipilimumab, so the hurdles associated with having more than one company work together on novel combinations were not present when that combination was able to be studied.” Both drugs are from BristolMyers Squibb, which also provided funding for the study.

Long-term Responses In an expanded phase I study of nivolumab, 33 of 107 patients (31%) treated with five different doses of the drug experienced tumor shrinkage of

ported study lead author Mario Sznol, MD, Professor of Medicine at Yale Cancer Center in New Haven, Connecticut, at a press conference held during the 2013 ASCO Annual Meeting. Among the 17 responders who stopped taking nivolumab for reasons other than disease progression, “12 continued to respond for at least 4 months after stopping the drug,” Dr. Sznol stated. Asked whether that kind of carryover effect could be an expected feature of immunotherapy agents or is unique to nivolumab, Dr. Margolin

Mario Sznol, MD

responded, “I don’t think either one of those ends of the spectrum is necessarily the answer. We have learned the lessons from transplantation immunology [and other areas] that you probably cannot cavalierly assume that whatever therapeutic manipulation you make in the immune system is going to last unless you continue to actively pursue it. So, yes, there are some long-term responses after stopping the drug, but I think until we

ASCOPost.com | JULY 10, 2013

PAGE 95

In the News

have more data, it would be a little too rosy to expect that.”

Recapturing Responses Patients with advanced melanoma who have experienced initial benefit from ipilimumab therapy and then had disease progression, can safely be retreated with ipilimumab, according to an analysis of patients treated in an ipilimumab expanded access program.4 These patients had unresectable stage III/IV melanoma, had progressed following one or more systemic therapies, and had no alternative treatment options. The potential benefit of retreatment on overall survival is being prospectively evaluated in an ongoing phase II study randomizing patients to ipilimumab retreatment or the physician’s choice of an alternative therapy. “People who get retreated are, by definition, people who (A) did well for some period of time, then stopped doing well, and then were well enough to get the drug, (B) did

not experience severe toxicities from treatment the first time around, and (C) lasted long enough to get to that point. Those are all relatively high bars,” Dr. Margolin said. “So you are looking at a highly selected, very biased group of patients. That having been said, it is very encouraging to know that you may be able to recapture responses that have been lost if the patient has been off therapy.”

‘Used to Failure’ A New York Times article5 on immunotherapy trials results from the 2013 ASCO Annual Meeting quoted Dr. Margolin as saying, “We’re so used to failure, we get excited very easily.” In an interview with The ASCO Post, Dr. Margolin elaborated on that thought. “In some historical phase I studies, surely in the age of cytotoxics when we didn’t have agents that were molecularly or otherwise tailored to the patient, we had drugs that were tested in phase I across a broad spectrum of different tumor types. Patients were often heavily pretreated and not good candidates

for likelihood of benefit. You were looking for toxicities, and maybe if you saw a little signal, you would then pursue that drug in those patients at that dose,” she said. “Times have changed dramatically since then,” she continued. “In the area of targeted therapies, they’ve changed in the direction of picking patients based on molecular target expression, and often treating in earlier stages, in patients who haven’t been so heavily pretreated. Some of these immunotherapies are restricted to certain histologies. So we have an opportunity to see these efficacy signals earlier in groups of patients who are better characterized and in narrower histologic groups,” she added. “That is why I could say we are used to failure, certainly in the phase I setting. The old way of doing phase I studies pretty much guaranteed failure,” she said. “Melanoma is a highly complicated malignancy, and it has taken decades of work and perseverance, but now we are seeing some pretty amazing turnaround of those results.” n

Disclosure: Dr. Margolin receives research support from Bristol-Myers Squibb. Dr. Sznol is a paid consultant for Bristol-Myers Squibb.

References 1. Wolchok JD, Kluger H, Callahan MK, et al: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. June 2, 2013 (early release online). 2. Wolchok JD, Kluger HM, Callahan MK, et al: Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9012. Presented June 2, 2013. 3. Sznol M, Kluger HM, Hodi S, et al: Survival and long-term follow-up of safety and response in patients with advanced melanoma in a phase I trial of nivolumab (antiPD-1, BMS-936558, ONO-4538). 2013 ASCO Annual Meeting. Abstract CRA9006. Presented June 1, 2013. 4. Margolin KA: Ipilimumab retreatment following induction therapy: The expanded access program (EAP) experience. 2013 ASCO Annual Meeting. Abstract 9041. Presented June 1, 2013. 5. Pollack A: Promising new cancer drugs empower the body’s own defense system. NY Times. June 3, 2013.

Lab Notes

Ongoing Molecular Research in the Science of Oncology TARGETED THERAPY Treating BRAF V600E Colorectal Cancer May Require Concomitant BRAF and PI3K/mTOR Inhibition BRAF V600E mutations are associated with poor prognosis in colorectal cancer. A study by Coffee and colleagues examined PI3K/mTOR signaling in BRAF V600E colorectal cancer cell lines after BRAF inhibition as well as cell viability and apoptosis after combined BRAF and PI3K/ mTOR inhibition. Western blot analysis showed sustained PI3K/mTOR signaling after BRAF inhibition. In a novel genetically engineered mouse model for BRAF V600E colorectal cancer, mice developed sessile serrated adenomas/polyps similar to those in humans. Combination treatment with BRAF and PI3K/mTOR inhibitors

resulted in induction of apoptosis and tumor regression. The investigators stated, “We have established a novel [genetically engineered mouse model] to interrogate BRAF V600E [colorectal cancer] biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials.” Coffee EM, et al: Clin Cancer Res 19:2688-2698, 2013.

Effect of Radium-223 Dichloride in Breast Cancer Bone Metastasis Model Radium-223 dichloride (Xofigo) is an alpha particle–emitting radiotherapeutic drug that mimics calcium and localizes to areas of high bone turnover, providing targeted therapy for skeletal metastasis. The drug was recently approved for treatment of patients with castration-resistant prostate cancer, symptomatic

bone metastases, and no known visceral metastatic disease. Suominen and colleagues assessed effects of the drug in breast cancer cell, osteoclast, and osteoblast cultures and in a mouse model of breast cancer bone metastasis. A single dose of radium-223 dichloride was used in three different settings mimicking the prevention or treatment of bone metastasis. In culture, radium-223 dichloride incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P < .001). In the mouse model of established bone metastasis, the drug prevented tumor-induced cachexia (0/14 vs 7/14 control mice) and decreased osteolysis by 56% and tumor growth by 43% (all P < .05). Double-strand DNA breaks were observed in cancer cells in vivo. In the established bone metas-

tasis model, radium-223 dichloride extended survival as a monotherapy (29.2 days, P = .039) and in combination with zoledronic acid (31.4 days, P = .004) or doxorubicin (31.5 days, P < .001) compared with vehicle (24.9 days). Similar but more pronounced effects were observed when radium-223 dichloride was administered in a preventive or micrometastatic setting. The investigators concluded, “Our findings strongly support the development of radium-223 dichloride for the treatment of breast cancer patients with or at high risk of developing bone metastases.” n

Suominen MI, et al: J Natl Cancer Inst. May 16, 2013 (early release online). Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

To prevent SREs in patients with BREAST CANCER and bone metastases

vs zoledronic acid

Better prevent SREs1 MEDIAN TIME TO FIRST SRE IN BREAST CANCER1*

27 26.4 At

Months (study end)

median time not yet reached

Months

XGEVA® 120 mg Q4W (n = 1,026)

XGEVA® acts precisely to bind RANK Ligand, a key mediator of bone resorption, and inhibit osteoclast formation, function, and survival1

zoledronic acid 4 mg Q4W (n = 1,020)

HR = 0 0.82; 82; P = 0 0.010, 010 0 superiority

• XGEVA® reduced the risk of first SRE by 16% vs zoledronic acid in patients with other solid tumors or multiple myeloma (P < 0.001, noninferiority; P = 0.060, NS for superiority)1* XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma Convenient 120 mg subcutaneous injection administered once every 4 weeks1 Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia1 Approximately 70% of patients are expected to have $0 out-of-pocket cost for XGEVA®2† *Data from the international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046) and in patients with bone metastases from other solid tumors (excluding breast and prostate cancer) or multiple myeloma (N = 1,776). The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.1 † Estimated amount of Medicare beneficiaries with supplemental coverage and commercially insured patients with no OOP cost; based on XGEVA® payor mix and coverage of XGEVA® and other similar products. Does not include costs related to office visit, physician, staff, or administrative charges associated with administering XGEVA®.

INDICATION XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

IMPORTANT SAFETY INFORMATION Hypersensitivity • XGEVA® is contraindicated in patients with clinically signiﬁcant hypersensitivity to any component of the product.

Hypocalcemia • XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct preexisting hypocalcemia prior to XGEVA® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. • Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ) • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®.

• Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture • Atypical femoral fracture has been reported with XGEVA®. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents. A number of reports note that patients were also receiving treatment with glucocorticoids at the time of fracture. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Interruption of XGEVA® therapy should be considered, pending a risk/ beneﬁt assessment, on an individual basis.

Pregnancy • Women should be advised not to become pregnant when taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

Please see brief summary of Prescribing Information on the following page.

REFERENCES: 1. XGEVA® (denosumab) prescribing information, Amgen. 2. Data on ﬁle, Amgen.

