TAP Vol 4 Issue 2 by Harborside Press LLC

Cabozantinib in Thyroid Cancer

| Patient Expectations in Advanced Cancer

| Extending Tamoxifen Therapy

VOLUME 4, ISSUE 2

FEBRUARY 1, 2013

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

ASCOPost.com

Cost of Cancer Drugs: What Price for What Benefit?

ASH Annual Meeting

Survival Benefit Achieved with Four Drugs plus Maintenance in Myeloma By Caroline Helwick

n overall survival benefit in newly Four-drug Induction and Maintenance in Myeloma diagnosed multiple ■■ In patients not eligible for transplant, induction with bortezomib, myeloma was attained melphalan, prednisone, and thalidomide followed by 2 years of with a four-drug induction maintenance therapy with bortezomib and thalidomide was associated regimen followed by a duet with improvements in overall survival as well as progression-free survival. for maintenance in a study ■■ The regimen was compared to a three-drug induction regimen from the Italian GIMEMA (bortezomib, melphalan, and prednisone) and no maintenance. network. Antonio Palumbo, MD, Chief of ■■ Median progression-free survival was 35.3 vs 24.8 months (P < .0001). the Myeloma Unit at the Overall survival at 5 years was 61% vs 51% (P = .01). Median overall survival has not been reached in the experimental arm. University of Torino in Italy, reported the findings at the 2012 American The study compared what Dr. Palumbo called Society of Hematology (ASH) Annual Meeting.1 “What we see is that the preclinical synergy obthe “best experimental therapy” with the “best stanserved between bortezomib [Velcade] and an immudard of care.” The four-drug induction regimen was nodulatory drug may translate into clinical benefit,” VMPT (bortezomib, melphalan, prednisone, and continued on page 10 Dr. Palumbo said. JCO Spotlight

Patient Expectations of Benefit in Early-phase Trials: Ethics Issues in Informed Consent By Matthew Stenger

t has been found that many patients in early-phase oncology trials believe their chance of benefit to be much higher than estimates derived from historical data.1-3 In a recently reported study in Journal of Clinical Oncology, Kevin P. Weinfurt, PhD, of Duke Clinical Research Institute, and colleagues attempted to discern whether patients’ expectations differed according to how questions about expected benefit were asked during the process of obtaining informed consent.4

Study Details

Of 213 patients enrolled in phase�� I or II trials in three U.S. tertiary care centers who were invited to participate in the study, 171 (80%) agreed. These 171 patients See Page 61 were randomly assigned to one of three groups corresponding to three queries about expectations: “frequency type,” “belief type,” or both. A frequency-type probability refers to Instead of trying to dissuade relative frequency of an event in a given populapatients from expressing hope or tion—eg, “On average, positive attitude, we might work with 5 of every 100 patients them to make sure they are planning will have a response to experimental treatment.” for all possible outcomes. A belief-type probability Kevin P. Weinfurt, PhD refers to an individual’s

By Hagop M. Kantarjian, MD, and Leonard Zwelling, MD, MBA

n 2011, national health-care spending in the United States was about $2.7 trillion, larger than the entire French national budget.1 U.S. national health-care spending is about 17% of the national gross domestic product. Total Medicare expenditures in 2011 were $549 million.2 In the debate about health care and Medicare solvency, strategies to reduce health-care costs without compromising treatment efficacy and patient safety should be explored. With all the new targeted therapies in cancer hitting the market at prices exceeding $120,000 per year, this area is becoming a fast-growing economic concern in health care.

Recent Trends Compared to a decade ago, the price range of new anticancer agents has more than doucontinued on page 33

Dr. Kantarjian is Professor in the Department of Leukemia, and Dr. Zwelling is Professor in the Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston.