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Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: Hypersensitivity. Xgeva is contraindicated in patients with clinically signiﬁcant hypersensitivity to any component of the product (see Adverse Reactions). WARNINGS AND PRECAUTIONS: Hypocalcemia. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva (see Adverse Reactions). These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis. PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth (see Use in Specific Populations). There are no adequate and well controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and beneﬁts in continuing or discontinuing treatment with Xgeva. Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other ﬁndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone a Table 1. Per-patient Incidence of Selected Adverse Reactions of Any Severity growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth (Trials 1, 2, and 3) malalignment; and decreased neonatal growth. At birth out to one month of age, infants Xgeva Zoledronic Acid had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and Body System n = 2841 n = 2836 strength returned to normal; there were no adverse effects on tooth eruption, though % % dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; GASTROINTESTINAL and minimal to moderate mineralization in multiple tissues was seen in one recovery Nausea 31 32 animal. There was no evidence of maternal harm prior to labor; adverse maternal Diarrhea 20 19 effects occurred infrequently during labor. Maternal mammary gland development was GENERAL normal. There was no fetal NOAEL (no observable adverse effect level) established for Fatigue/ Asthenia 45 46 this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis INVESTIGATIONS and led to postnatal impairment of dentition and bone growth. Pregnant RANKL 18 9 Hypocalcemiab knockout mice showed altered maturation of the maternal mammary gland, leading Hypophosphatemiab 32 20 to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in NEUROLOGICAL full Prescribing Information). Headache 13 14 Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, a decision should be made whether to discontinue nursing or discontinue the drug, 2, and 3, and meeting one of the following criteria: taking into account the importance of the drug to the mother. Maternal exposure • At least 1% greater incidence in Xgeva-treated patients, or to Xgeva during pregnancy may impair mammary gland development and lactation • Between-group difference (either direction) of less than 1% and more than based on animal studies in pregnant mice lacking the RANK/RANKL signaling 5% greater incidence in patients treated with zoledronic acid compared to pathway that have shown altered maturation of the maternal mammary gland, placebo (US Prescribing Information for zoledronic acid) leading to impaired lactation postpartum. However, in cynomolgus monkeys treated b with denosumab throughout pregnancy, maternal mammary gland development Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; (0.71 – 0.9 mmol/L) for phosphorus] however, development and lactation have not been fully evaluated (see Nonclinical Severe Mineral/Electrolyte Abnormalities Toxicology [13.2] in Full Prescribing Information). • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment of patients treated with zoledronic acid. Of patients who experienced severe with Xgeva may impair bone growth in children with open growth plates and hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) Use in Specific Populations). at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than eruption. Adolescent primates treated with denosumab at doses 5 and 25 times 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of (10 and 50 mg/kg dose) higher than the recommended human dose of patients treated with zoledronic acid. 120 mg administered once every 4 weeks, based on body weight (mg/kg), had Osteonecrosis of the Jaw abnormal growth plates, considered to be consistent with the pharmacological In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Warnings and Precautions). When events occurring during an extended treatment decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and phase of approximately 4 months in each trial are included, the incidence of mesenteric lymph nodes. Some bone abnormalities recovered once exposure was confirmed ONJ was 2.2% in patients who received Xgeva. The median time to ONJ ceased following birth; however, axillary and inguinal lymph nodes remained absent was 14 months (range: 4 – 25). 6 months post-birth (see Use in Pregnancy). Postmarketing Experience. Because postmarketing reactions are reported Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) voluntarily from a population of uncertain size, it is not always possible to reliably were 65 years of age or older. No overall differences in safety or efficacy were estimate their frequency or establish a causal relationship to drug exposure. observed between these patients and younger patients. The following adverse reactions have been identified during post approval use of Xgeva: Renal Impairment. In a trial of 55 patients without cancer and with varying • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. degrees of renal function who received a single dose of 60 mg denosumab, Immunogenicity. As with all therapeutic proteins, there is potential for patients with a creatinine clearance of less than 30 mL/min or receiving dialysis immunogenicity. Using an electrochemiluminescent bridging immunoassay, less were at greater risk of severe hypocalcemia with denosumab compared to than 1% (7/2758) of patients with osseous metastases treated with denosumab patients with normal renal function. The risk of hypocalcemia at the recommended doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to dosing schedule of 120 mg every 4 weeks has not been evaluated in patients 3 years tested positive for binding antibodies. No patient with positive binding with a creatinine clearance of less than 30 mL/min or receiving dialysis (see antibodies tested positive for neutralizing antibodies as assessed using a Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] chemiluminescent cell-based in vitro biological assay. There was no evidence of in full Prescribing Information). altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly OVERDOSAGE: There is no experience with overdosage of Xgeva. dependent on the sensitivity and specificity of the assay. Additionally, the observed HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. incidence of a positive antibody (including neutralizing antibody) test result may be Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. influenced by several factors, including assay methodology, sample handling, timing Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to of sample collection, concomitant medications, and underlying disease. For these temperatures above 25°C/77°F or direct light and must be used within 14 days. reasons, comparison of antibodies to denosumab with the incidence of antibodies Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted shaking of Xgeva.

RESPIRATORY Dyspnea Cough

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PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) • Persistent pain or slow healing of the mouth or jaw after dental surgery (see Warnings and Precautions) • Pregnancy or nursing (see Warnings and Precautions and Use in Specific Populations) Advise patients of the need for: • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva on ﬁndings in animals. In utero denosumab exposure in cynomolgus monkeys Advise patients that denosumab is also marketed as Prolia®. Patients should resulted in increased fetal loss, stillbirths, and postnatal mortality, along inform their healthcare provider if they are taking Prolia. with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva Amgen Manufacturing Limited, a subsidiary of Amgen Inc. in pregnant women. Women should be advised not to become pregnant when One Amgen Center Drive taking Xgeva. If this drug is used during pregnancy, or if the patient becomes Thousand Oaks, California 91320-1799 pregnant while taking this drug, the patient should be apprised of the potential ©2010-2013 Amgen Inc. All rights reserved. hazard to the fetus. Women who become pregnant during Xgeva treatment Printed in USA. 68257-R2-V2

with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There ADVERSE REACTIONS: The following adverse reactions are discussed below and was no evidence that various anticancer treatments affected denosumab systemic elsewhere in the labeling: exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 • Hypocalcemia (see Warnings and Precautions) months were not altered by concomitant chemotherapy and/or hormone therapy. The • Osteonecrosis of the Jaw (see Warnings and Precautions) median reduction in uNTx/Cr from baseline to month 3 was similar between patients The most common adverse reactions in patients receiving Xgeva (per-patient receiving concomitant chemotherapy and/or hormone therapy (see Clinical incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, Pharmacology [12.2] in full Prescribing Information). and nausea (see Table 1). The most common serious adverse reaction in patients USE IN SPECIFIC POPULATIONS: receiving Xgeva was dyspnea. The most common adverse reactions resulting in Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: discontinuation of Xgeva were osteonecrosis and hypocalcemia. Xgeva can cause fetal harm when administered to a pregnant woman based Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reﬂect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were

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Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-ﬁve percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-ﬁve percent of patients who received Xgeva received concomitant chemotherapy.

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Patient’s Corner

Driven by the Past

Diagnosed with ovarian cancer at age 9, I didn’t learn I had the disease, or the ramifications I would suffer as a result, until years later. By Hope Haefner, MD, as told to Jo Cavallo

hen I was 9 years old, a bout of nausea, vomiting, and abdominal pain sent me to the emergency room. The physicians diagnosed appendicitis and rushed me to the operating room. But what the surgeon found instead was a 10-cmwide, grade 2, immature teratoma. In 1968, treatment for malignant ovarian tumors typically involved total abdominal hysterectomy with bilateral salpingo-oophorectomy and massive doses of cobalt radiotherapy. Even with all this radical therapy, the doctors informed my parents that I would be dead within 6 months and that they should make me happy in the time I had left and not tell me that I had cancer. After 6 months passed and I remained well with no signs of recurrence, my parents decided that if I could stay cancer-free for 5 years, they would tell me then about my cancer diagnosis and be able to reassure me with some certainty that I was cured of the disease. Unfortunately, right before I reached the fifth-year mark, when I was 14, episodes of nausea, vomiting, and abdominal pain once again sent me to the emergency room. When the resident on duty asked about my having had my ovaries and uterus removed because of ovarian cancer, I told him he had me mixed up with another patient. When he assured me that he was reading the right medical chart, the news was devastating. A medication error, which sent me into cardiac arrest—and near death again—added to the horror and confusion I was feeling. The good news was that my symptoms

were the result of a bowel obstruction caused by scar tissue from my past surgeries and not a recurrence of my cancer.

in discussions of their cancer and treatment options.