MORE IN THIS ISSUE Oncology Meetings Coverage San Antonio Breast Cancer Symposium �� 3, 4, 13 ASH Annual Meeting �� 5, 12, 18 FDA Update �� 14-17 Postoperative Radiation in Prostate Cancer �� 24 Direct from ASCO �� 29-32 Pioneers in Oncology: James F. Holland, MD ��52 Letters to the Editor �� 66

continued on page 38

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The ASCO Post | FEBRUARY 1, 2013

PAGE 2

News Thoracic Oncology

ACS Releases Lung Cancer Screening Guidelines

Editorial Board

By Ronald Piana

James O. Armitage, MD Editor-in-Chief

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

Associate Editors Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

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

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Douglas W. Blayney, MD Stanford University Medical Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Philip D. Bonomi, MD Rush University Medical Center

George W. Sledge, MD Indiana University

Richard Boxer, MD University of Miami

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

Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

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

Lynn D. Wilson, MD Yale University School of Medicine

Jay S. Cooper, MD Maimonides Medical Center

Stanley H. Winokur, MD Singer Island, Florida

John Cox, DO Texas Oncology

William C. Wood, MD Winship Cancer Institute, Emory University

E. David Crawford, MD University of Colorado

International Editors

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

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

George D. Demetri, MD Dana-Farber Cancer Institute

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

Paul F. Engstrom, MD Fox Chase Cancer Center

Nagi El-Saghir, MD American University of Beirut, Lebanon

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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

John A. Fracchia, MD New York Urological Associates

Jacek Jassem, MD Medical University of Gdansk, Poland

Louis B. Harrison, MD Continuum Cancer Centers of New York

David Khayat, MD Pitie-Salpetriere Hospital Paris, France

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

Michael P. Link, MD Stanford University Medical Center

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

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

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press® Publishing Staff

s reported online in CA: A Cancer Journal for Clinicians, 1 based on results from the National Lung Screening Trial (NLST) sponsored by the National Cancer Institute (NCI), the American Cancer Society (ACS) has released lung cancer screening guidelines recommending that select clinicians should initiate informed discussions about screening with age-appropriate patients who have a minimum 30-pack-

Systematic Review Following the NLST results, the American Cancer Society joined with the American College of Chest Surgeons, ASCO, and the National Comprehensive Cancer Network to produce a systematic review of the evidence gleaned from literature published from January 1996 through April 2012. Randomized controlled trials and observational studies were included in the study.

Clinicians with access to high-volume, high-quality screening centers should initiate a discussion about screening with outwardly healthy patients, aged 55 to 74 years, who have a minimum 30-pack-year smoking history and currently smoke, or have quit within the past 15 years. year smoking history and who still smoke or have quit within the past 15 years.

Significant Results On November 4, 2010, NCI announced that ongoing NLST data demonstrated a 20% reduction in lung cancer mortality in a high-risk group randomized to 3 consecutive years of low-dose computed tomography (CT) screening examinations, compared with an equivalent group receiving chest x-rays. Equally important, NLST’s Data Safety and Monitoring Board found “no evidence of unforeseen screening effects that warranted acting contrary to the trial’s prespecified monitoring plan.” On June 30, 2011, the NLST published its results, providing first-ever evidence from a prospective randomized controlled trial that low-dose CT screening in high-risk populations reduced lung cancer mortality.

The joint group force looked at four key areas: potential benefits, potential harms, which populations are likely to benefit, and what screening setting is likely to be effective. In developing the guidelines, the ACS group gave findings from the NLST particular weight based on its superior size. Moreover, the majority of the NLST study sites were NCI-designated cancer centers and large academic medical centers that established quality parameters for the study.

Recommendations After completing the review process, the subsequent guideline recommended that clinicians with access to high-volume, high-quality screening centers should initiate a discussion about screening with outwardly healthy patients, aged 55 to 74 years, who have a minimum 30-pack-year smoking history and currently smoke, or have quit within the past 15 years.