Keeping Cancer a Secret

Raising Awareness of Childhood Gynecologic Cancers

After I was released from the hospital, my parents explained why they had kept their secret of my cancer diagnosis from me. I knew my parents meant well and had just wanted to protect me, but that didn’t stop me from feeling angry and resentful that I hadn’t been told the truth from the beginning. As I reached puberty, I had often wondered why I didn’t start menstru-

As an adolescent, I was never able to completely come to terms with my diagnosis and its cover-up, and by the time I was in my 20s, I was still having a difficult time accepting my being a cancer survivor and the aftereffects of infertility. However, that experience led me to a career in medicine, specializing in obstetrics and gynecology, and a deep desire to make a difference in the lives of

My parents were so concerned with getting me to that all-important 5-year survival benchmark, they didn’t realize the long-term impact their actions would have on my life. —Hope Haefner, MD

ating like my friends, but my parents would tell me not to worry. They were so concerned with getting me to that all-important 5-year benchmark, they didn’t realize the longterm impact their actions would have on my life. Today, the dialogue between physicians and their young patients is more open and honest. In my work as a physician at University of Michigan Health System, my colleagues and I routinely include children and adolescents along with their parents

children and adolescents with gynecologic cancers. It has also made me a more compassionate physician. As a cancer survivor, I have a better understanding of the fear and confusion patients face when given a cancer diagnosis. I will often ignore the brief time allotted to spend with patients and instead give them ample face-to-face contact so they can process their diagnosis. I’m also very involved in raising awareness of childhood gynecologic

cancers and in bringing the various medical disciplines—medical, surgical, radiation, and pediatric oncologists—together to treat cancers of the ovary, uterus, cervix, vagina, and vulva. Although the exact numbers of girls affected by childhood gynecologic cancers is unknown, according to the National Cancer Institute, ovarian cancer alone affects nearly 290 children in the United States under the age of 20.1

Coming to Terms with the Past Although I’ve been cancer-free for 46 years, I worry about the small potential for a soft-tissue sarcoma developing from all the cobalt radiation I had. But mostly I concentrate on the wonderful life I have. I’m happily married, and we adopted two terrific children to complete our family. I also have a profession I love that gives me the opportunity to work with other providers to help young patients with cancer participate in their treatment decisions, recovery, and survival. And in the process, I’ve finally made my peace with my own cancer history. n Reference 1. National Cancer Institute: Surveillance Epidemiology and End Results. SEER Stat Fact Sheets: Ovary. Available at http://seer.cancer.gov/statfacts/html/ ovary.html. Accessed May 23, 2013. Hope Haefner, MD, 55, is Professor in the Department of Obstetrics and Gynecology at the University of Michigan Health System in Ann Arbor, Michigan, and the Founder and Executive Director of the Childhood Gynecologic Cancer Association, cgynca.org.

Don’t Miss These Important Reports in This Issue of The ASCO Post Sarah-Jane Dawson, FRACP, PhD, on Circulating Tumor DNA in Breast Cancer see page 60

Janice Dutcher, MD, on AXIS Trial in RCC see page 77

Visit The ASCO Post online at ASCOPost.com

Kim A. Margolin, MD, on Immunotherapies in Melanoma see page 94

The ASCO Post | JULY 10, 2013

PAGE 100

Integrative Oncology Shiitake Mushroom

By Jyothirmai Gubili, MS Editor, Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center Scientific name: Lentinula edodes Common names: Forest mushroom, lentinula, pasania fungus, black mushroom, hua gu

the fresh and dried forms of the mushroom are a staple in East Asian cooking. Shiitake is considered a medicinal mushroom based on its use in tradi-

he use of dietary supplements by patients with cancer has increased significantly over the past 2 decades despite insufficient evidence of safety and effectiveness. Finding reliable sources of information about dietary supplements can be daunting. Patients typically rely on family, friends, and the Internet, often receiving misleading information. The ASCO Post’s Integrative Oncology series is intended to facilitate the availability of evidence-based information on integrative and complementary therapies commonly used by patients with cancer. We chose shiitake mushroom for this issue because its extracts are used increasingly by patients with cancer. Integrative Oncology is compiled by Barrie R. Cassileth, MS, PhD, and Jyothirmai Gubili, MS, Memorial Sloan-Kettering Cancer Center. The free About Herbs website is managed by K. Simon Yeung, PharmD, LAc, Memorial Sloan-Kettering Cancer Center.

Overview

Shiitake, an edible mushroom indigenous to East Asia, is cultivated worldwide for its health benefits. Both

tional medicine. It is also valued as an anticancer agent. Lentinan, a polysaccharide isolated from shiitake, has been well studied and is thought responsible for the mushroom’s beneficial effects. An injectable form of lentinan is used for cancer treatment in some countries but has not been evaluated in large clinical trials. Shiitake is available in most supermarkets, in many restaurants and in Asian grocery stores.

The Science

Lentinan demonstrated anticancer effects in colon cancer cells in vitro,1 which may be due to suppression of cytochrome P450 1A enzymes that metabolize procarcinogens to their active form.2 Lentin, the protein com-

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, Barrie R. Cassileth, MS, PhD minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan-Kettering Cancer Center’s very first mobile application, was launched last fall. In the week following its release on September 21, the app was downloaded more than 6,300 times, making it #4 on the top new medical apps chart. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http:// itunes.apple.com/us/app/about-herbs/id554267162?mt=8. ponent of shiitake, showed antifungal and antiproliferative properties and suppressed the activity of human immunodeficiency virus–1 reverse transcriptase.3 Studies of shiitake extracts indicate antiproliferative,4 immunostimulatory,4 hepatoprotective,5 antimutagenic,6 and anticaries7 effects in vitro and in

OF NOTE Shiitake mushroom is a popular medicinal mushroom, but its efficacy as an oral anticancer agent is yet to be established.

mice. But a clinical trial failed to show efficacy of an oral shiitake extract in the treatment of prostate cancer.8 Nevertheless, small studies conducted in Japan using an oral formulation of superfine dispersed lentinan showed improved quality of life and survival in patients with hepatocellular carcinoma9 as well as gastric,10 colorectal,11 and pancreatic12 cancers. Larger trials are warranted.

Adverse Effects

Case Reports: Chronic hypersensitivity pneumonitis was observed in a patient with lung cancer following excontinued on page 102

Learn More About

Herbs, Botanicals, & Other Products Visit the About Herbs website at

www.mskcc.org/aboutherbs www.mskcc.

Leaders in antibody-drug conjugate development Extending the reach of our technology through collaboration Company AbbVie Agensys, a subsidiary of Astellas Pharma Bayer Celldex Therapeutics Daiichi Sankyo Genentech, a member of the Roche Group Genmab GlaxoSmithKline Millennium: The Takeda Oncology Company Pfizer Progenics Pharmaceuticals There are more than a dozen collaborator antibody-drug conjugates (ADCs) in clinical development using Seattle Genetics’ technology, including 8 from Genentech.

Empowering antibodies by linking precision with potency Seattle Genetics has developed proprietary, industry-leading technology that employs a monoclonal antibody specific for a tumor-associated antigen, plus potent cytotoxic agents connected by stable linker systems designed to securely bind the cytotoxic agent to the antibody and then release the agent within the targeted cell.

Cytotoxic agent Designed to kill target cells when internalized and released.1,2

Linker Antibody Specific for a tumorassociated antigen that has restricted expression on normal cells.1,2

Attaches the cytotoxic agent to the antibody. Seattle Genetics’ linker system is designed to be stable in circulation and release the cytotoxic agent inside targeted cells.1-3

In addition to licensing its ADC technology, Seattle Genetics is developing 7 proprietary ADCs. The company’s robust pipeline of empowered antibody-based therapies and one approved ADC are designed to address significant unmet medical needs.

For more information about our ADC technology and to download an educational slide deck, please visit seattlegenetics.com/technology. REFERENCES: 1. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3):154-169. 2. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235-244. 3. Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the treatment of non–Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6):2358-2364.

The ASCO Post | JULY 10, 2013

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Integrative Oncology Shiitake Mushrooms continued from page 100

posure to shiitake spores.13 Prolonged consumption of shiitake mushrooms resulted in dermatitis,14 photosensitivity,15 eosinophilia, and gastrointestinal upset.16 Food allergy, manifested as esophageal symptoms, was reported following consumption of shiitake mushroom.17 n References 1. Ng ML, Yap AT: Inhibition of human colon carcinoma development by lentinan from shiitake mushrooms (Lentinus edodes). J Altern Complement Med 8:581-589, 2002. 2. Okamoto T, Kodoi R, Nonaka Y,

et al: Lentinan from shiitake mushroom (Lentinus edodes) suppresses expression of cytochrome P450 1A subfamily in the mouse liver. Biofactors 21:407-409, 2004. 3. Ngai PH, Ng TB: Lentin, a novel and potent antifungal protein from shitake mushroom with inhibitory effects on activity of human immunodeficiency virus-1 reverse transcriptase and proliferation of leukemia cells. Life Sci 73:3363-3374, 2003. 4. Israilides C, Kletsas D, Arapoglou D, et al: In vitro cytostatic and immunomodulatory properties of the medicinal mushroom Lentinula edodes. Phytomedicine 15:512-519, 2008. 5. Akamatsu S, Watanabe A, Tamesada M, et al: Hepatoprotective effect of

extracts from Lentinus edodes mycelia on dimethylnitrosamine-induced liver injury. Biol Pharm Bull 27:1957-1960, 2004. 6. de Lima PL, Delmanto RD, Sugui MM, et al: Letinula edodes (Berk.) Pegler (Shiitake) modulates genotoxic and mutagenic effects induced by alkylating agents in vivo. Mutat Res 496:23-32, 2001. 7. Shouji N, Takada K, Fukushima K, et al: Anticaries effect of a component from shiitake (an edible mushroom). Caries Res 34:94-98, 2000. 8. deVere White RW, Hackman RM, et al: Effects of a mushroom mycelium extract on the treatment of prostate cancer. Urology 60:640-644, 2002. 9. Isoda N, Eguchi Y, Nukaya H, et al: Clinical efficacy of superfine dispersed

Memorial Sloan-Kettering Cancer Center’s Integrative Medicine Service seeks a board-certified Internist or Medical Oncologist with background or substantive interest in Integrative Medicine. This full-time academic position includes clinical activities, research and education. Our > 60 person Integrative Medicine team provides inpatient and outpatient complementary therapies; our faculty provides integrative medicine patient consultation and conducts research with Services and departments throughout the institution. Our program serves as an international prototype. This is a full-time faculty position; salary and rank are commensurate with experience. MSKCC is an equal opportunity and affirmative action employer committed to diversity and inclusion in all aspects of recruiting and employment. All qualified individuals are encouraged to apply. For further information, or to apply, please send a letter of interest, the names of 3 references and curriculum vitae to Dr. Barrie Cassileth, Chief, Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, 1429 1st Avenue, New York, NY 10021 or e-mail: Cassileth@MSKCC.org.

lentinan (beta-1,3-glucan) in patients with hepatocellular carcinoma. Hepatogastroenterology 56:437-41, 2009. 10. Oba K, Kobayashi M, Matsui T, et al: Individual patient based meta-analysis of lentinan for unresectable/recurrent gastric cancer. Anticancer Res 29:2739-2745, 2009. 11. Hazama S, Watanabe S, Ohashi M, et al: Efficacy of orally administered superfine dispersed lentinan (beta-1,3-glucan) for the treatment of advanced colorectal cancer. Anticancer Res 29:2611-2617, 2009. 12. Shimizu K, Watanabe S, Watanabe S, et al: Efficacy of oral administered superfine dispersed lentinan for advanced pancreatic cancer. Hepatogastroenterology 56:240-244, 2009. 13. Suzuki K, Tanaka H, Sugawara H, et al: Chronic hypersensitivity pneumonitis induced by Shiitake mushroom spores associated with lung cancer. Intern Med 40:1132-1135, 2001. 14. Garg S, Cockayne SE: Shiitake dermatitis diagnosed after 16 years! Arch Dermatol 144:1241-1242, 2008. 15. Hanada K, Hashimoto I: Flagellate mushroom (Shiitake) dermatitis and photosensitivity. Dermatology 197:255-257, 1998. 16. Levy AM, Kita H, Phillips SF, et al: Eosinophilia and gastrointestinal symptoms after ingestion of shiitake mushrooms. J Allergy Clin Immunol 101:613620, 1998. 17. Goikoetxea MJ, Fernández-Benítez M, Sanz ML: Food allergy to Shiitake (Lentinus edodes) manifested as oesophageal symptoms in a patient with probable eosinophilic oesophagitis. Allergol Immunopathol (Madr) 37:333-334, 2009.

Erratum

n the June 10 issue of The ASCO Post, the article, “Study Questions Routine Use of Imaging after Treatment for Diffuse Large B-cell Lymphoma,” includes an error in an Expert Point of View box featuring an interview with Andrew D. Zelenetz, MD, PhD. Dr. Zelenetz is quoted as saying that at his institution (Memorial Sloan-Kettering Cancer Center), “80% of [diffuse large B-cell lymphoma] relapses are detected by scans.” He actually said that “80% of relapses are detected clinically and 20% by scans.” We regret the error. A corrected version of the article can be found on ASCOPost.com. n

News and Views from the World of Clinical Oncology and Hematology

Visit The ASCO Post website at

www.ASCOPost.com

When hemoglobin falls...

Catch hemoglobin levels before they fall too far Reduce RBC transfusions and achieve a gradual and steady Hb rise with Aranesp

®1-4

• In untreated patients whose Hb fell below 10 g/dL, 1 in 3 required an RBC transfusion within 6 weeks.5* • Aranesp® significantly reduced the need for RBC transfusions by 48% compared to placebo.2,3† • Aranesp® can be synchronized with the majority of chemotherapy regimens, including Q3W.6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa ACC trials. Patients had baseline Hb ≥ 10 g/dL and decline to Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of patients with transfusions by Weeks 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Seventy-two percent of patients had lung cancer.5 †Data from a randomized, double-blind, placebo-controlled trial of 314 anemic (Hb ≤ 11 g/dL) patients with lung cancer receiving platinum-containing chemotherapy. Patients received once-weekly treatment with either Aranesp® (2.25 mcg/kg) or placebo, administered by subcutaneous injection, for up to 12 weeks. Per the pivotal trial protocol, doses were withheld if Hb exceeded 14 g/dL for women or 15 g/dL for men.2,3

Aranesp® (darbepoetin alfa) Indication Aranesp® is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

Limitations of Use: Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp® is not for use: • In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. • In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • As a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia.

References: 1. Vansteenkiste J, Hedenus M, Gascon P, et al. BMC Cancer. 2009;9:311. doi:10.1186/1471-2407-9-311. 2. Aranesp® (darbepoetin alfa) Prescribing Information, Amgen. 3. Vansteenkiste J, Pirker R, Massuti B, et al. J Natl Cancer Inst. 2002;94:1211-1220. 4. Canon JL, Vansteenkiste J, Bodoky G, et al. J Natl Cancer Inst. 2006;98:273-284. 5. Pirker R, Collins H, Legg J, et al. J Clin Oncol. 2011;29(suppl). Abstract e19637. 6. Data on file, Amgen; [Tandem Anti-cancer and Tumor Audit].

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799 www.amgen.com

RBC = red blood cell.

Hb = hemoglobin.

Q3W = once every three weeks.

Important Safety Information including Boxed WARNINGS for Aranesp® (darbepoetin alfa) WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, Aranesp® dose, or dosing strategy that does not increase these risks. • Use the lowest Aranesp® dose sufficient to reduce the need for red blood cell (RBC) transfusions. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. • Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/ or dispense Aranesp® to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions. • Use ESAs only for anemia from myelosuppressive chemotherapy. • ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • Discontinue following the completion of a chemotherapy course. • Aranesp® is contraindicated in patients with: − Uncontrolled hypertension − Pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs − Serious allergic reactions to Aranesp®

• In controlled clinical trials of patients with cancer, Aranesp® and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures. • Control hypertension prior to initiating and during treatment with Aranesp®. • For lack or loss of hemoglobin response to Aranesp®, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. • Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp®. − This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. − PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp® is not approved). − If severe anemia and low reticulocyte count develop during treatment with Aranesp®, withhold Aranesp® and evaluate patients for neutralizing antibodies to erythropoietin. − Permanently discontinue Aranesp® in patients who develop PRCA following treatment with Aranesp® or other erythropoietin protein drugs. Do not switch patients to other ESAs. • Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp®. Immediately and permanently discontinue Aranesp® if a serious allergic reaction occurs. • Adverse reactions (≥ 1%) in clinical studies in cancer patients receiving chemotherapy were abdominal pain, edema, and thrombovascular events. Please see Aranesp® brief summary of prescribing information, including Boxed WARNINGS, on the adjacent page. Visit Aranesp.com for more information.

BRIEF SUMMARY: Consult package insert for complete prescribing information. Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *O DPOUSPMMFE USJBMT QBUJFOUT FYQFSJFODFE HSFBUFS SJTLT GPS EFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJT TUJNVMBUJOH BHFOUT &4"T UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM "SBOFTQ EPTF PS EPTJOH TUSBUFHZ UIBU EPFT OPU JODSFBTF UIFTF SJTLT t 6TF UIF MPXFTU "SBOFTQ EPTF TVGmDJFOU UP SFEVDF UIF OFFE GPS SFE CMPPE cell (RBC) transfusions. Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOE PS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU OPO TNBMM DFMM MVOH IFBE BOE OFDL MZNQIPJE BOE DFSWJDBM DBODFST t #FDBVTF PG UIFTF SJTLT QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS 5P FOSPMM JO UIF &4" "113*4& 0ODPMPHZ 1SPHSBN WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF t 5P EFDSFBTF UIFTF SJTLT BT XFMM BT UIF SJTL PG TFSJPVT DBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF &4"T POMZ GPS BOFNJB GSPN NZFMPTVQQSFTTJWF DIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF BOUJDJQBUFE PVUDPNF JT DVSF t %JTDPOUJOVF GPMMPXJOH UIF DPNQMFUJPO PG B DIFNPUIFSBQZ DPVSTF

INDICATION AND USAGE "OFNJB %VF UP $IFNPUIFSBQZ JO 1BUJFOUT 8JUI $BODFS Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp is not indicated for use: t *O QBUJFOUT XJUI DBODFS SFDFJWJOH IPSNPOBM BHFOUT CJPMPHJD QSPEVDUT or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *O QBUJFOUT XJUI DBODFS SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF anticipated outcome is cure. t "T B TVCTUJUVUF GPS 3#$ USBOTGVTJPOT JO QBUJFOUT XIP SFRVJSF JNNFEJBUF correction of anemia.