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PAGE 3

San Antonio Breast Cancer Symposium Breast Cancer

Key Pathways Identified in Triple-negative Breast Cancer By Caroline Helwick

ive key biologic pathways have become evident in triple-negative breast cancer tumors, and these pathways may be targetable with agents that are currently available or in development, results from an international genetic analysis revealed at the 2012 San Antonio Breast Cancer Symposium.1

Justin M. Balko, PharmD, PhD

Justin M. Balko, PharmD, PhD, Postdoctoral Research Fellow at Vanderbilt-Ingram Cancer Center in Nashville, reported that 90% of patients in the study had mutations in five well-recognized pathways. “Neoadjuvant chemotherapy is increasingly used in patients with triple-negative breast cancer. It can induce a pathologic complete response in about 30% of patients, which portends a favorable prognosis, while those patients with residual disease in the breast at surgical resection exhibit worse outcomes,” Dr. Balko said. “There are currently no targeted therapeutic options for triple-negative patients with residual disease after neoadjuvant chemotherapy to

Genetic Analysis The investigators conducted a genetic analysis of residual tumor tissue from 114 women. Ultimately, 81 samples were sequenced for 182 oncogenes and tumor suppressors. Additionally, gene expression (mRNA) was measured for 450 genes. They found amplifications, deletions, or mutations of known or implied functional significance in about two dozen genes, and approximately 90% of all patients had at least one aberration in pathways related to P13K/mTOR (involved in signaling and cellular death), DNA repair genes (such as BRCA1 and BRCA2), Ras/MAP kinase (cellular proliferation, differentiation and death), cell-cycle genes, and growth factor receptors. Novel mutations of unknown significance could not be assessed due to the lack of normal controls, he added. The most common aberrations were mutations in the well-known tumor-suppressor protein P53 and amplifications of MCL1 and MYC. Amplification of MCL1 was observed in 56% of tumors, while MYC amplification was observed in 33%. The two genes were coamplified in many patients, suggesting that MCL1 amplification may circumvent oncogene-induced apoptosis and senescence.

andra M. Swain, MD, FACP, Medical Director, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC, who moderated the session, said these interesting observations must now be validated in preclinical models of triple-negative tumors, and then tested in patients. “Residual disease after aggressive neoadjuvant therapy is a challenging problem,” she said, “especially in triple-negative patients, for Sandra M. Swain, MD, FACP whom we have limited effective options.” Lisa Carey, MD, Preyer Distinguished Professor in Breast Cancer Research at the University of North Carolina School of Medicine, Chapel Hill, commented as well. “More and more, we are collecting serum and tumor markers in our clinical trials, trying to get a handle on ways to be smarter and more rational with treatment. Triple-negative breast cancer is where we really need a genome-forward approach. The alignment of tissue-based markers and clinical trials will be the key to our success.” n Disclosure: Drs. Swain and Carey reported no potential conflicts of interest.

survival,” Dr. Balko reported. About 40% of patients with only one of these aberrations were alive at 6 years, but in cases where both genes were amplified, essentially no patient lived beyond 2 years.

Higher-risk Factors For some combinations of genetic alterations, prognosis was worse. A univariate analysis of 62 patients showed that high expression of the

Molecular Profile of Triple-negative Breast Cancer ■■ Next-generation sequencing identified five key pathways that may be targetable in triple-negative breast cancer tumors.

■■ Approximately 90% of patients had an aberration in at least one of these pathways.

■■ Novel JAK2 amplifications were observed in 11% of patients, offering another potential therapeutic target.

be used in the adjuvant setting,” he noted. “We hypothesized that molecular analysis of the residual disease would identify genetic alterations that are ultimately responsible for disease recurrence and could be targeted with clinically available medications,” he said.

EXPERT POINT OF VIEW

MEK kinase gene plus amplification of the MYC oncogene was synergistic, and was associated with a greater risk of relapse compared with the presence of just one of the variants. “MYC amplification coinciding with high MEK pathway transcriptional output identified a subset with short