CONTRAINDICATIONS

Aranesp is contraindicated in patients with: t 6ODPOUSPMMFE IZQFSUFOTJPO t 1VSF SFE DFMM BQMBTJB 13$" UIBU CFHJOT BGUFS USFBUNFOU XJUI "SBOFTQ PS PUIFS erythropoietin protein drugs. t 4FSJPVT BMMFSHJD SFBDUJPOT UP "SBOFTQ

WARNINGS AND PRECAUTIONS *ODSFBTFE .PSUBMJUZ .ZPDBSEJBM *OGBSDUJPO 4USPLF BOE 5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT H E- UP MPXFS UBSHFUT H E- "SBOFTQ BOE PUIFS &4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. 6TJOH "SBOFTQ UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- JODSFBTFT UIF SJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBM CFOFmU 6TF DBVUJPO JO QBUJFOUT XJUI DPFYJTUFOU DBSEJPWBTDVMBS EJTFBTF BOE TUSPLF 1BUJFOUT XJUI $,% BOE BO JOTVGmDJFOU IFNPHMPCJO SFTQPOTF UP &4" UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT " SBUF PG IFNPHMPCJO SJTF PG HSFBUFS UIBO H E- PWFS XFFLT NBZ DPOUSJCVUF to these risks. * O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI DBODFS "SBOFTQ BOE PUIFS &4"T increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. *O DPOUSPMMFE DMJOJDBM USJBMT &4"T JODSFBTFE UIF SJTL PG EFBUI JO QBUJFOUT VOEFSHPJOH DPSPOBSZ BSUFSZ CZQBTT HSBGU TVSHFSZ $"#( BOE UIF SJTL PG EFFQ WFOPVT UISPNCPTJT %75 JO QBUJFOUT VOEFSHPJOH PSUIPQFEJD QSPDFEVSFT 1BUJFOUT XJUI $BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFE JO QBUJFOUT XJUI DBODFS USFBUFE XJUI &4"T *O B SBOEPNJ[FE QMBDFCP DPOUSPMMFE TUVEZ TFF 4UVEZ JO 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO PG XPNFO XJUI NFUBTUBUJD CSFBTU DBODFS SFDFJWJOH DIFNPUIFSBQZ patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered UP QSFWFOU BOFNJB NBJOUBJO IFNPHMPCJO MFWFMT CFUXFFO BOE H E- PS IFNBUPDSJU CFUXFFO BOE 5IJT TUVEZ XBT UFSNJOBUFE QSFNBUVSFMZ XIFO JOUFSJN SFTVMUT EFNPOTUSBUFE B IJHIFS NPSUBMJUZ BU NPOUIT WT BOE B IJHIFS SBUF PG GBUBM UISPNCPUJD SFBDUJPOT WT JO UIF mSTU NPOUIT PG UIF TUVEZ BNPOH QBUJFOUT USFBUFE XJUI FQPFUJO BMGB #BTFE PO ,BQMBO .FJFS FTUJNBUFT BU UIF UJNF PG TUVEZ UFSNJOBUJPO UIF NPOUI TVSWJWBM XBT MPXFS JO UIF FQPFUJO BMGB HSPVQ UIBO JO UIF QMBDFCP HSPVQ WT )3 $* Q 1SFTDSJCJOH BOE %JTUSJCVUJPO 1SPHSBN GPS "SBOFTQ JO 1BUJFOUT 8JUI $BODFS *O PSEFS UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS BOE BOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN SFRVJSFNFOUT 5P FOSPMM WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF "EEJUJPOBMMZ QSJPS UP each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.

*ODSFBTFE .PSUBMJUZ BOE PS *ODSFBTFE 3JTL PG 5VNPS 1SPHSFTTJPO PS 3FDVSSFODF JO 1BUJFOUT 8JUI $BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPM QSPHSFTTJPO GSFF TVSWJWBM BOE PS PWFSBMM TVSWJWBM 4FF 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO 5IFTF mOEJOHT XFSF observed in studies of patients with advanced head and neck cancer receiving SBEJBUJPO UIFSBQZ 4UVEJFT BOE JO QBUJFOUT SFDFJWJOH DIFNPUIFSBQZ GPS NFUBTUBUJD CSFBTU DBODFS 4UVEZ PS MZNQIPJE NBMJHOBODZ 4UVEZ BOE JO QBUJFOUT XJUI OPO small cell lung cancer or various malignancies who were not receiving chemotherapy PS SBEJPUIFSBQZ 4UVEJFT BOE Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT BQQSPYJNBUFMZ PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWF FODFQIBMPQBUIZ BOE TFJ[VSFT IBWF CFFO SFQPSUFE JO QBUJFOUT XJUI $,% receiving Aranesp. Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ 3FEVDF PS XJUIIPME "SBOFTQ JG CMPPE QSFTTVSF CFDPNFT EJGmDVMU UP DPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Seizures "SBOFTQ JODSFBTFT UIF SJTL PG TFJ[VSFT JO QBUJFOUT XJUI $,% %VSJOH UIF mSTU TFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFX POTFU TFJ[VSFT QSFNPOJUPSZ TZNQUPNT PS DIBOHF JO TFJ[VSF GSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST F H JSPO EFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *G UZQJDBM DBVTFT PG MBDL PS MPTT PG IFNPHMPCJO SFTQPOTF BSF FYDMVEFE FWBMVBUF GPS 13$" *O UIF BCTFODF PG 13$" GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy. Pure Red Cell Aplasia $BTFT PG 13$" BOE PG TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT UIBU BSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in QBUJFOUT XJUI $,% SFDFJWJOH &4"T CZ TVCDVUBOFPVT BENJOJTUSBUJPO 13$" IBT BMTP CFFO SFQPSUFE JO QBUJFOUT SFDFJWJOH &4"T GPS BOFNJB SFMBUFE UP IFQBUJUJT $ USFBUNFOU BO JOEJDBUJPO GPS XIJDI "SBOFTQ JT OPU BQQSPWFE *G TFWFSF BOFNJB BOE MPX SFUJDVMPDZUF DPVOU EFWFMPQ EVSJOH USFBUNFOU XJUI "SBOFTQ XJUIIPME "SBOFTQ BOE FWBMVBUF QBUJFOUT GPS OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO $POUBDU "NHFO ".(&/ UP QFSGPSN BTTBZT GPS CJOEJOH BOE OFVUSBMJ[JOH BOUJCPEJFT 1FSNBOFOUMZ EJTDPOUJOVF "SBOFTQ JO QBUJFOUT XIP EFWFMPQ 13$" GPMMPXJOH USFBUNFOU XJUI "SBOFTQ PS PUIFS FSZUISPQPJFUJO QSPUFJO ESVHT %P OPU TXJUDI QBUJFOUT UP PUIFS &4"T Serious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT JODMVEJOH BOBQIZMBDUJD SFBDUJPOT BOHJPFEFNB CSPODIPTQBTN TLJO SBTI BOE VSUJDBSJB NBZ PDDVS XJUI "SBOFTQ *NNFEJBUFMZ BOE permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs. Dialysis Management 1BUJFOUT NBZ SFRVJSF BEKVTUNFOUT JO UIFJS EJBMZTJT QSFTDSJQUJPOT BGUFS JOJUJBUJPO PG "SBOFTQ 1BUJFOUT SFDFJWJOH "SBOFTQ NBZ SFRVJSF JODSFBTFE BOUJDPBHVMBUJPO XJUI IFQBSJO UP QSFWFOU DMPUUJOH PG UIF FYUSBDPSQPSFBM DJSDVJU EVSJOH IFNPEJBMZTJT Laboratory Monitoring &WBMVBUF USBOTGFSSJO TBUVSBUJPO BOE TFSVN GFSSJUJO QSJPS UP BOE EVSJOH "SBOFTQ treatment. Administer supplemental iron therapy when serum ferritin is less than NDH - PS XIFO TFSVN USBOTGFSSJO TBUVSBUJPO JT MFTT UIBO 5IF NBKPSJUZ PG QBUJFOUT XJUI $,% XJMM SFRVJSF TVQQMFNFOUBM JSPO EVSJOH UIF DPVSTF PG &4" UIFSBQZ 'PMMPXJOH JOJUJBUJPO PG UIFSBQZ BOE BGUFS FBDI EPTF BEKVTUNFOU NPOJUPS IFNPHMPCJO XFFLMZ VOUJM UIF IFNPHMPCJO JT TUBCMF BOE TVGmDJFOU UP NJOJNJ[F UIF OFFE GPS 3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM 5SJBM &YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UP SBUFT JO UIF DMJOJDBM USJBMT PG PUIFS ESVHT BOE NBZ OPU SFnFDU UIF SBUFT PCTFSWFE in practice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tudy Adverse Reaction 5ISPNCPFNCPMJD "EWFSTF 3FBDUJPOT O

Arterial .ZPDBSEJBM JOGBSDUJPO 7FOPVT 1VMNPOBSZ FNCPMJTN $FSFCSPWBTDVMBS EJTPSEFST

"MM 1MBDFCP controlled Studies

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DRUG INTERACTIONS

/P GPSNBM ESVH JOUFSBDUJPO TUVEJFT IBWF CFFO DPOEVDUFE XJUI "SBOFTQ

USE IN SPECIFIC POPULATIONS Pregnancy 1SFHOBODZ $BUFHPSZ $ There are no adequate and well-controlled studies of Aranesp use in pregnant women. *O BOJNBM SFQSPEVDUJPO BOE EFWFMPQNFOUBM UPYJDJUZ TUVEJFT "SBOFTQ JODSFBTFE FBSMZ QPTU JNQMBOUBUJPO MPTT 6TF "SBOFTQ EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFmU KVTUJmFT UIF QPUFOUJBM SJTL UP UIF GFUVT 8IFO "SBOFTQ XBT BENJOJTUFSFE JOUSBWFOPVTMZ to healthy pregnant rats and rabbits, there was no evidence of embryofetal UPYJDJUZ PS PUIFS BEWFSTF PVUDPNFT BU UIF JOUSBWFOPVT EPTFT UFTUFE VQ UP NDH LH EBZ 5IJT BOJNBM EPTF MFWFM PG NDH LH EBZ JT BQQSPYJNBUFMZ GPME IJHIFS UIBO UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF EFQFOEJOH PO UIF QBUJFOU T USFBUNFOU JOEJDBUJPO 4MJHIUMZ SFEVDFE GFUBM XFJHIUT XFSF PCTFSWFE XIFO IFBMUIZ SBU BOE SBCCJU NPUIFST SFDFJWFE EPTFT PG NDH LH PS NPSF 5IJT EPTF PG NDH LH JT OFBS UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF 8IJMF OP BEWFSTF FGGFDUT on uterine implantation occurred in animals, there was an increase in early postJNQMBOUBUJPO MPTT JO BOJNBM GFSUJMJUZ TUVEJFT *U JT OPU DMFBS XIFUIFS UIF JODSFBTFE QPTU JNQMBOUBUJPO MPTT SFnFDUT B ESVH FGGFDU PO UIF VUFSJOF FOWJSPONFOU PS PO UIF DPODFQUVT /P TJHOJmDBOU QMBDFOUBM USBOTGFS PG "SBOFTQ XBT EFUFDUFE *O B QFSJ QPTUOBUBM EFWFMPQNFOU TUVEZ QSFHOBOU GFNBMF SBUT SFDFJWFE "SBOFTQ intravenously every other day from implantation throughout pregnancy and MBDUBUJPO 5IF MPXFTU EPTF UFTUFE NDH LH EJE OPU DBVTF GFUBM UPYJDJUZ UIJT EPTF JT BQQSPYJNBUFMZ FRVJWBMFOU UP UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF "U NBUFSOBM EPTFT PG NDH LH BOE IJHIFS QVQT IBE EFDSFBTFE GFUBM CPEZ XFJHIUT which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. 8PNFO XIP CFDPNF QSFHOBOU EVSJOH "SBOFTQ USFBUNFOU BSF FODPVSBHFE UP FOSPMM JO "NHFO T 1SFHOBODZ 4VSWFJMMBODF 1SPHSBN 1BUJFOUT PS UIFJS QIZTJDJBOT TIPVME DBMM ".(&/ UP FOSPMM /VSTJOH .PUIFST *U JT OPU LOPXO XIFUIFS "SBOFTQ JT FYDSFUFE JO IVNBO NJML #FDBVTF NBOZ ESVHT BSF FYDSFUFE JO IVNBO NJML DBVUJPO TIPVME CF FYFSDJTFE XIFO "SBOFTQ JT BENJOJTUFSFE to a nursing woman. Pediatric Use The safety and efямБcacy of Aranesp in pediatric cancer patients have not been established. Geriatric Use 0G UIF QBUJFOUT XJUI $,% JO DMJOJDBM TUVEJFT PG "SBOFTQ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS 0G UIF QBUJFOUT JO DMJOJDBM TUVEJFT SFDFJWJOH "SBOFTQ BOE DPODPNJUBOU DBODFS DIFNPUIFSBQZ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS /P EJGGFSFODFT JO TBGFUZ PS FGmDBDZ XFSF PCTFSWFE between older and younger patients.

OVERDOSAGE

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Manufactured by: "NHFO .BOVGBDUVSJOH -JNJUFE B TVCTJEJBSZ PG "NHFO *OD 0OF "NHFO $FOUFS %SJWF 5IPVTBOE 0BLT $" This product, the process of its manufacture, or its use, may be covered by one or NPSF 6 4 1BUFOUT JODMVEJOH 6 4 1BUFOU /P ┬к "NHFO *OD "MM SJHIUT SFTFSWFE 3 7

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Patient’s Corner

Not Surrendering to Cancer continued from page 1

die. For 1 year prior, I first felt a painful, palpable hard mass in my left breast, I couldn’t get a doctor to take my suspicions seriously and biopsy the tumor. Every doctor I saw insisted I was too young to have breast cancer. Finally, a surgeon I knew agreed to biopsy the mass, and the pathology report showed it was malignant. The diagnosis changed the course of my life. I left college, where I was studying medical sociology, and underwent aggressive treatment to cure my cancer, including a regimen of CMF (cyclophosphamide, methotrexate, and fluorouracil), and a lumpectomy, followed by radiation. I also founded Vital Options, the first advocacy organization for young adults with cancer. In 1999, when BRCA1/2 mutation testing was still investigational, my father, older sister, and I were screened, and both my sister and I tested positive. We repeated the test again after it became available for clinical use. The miracle of this story is that all four of my nieces are negative for the BRCA gene mutation. Since I don’t have children, this terrible genetic legacy that has plagued my family for generations has come to an end.

Palliative Care Is Transforming My Life Ten years ago—hoping to escape my genetic fate, and in celebration of being cancer-free for 20 years—I decided to have a prophylactic oophorectomy. Although the decision was a difficult one,

I wanted to reaffirm my life and be as proactive as I could to stay healthy. But when I awoke from the surgery, I was told that I already had confined, very early-stage ovarian cancer. I was treated with carboplatin and paclitaxel, and we all expected a good outcome. Unfortunately, multiple lo-

Palliative care connects the physical and psychosocial dots around the whole patient. It has transformed the quality of my life and enhances the active clinical treatment I receive from my oncologist. —Selma R. Schimmel

calized lesions have appeared over the years, requiring various therapeutic approaches, including an experimental protocol with a PARP inhibitor. Despite these efforts, last year the cancer spread to my lungs. Although those lesions responded quickly to treatment, a mass in my psoas muscle and near my bowel caused me so much pain, I was referred to a palliative care specialist for pain management. The experience has given me a good deal more than just pain relief. I now recognize in a very personal way the great value palliative care brings to the continuum of cancer care. Palliative care connects the physical and psychosocial dots around the whole patient. It has transformed the quality of my life and enhances the active clinical treat-

More on Palliative Care from Selma Schimmel

ment I receive from my oncologist. While I know that I will most likely follow in the footsteps of my grandmother and mother and never see old age, I’m not giving up. I am also finding new meaning and purpose in this phase of my cancer journey. I’m currently on a regimen of oral cyclophosphamide

t the 2013 ASCO Annual Meeting, Selma Schimmel conducted a series of interviews with prominent oncologists, to get their perspectives on palliative care. These discussions can be viewed via The Group Room website here: http://thegrouproom.tv/category/cancer-topics/palliative-care/ All Vital Options interviews are available upon request (without charge) for posting or educational purposes. n

and infusions of bevacizumab (Avastin), and I’m pleased that early indications suggest the combination may be slowing the spread of cancer.

Going Public The transition to palliative care has made all the difference in my ability to maintain my fast-paced career and continue to function at a high level in all areas of my life. For the first time in 30 years, cancer is almost incidental to my care. Now, the quality of my life is paramount. I decided to go public with my ovarian cancer recurrence because I felt an obligation to help other cancer survivors as well as physicians understand that the transition to palliative care does not mean surrender. My experience is proof that patients can live with advanced disease and still be a vital force, maintaining control of their lives. I think many people associate palliative care with end-of-life hospice care, and that misperception needs to change. The best way to do that is by introducing the subject of palliative care into standard cancer care earlier on—soon after the initial diagnosis— and certainly by integrating the two

practices as soon as a patient is diagnosed with metastatic disease. In addition to my first-hand experience with the benefits of palliative care, I’ve also become educated about the importance of increasing the understanding and use of palliative care through the work I do as a member of C-Change, an organization dedicated to eliminating cancer as a major public health problem, and its National Conversation Subcommittee of the Assuring Value in Cancer Care Advisory Committee, a collaborative effort by ASCO and CChange. Our efforts are focused on stimulating a national dialogue about palliative and hospice care. Through this work and my activities with Vital Options, I realize what a wonderful opportunity I have to be the messenger to both patients and physicians about the importance of demystifying palliative care by incorporating it into the medical oncology discussion. With routinely accessible palliative care, all of the patient’s needs—physical, emotional, practical, and spiritual—can be met.

Living a Full Life Coming to terms with having metastatic disease is difficult, and while I am fortunate to still be able to receive beneficial treatment with the possibility of a longer life, I must also be realistic: My disease may one day lead to that transition from palliative care to hospice care. But I’m not there yet. Although I can’t control the progress of my cancer, I can control how I choose to cope with the seriousness of my situation. My work has given my life meaning, and I am grateful to have the opportunity to tell my story and, hopefully, educate both survivors and oncologists about the possibilities of living a full life with advanced cancer. Everything that happens to me now is a gift. n

ASCO Meetings 2013 Best of ASCO Chicago Meeting

boa.asco.org

August 9–10, 2013 | Chicago, Illinois

2013 Best of ASCO Los Angeles Meeting

boa.asco.org

August 16–17, 2013 | Los Angeles, California

2013 Best of ASCO Boston Meeting

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August 23–24, 2013 | Boston, Massachusetts

2013 Breast Cancer Symposium

breastcasym.org

Saturday, September 7–Monday, September 9, 2013 | San Francisco, California

Cosponsored with: American Society of Breast Disease, American Society of Breast Surgeons, American Society for Radiation Oncology, National Consortium of Breast Centers, Inc., and Society of Surgical Oncology

ASCO’s Quality Care Symposium

quality.asco.org

November 1–2, 2013 | San Diego, California

Markers in Cancer 2013

markersincancer.eu

A Joint Meeting by by ASCO, EORTC, and NCI November 7–9, 2013 | Brussels, Belgium

(with Diagnostic Development Tutorial on November 5-7, 2013)

2014 Gastrointestinal Cancers Symposium

gicasym.org

January 16–18, 2014 | San Francisco, California

Cosponsored with: American Gastroenterological Association Institute, American Society for Radiation Oncology, and Society of Surgical Oncology

Celebrating Ten Years

2014 Genitourinary Cancers Symposium

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January 30–February 1, 2014 | San Francisco, California

Cosponsored with: American Society for Radiation Oncology and Society of Urologic Oncology

2014 ASCO Annual Meeting May 30–June 3, 2014 | Chicago, Illinois

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PAGE 109

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Survival Benefits of DCIS Management Strategies Compared Overall survival benefits of six management strategies for ductal carcinoma in situ (DCIS) are within 1 year of each other, according to a disease simulation model integrating empirical data from published literature and quantifying the tradeoffs among the different management strategies with respect to disease outcomes and breast preservation. The model simulates the clinical events for women with newly diagnosed DCIS after these six treatments: lumpectomy alone, lumpectomy with radiation, lumpectomy with radiation and tamoxifen, lumpectomy with tamoxifen, and mastectomy with and without breast reconstruction. “For a cohort of 1 million million simulated women aged 45 years at diagnosis, both mastectomy and lumpectomy with radiation and tamoxifen were associated with a 12-month improvement in overall survival relative to lumpectomy alone,” the investigators reported in the Journal of the National Cancer Institute. “Adding radiation therapy to lumpectomy resulted in a 6-month improvement in overall survival but decreased long-term breastpreservation outcomes (likelihood of lifetime breast preservation = 0.781 vs 0.843 for lumpectomy alone). This decrement with radiation therapy was mitigated by the addition of tamoxifen (likelihood of lifetime breast preservation = 0.846).”

Consistent with Previous Evidence The results were more pronounced for disease-free survival. Compared with lumpectomy alone, mastectomy yielded an additional 9.1 diseasefree years (either from DCIS or invasive cancer). “Both mastectomy and lumpectomy with radiation and tamoxifen yielded the greatest invasive disease-free survival, providing an additional 5 years without invasive breast cancer compared with lumpectomy,” the researchers wrote. The authors noted that their finding that the magnitude of overall survival benefits is within year is “consistent with the lack of difference observed in

the randomized trials of radiation for DCIS and with prior DCIS modeling efforts. The magnitude of benefit is a critical factor in determining which treatment choice is appropriate for an individual patient. However, this should be weighed against the consequences of treatment in terms of breast preservation,” the authors added. “Population-based analyses reveal large regional variation in treatment of DCIS,” the researchers noted in their conclusion. “This type of variation as opposed to selection of treatment according to patient preference is a marker of poor quality of care. Our delineation of personalized outcomes for each strategy can help patients understand the implications of their treatment choice, so their decisions may reflect their own personal values and help improve the quality of care for patients with DCIS,” they wrote.

Most Important Finding “Perhaps the greatest contribution of the study is its finding that survival after mastectomy is similar to that after lumpectomy, radiation, and tamoxifen for all three patient ages” (45, 60, and 70 years old). This opinion was voiced in an accompanying editorial that noted, “A randomized trial of mastectomy versus breast conservation for DCIS is extremely unlikely to be feasible. Therefore, it is useful to be able to refer to these model results to reassure patients that they do not have to sacrifice the native breast to maximize survival.” If the model developers truly want to realize their goal of having the model used as an aid in patient decision-making, “their next step should be to develop a user-friendly decision aid incorporating the findings of their model,” the editorial continued. “As clinicians, where we will find these results most useful is in counseling patients who believe that mastectomy is necessary to maximize survival. After many years of decreasing, some evidence suggests that mastectomy rates have again begun to rise. The current study may help to stem this concerning tide by providing reassuring evidence of the safety of breast conservation for patients with DCIS.”

Soeteman DI, et al: J Natl Cancer Inst 105:774–781, 2013. Jagsi R, Hayman J: J Natl Cancer Inst 105:758–759, 2013.

Cognitive Complaints after Breast Cancer Treatment and Neuropsychological Testing About one in five patients who had completed primary breast cancer treatments but had not started endocrine therapy “had elevated memory and/or executive function complaints that were statistically significantly associated with domain-specific” neuropsychological test performances and depressive symptoms. Combined chemotherapy and radiation treatment in these patients “was also statistically significantly associated with memory complaints.” These and other findings from a prospective cohort study of 189 women diagnosed with stage 0 to IIIA breast cancer were published in the Journal of the National Cancer Institute. The women were aged 21 to 65 years. “Most were white, married, college educated, and postmenopausal prior to their breast cancer diagnosis. Two-thirds received breast-conserving surgery; more than half had received chemotherapy; and three-quarters had received radiation therapy,” the researchers reported. Exclusion criteria included current or past disease of the central nervous system or a medical condition affecting cognitive function, as well as daily tobacco and alcohol use, and prior cancer diagnosis or chemotherapy treatment. Neuropsychological testing “was conducted by a trained technician, closely supervised by a licensed clinical neuropsychologist,” the investiga-

tors explained. Self-report questionnaires were used to assess cognitive complaints in four subscales: memory, higher-level cognition measuring executive function, language and communication, and motor-sensory perception.

Significant Associations The researchers found that 23.3% of patients had higher memory complaints and 19% reported higher executive function complaints than found in age-matched healthy women without breast cancer. “Regression modeling demonstrated a statistically significant association of higher memory complaints with combined chemotherapy and radiation treatments (P = .01), poorer [neuropsychological] verbal memory performance (P = .02), and higher depressive symptoms (P < .001), controlling for age and IQ,” the researchers reported. Higher memory complaints were not, however, statically significantly associated with chemotherapy alone. “For executive functioning complaints, multivariable modeling controlling for age, IQ, and other confounds demonstrated statistically significant associations with better [neuropsychological] visual memory performance (P = .03) and higher depressive symptoms (P < .001), whereas combined chemotherapy and radiation treatment (P = .05) approached statistical significance,” the investigators stated.

continued on page 110

The ASCO Post | JULY 10, 2013

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In the Literature

Emerging Clinical Data continued from page 109

Value of Patient-reported Outcomes “These results and other emerging studies suggest that subjective cognitive complaints in part reflect objective [neuropsychological] performance, although their etiology and biology appear to be multifactorial, motivating further transdisciplinary research,” the authors concluded. They also stated that their findings “add further support for the value of patient-reported outcomes as a central measurement in evaluation of cancer treatment-related morbidities.” An accompanying editorial pointed out the true incidence of cognitive symptoms in patients with breast cancer may be underestimated and that neurocognitive, emotional, and behavioral symptoms can interfere with academic, vocational, and social pursuits. “However, many cancer survivors can enjoy improved levels of functioning if properly diagnosed and provided with the right support,” the editorial continues. “Symptom assessment coupled with effective and proactive intervention strategies are a critical component throughout and after cancer treatment.”

Ganz PA, et al: J Natl Cancer Inst 105:791-801, 2013. Meyers CA: J Natl Cancer Inst 105:761762, 2013.

RENAL CELL CARCINOMA Using Quality Indicators Can Improve Outcomes among Patients with Renal Cell Carcinoma An expert panel of 13 urologic and medical oncologists worked together to identify 23 quality indicators for renal cell carcinoma, as described in an article in the Journal of Oncology Practice. “These 23 [quality indicators] will provide a means of evaluating the quality of [renal cell carcinoma] care in an effort to improve outcomes in patients. The next step will be to establish a means of measuring each [quality indicator] based on defined or yet-tobe-defined benchmarks,” the authors stated. The investigators used a modified Delphi technique to select quality indicators that they deemed relevant and practical to renal cell carcinoma care. “Delphi methodology is commonly used when sufficient evidence is available from which to derive indicators

but requires review and deliberation by experts,” they explained. The panel members were considered experts in the field of kidney cancer through their clinical work, research, and participation in the annual Canadian Kidney Forum. A literature search revealed 233 relevant citations. From these, 34 possible quality indicators were identified. Another 24 potential quality indicators were suggested by panel members during a three-round review process. The final set of 23 quality indicators was distributed across the disease spectrum of renal cell carcinoma. Examples include the proportions of patients undergoing appropriate risk-specific staging, with positive margins after partial nephrectomy, with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy, and with metastatic renal cell carcinoma referred to palliative care before death. “Our future research will define ideal rates of delivery and appropriate benchmarks,” the authors wrote. “Certain indicators are easily measured via administrative data. However, others will require different approaches such as medical record review or patient/ caregiver interview. Once benchmarks are established, periodic assessments can measure performance, and strategies can be implemented to improve domains of care in specific jurisdictions as needed. A parallel initiative that will enrich this exercise is the development of a national kidney cancer database (Canadian Kidney Cancer Information System), which has been activated at several centers with pointof-care data entry.” Wood L, et al: J Oncol Pract. June 4, 2013 (early release online).

PROSTATE CANCER Replacing Animal Fat with Vegetable Fat May Reduce Mortality Risk in Men with Nonmetastatic Disease “Among men with nonmetastatic prostate cancer, replacing carbohydrates and animal fat with vegetable fat may reduce the risk of all-cause mortality,” according to a prospective study of 4,577 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study. Vegetable fat intake after diagnosis of prostate cancer was also associated with a lower risk of lethal prostate cancer, defined as distant metastases or death

due to prostate cancer. “Replacing 10% of calories from carbohydrates with vegetable fat was associated with a 29% lower risk of lethal prostate cancer” (hazard ratio [HR] = 0.71; 95% confidence interval [CI] = 0.51–0.98; P = .04), the researchers reported. “The magnitude of the association was similar, but not statistically significant, when animal fat was replaced with vegetable fat” (HR = 0.76; 95% CI = 0.52–1.10; P = .14). The results were published online by JAMA Internal Medicine.

Study Design Men included in the analysis had to be free of cancer (except nonmelanoma skin cancer) when the study was initiated in 1986 and have a diagnosis of nonmetastatic prostate cancer between then and 2010. Study participants reported medical diagnoses, medication, weight, height, smoking, and physical activity at baseline and then every 2 years, and completed food frequency questionnaires at baseline and then every 4 years. The food frequency questionnaire “asked men to report their usual intake of approximately 130 foods and beverages during the previous year. In addition, they were asked to report fried food consumption, type of cooking fat, and whether visible fat on meat was consumed,” the investigators explained. At a median follow-up of 8.4 years, 315 events of lethal prostate cancer and 1,064 deaths occurred. “The primary causes of death were cardiovascular disease (31.2%), prostate cancer (21.3%), and other cancers (20.6%),” the researchers reported. “Crude rates of lethal prostate cancer (per 1,000 person years), comparing the highest and lowest quintiles for intake of each of the fats, were 7.6 vs 7.3 for saturated, 6.4 vs 7.2 for monounsaturated, 5.8 vs 8.2 for polyunsaturated, 8.7 vs 6.1 for trans, 8.3 vs 5.7 for animal, and 4.7 vs 8.7 for vegetable fat.” The rates of all-cause mortality were 28.4 vs 21.4 for saturated, 20.0 vs 23.7 for monounsaturated, 17.1 vs 29.4 for polyunsaturated, 32.4 vs 17.1 for trans, 32.0 vs 17.2 for animal, and 15.4 vs 32.7 for vegetable fat. “Red meat and poultry with skin were major sources of monounsaturated and polyunsaturated fat in our study population,” the authors reported, “and these foods are also sources of heme iron and heterocyclic amines, which may increase the risk of aggressive prostate cancer.” Among the top

food sources of vegetable fats in the study population were oils and nuts. “Consumption of these foods increases plasma antioxidants and reduces circulating insulin, low-density lipoprotein cholesterol, inflammatory markers, and markers of oxidative stress, all of which may affect prostate cancer progression,” the investigators noted.

Further Research Needed “Overall, our findings support counseling men with prostate cancer to follow a heart-healthy diet in which carbohydrate calories are replaced with unsaturated oils and nuts to reduce the risk of all-cause mortality,” the researchers concluded. “The potential benefit of vegetable fat for prostate cancer–specific outcomes merits further research.” In an invited commentary, Stephen J. Freedland, MD, of Duke University Medical Center, Durham, North Carolina, noted that “in the absence of randomized trial data, it is impossible to use these data as ‘proof ’ that vegetable intake lowers prostate cancer risk, and the authors have carefully avoided such statements.” Dr. Freedland continued, “When counseling patients, I remind them that obesity is the only known modifiable risk factor linked with prostate cancer mortality to date. Thus, avoiding obesity is essential. Exactly how this should be done remains unclear,” he wrote, although the study data “suggest that substituting healthy foods (ie, vegetable fats) for unhealthy foods (ie, carbohydrates) may have a benefit. Determining whether this benefit is due to reduced consumption of carbohydrates or greater intake of vegetables will require future prospective randomized trials,” he concluded. Richman EL, et al: JAMA Intern Med. June 10, 2013 (early release online). Freedland SJ: JAMA Intern Med. June 10, 2013 (early release online).

HODGKIN LYMPHOMA Plasma Epstein-Barr Virus DNA a Potential Marker for Treatment Response in Advanced Hodgkin Lymphoma Plasma Epstein-Barr Virus (EBV) DNA has prognostic significance in Hodgkin lymphoma, both prior to therapy and at 6 months of follow-up, accontinued on page 111

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PAGE 111

In Memoriam

MSKCC Community Mourns the Death of Trudy Nan Small, MD

Trudy Nan Small, MD

rudy Nan Small, MD, was a pediatric hematologist at Memorial Sloan-Kettering Cancer Center who specialized in the diagnosis and care of children undergoing hematopoietic stem cell transplan-

tation for hematologic malignanso as to most effectively stimulate sibling and half-matched parent-decies and those with life-threatening their newly transplanted immune sysrived marrow transplants to correct genetic disorders them. of the immune sysDr. Small re[Dr. Small’s] work provided evidence critical to the tem. She died on ceived her MD development of the National Centers for Disease June 14, 2013. degree from Dr. Small’s reSUNY Upstate Control and Prevention guidelines for vaccination of search focused on Medical Univerimmunocompromised transplant recipients the cellular interacsity and complettions that control ed residencies at recovery of the immune system after tems and protect patients from infecDuke University Medical Center and transplantation, and provided the first tions. the University of Minnesota. After evidence linking age-related changes Her work provided evidence criticompleting a fellowship at Memoin the human thymus with the decal to the development of the Nationrial Sloan-Kettering, she joined the layed restoration of cell-mediated imal Centers for Disease Control and faculty in 1987 and thereafter rose to munity observed in older adults after Prevention guidelines for vaccination its highest rank of full Member. She transplantation. She also conducted of immunocompromised transplant was also an Associate Professor of pioneering studies examining how recipients. She was also an authority Pediatrics at Weill Cornell Medical best to vaccinate patients after transon lethal genetic immune deficiencies College. plantation or other cancer treatments and the application of HLA-matched She will be deeply missed. n



In Memoriam: Trudy Nan Small, MD  Emerging Clinical Data continued from page 110

cording to results of a study published in Blood. “Plasma EBV-DNA positivity at month 6 is associated with particularly poor outcomes and may serve as an indicator of the need for further therapy,” the researchers concluded. Using specimens from a Cancer Cooperative Intergroup Hodgkin lymphoma treatment trial, investigators compared pretreatment plasma EBVDNA quantification with EBV tumor status as detected by in situ hybridization of viral nucleic acid in tumor cells. The clinical trial enrolled 794 eligible patients. Tumor specimens for microarray were available for 315 patients and pretreatment plasma specimens were available for 274 patients. The researchers chose the plasma cutoff of > 60 viral copies/100 μL for the failure-free survival analysis. This cutoff was used to designate plasma specimens as EBV-negative or EBVpositive. Patients with pretreatment EBV-positive plasma (n = 54) had inferior failure-free survival compared to those with pretreatment EBV-negative plasma (n = 274), log- rank P = .009. No difference in failure-free survival was observed when patients were stratified by

in situ hybridization of viral nucleic acid.

Further Analyses This discrepancy in failure-free survival outcomes led to further analyses and separate evaluations of each component of the International Prognostic Score, but plasma EBV-DNA remained an independent predictor of inferior failure-free survival. In multivariate analysis, pretreatment plasma EBV positivity was associated with inferior failure-free survival, with a hazard ratio of 2.0 (95% confidence interval = 1.2– 3.5, P = .01), .01), after after adjusting for International Prognostic Score, treatment arm, and histology, the researchers reported. Using plasma specimen obtained at 6 months after the initiation of therapy, the 3-year failure-free survival estimate for patients who were plasma EBVpositive at 6 months (n = 7) was 48% compared to 79% for patients who were plasma EBV-negative at 6 months (n = 125), log-rank P = .007, .007, the investigators stated. “The median [failure-free survival for patients who were plasma [EBV-positive] at month 6 was 1.3 years and has not yet been reached for patients who were plasma [EBV-negative]. Of note, a few of the patients who were plasma [EBV-positive] at month 6

were pre-treatment plasma [EBV-negative] and/or [negative by in situ hybridization of viral nucleic acid], with failure events not restricted to those known to be [EBV-positive] at baseline.”

Largest Study of Its Kind This study is “the largest prospective analysis of plasma EBV-DNA” reported in Hodgkin lymphoma patients and “the only such data from a randomized cooperative group trial,” according to the authors. “Plasma EBV-DNA assessment is an attractive potential marker in [Hodgkin lymphoma] given that blood collection is very feasible and the diagnostic technology is already available across clinical and research settings. Furthermore, as an alternative or adjunct, plasma EBVDNA monitoring may be informative in the posttreatment follow-up of patients with [Hodgkin lymphoma] as a low-risk, high sensitivity screen for relapsed disease,” the researchers wrote. “We would caution that the results presented here are limited to patients with histologically confirmed classical [Hodgkin lymphoma] with locally extensive or advanced stage disease. They may not be generalizable to early stage, favorable [Hodgkin lymphoma];

HIV-associated [Hodgkin lymphoma], [Hodgkin lymphoma] developing in the post-transplant setting, or other EBVrelated lymphomas. Nonetheless, in well-defined populations, pre-treatment plasma EBV-DNA may be useful as a surrogate for [in situ hybridization of viral nucleic acid] and should be considered a potential marker of disease status and treatment response in [Hodgkin lymphoma],” they commented. “If validated as prognostic, plasma EBV-DNA levels may facilitate conduct of clinical trials through use of the biomarker to stratify or enrich populations based on risk; as part of clinical care, patients might be better informed about treatment choices within a risk-benefit, patient-preference paradigm,” according to an accompanying observation. “Perhaps the most important role of plasma EBV-DNA levels will come with better understandings of the role of EBV in the pathogenesis of Hodgkin lymphoma and whether this varies across patients.” Kanakry JA, et al: Blood 121:35473553, 2013. Meyer RM: Blood 121: 3541-3542, 2013. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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