Andrei Goga, MD, PhD

UCSF Study Further implication of MYC was provided by different investigators, as reported by Andrei Goga, MD, PhD, Associate Professor of Cell & Tissue Biology and Medicine at the University of California, San Francisco.2 “MYC expression and signaling is increased in triple-negative breast cancer and is associated with worse prognosis,” Dr. Goga said. In his study, a MYC synthetic-lethality screen of the human kinases identified 13 targets, including metabolic, MAP kinase signaling pathways, and PIM1 in triple-negative cancers. PIM1 is overexpressed in triple-negative and basal-like tumors, and it correlated with MYC expression and poor prognosis. “We are now asking whether PIM1

inhibition can provide a new therapy for patients with triple-negative breast cancer,” he said. In addition, the JAK2 pathway appears to be involved in these tumors, added Dr. Balko, whose research identified novel JAK2 amplifications See Page 61 in 11% of patients, and these were associated with very poor survival. PanJAK and JAK2 inhibitors are currently in clinical trials. “These data provide a ‘targetable’ catalog of the alterations present in residual triple-negative disease after neoadjuvant chemotherapy, and support genomically driven adjuvant trials in this patient population,” Dr. Balko concluded. n Disclosure: Drs. Balko and Goga reported no potential conflicts of interest.

References 1. Balko JM, Giltnane JM, Shwartz LJ, et al: Profiling of triple-negative breast cancers after neoadjuvant chemotherapy identifies targetable molecular alterations in treatment-refractory residual disease. 2012 San Antonio Breast Cancer Symposium. Abstract S3-6. Presented December 6, 2012. 2. Goga A, Samson S, Horiuchi D: Identification of novel synthetic-lethal targets for MYC-driven triple-negative breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract S3-8. Presented December 6, 2012.

The ASCO Post | FEBRUARY 1, 2013

PAGE 4

San Antonio Breast Cancer Symposium Breast Cancer

Somatic HER2 Mutations That Drive Cancer Found in HER2-negative Breast Cancer By Alice Goodman

proportion of patients with breast cancer whose tumors test HER2-negative for gene amplification on fluorescence in situ hybridization or immunohistochemistry harbor HER2 mutations that are amenable to treatment with anti-HER2–targeted therapy, according to a gene-sequencing study presented at the 2012 San Antonio Breast Cancer Symposium.

13 Different Somatic Mutations “HER2 mutations predominantly occur in patients who are HER2-negative, and our work suggests that many of these mutations are activating events that cause oncogenic transformation;

patients with 13 different HER2 somatic mutations. Only one of the patients who harbored these mutations also had HER2 amplification, which is the hallmark of HER2-positive breast cancer. “Our study showed that the mutations were being expressed and occur predominantly in patients with normal HER2 gene copy numbers,” he noted. These mutations occur in an estimated 1% to 2% of patients with breast cancer, he estimated, but there may be subgroups where they are expressed more frequently. “This translates to about 4,000 women in the United States with these activating mutations, about the same number of people with chronic myelogenous leukemia,” he said.

ceptin) or lapatinib (Tykerb). However, all of the mutations, including two mutations associated with lapatinib resis-

Addition of Trastuzumab

C. Kent Osborne, MD

tance, were sensitive to neratinib. Based on these preclinical results,

HER2 Mutation in HER2-negative Breast Cancer ■■ About 1% to 2% of women with HER2-negative breast cancer on

conventional gene amplification testing (using fluorescence in situ hybridization or immunohistochemistry) harbor HER2 somatic mutations that drive cancer growth.

■■ Many of the mutant cell lines are sensitive to available anti-HER2 Ron Bose, MD, PhD

thus, they are highly likely to be driver events in these breast cancers,” stated Ron Bose, MD, PhD, Assistant Professor of Medicine, Washington University School of Medicine, St. Louis. Dr. Bose explained that progress in genome sequencing has led to the identification of HER2 somatic mutations that occur in the DNA of breast cancer, but not in normal DNA. “These are not inherited mutations,” he said. He and his colleagues analyzed eight genomic sequencing studies that included data on nearly 1,500 patients with breast cancer. They identified 25

therapies, and all 13 of these mutant cell lines are sensitive to neratinib, an investigational pan-ErbB tyrosine kinase inhibitor.

■■ A phase II study is being launched to evaluate neratinib in HER2-negative patients with HER2 mutations.

Two Domains The investigators did extensive testing on the 13 mutations. Their findings were published in Cancer Discovery,2 to coincide with Dr. Bose’s presentation at the San Antonio meeting. The mutations occurred mainly in two regions: the extracellular domain and the kinase domain. Mutation-bearing cells grown in culture formed irregular growths. Many of the growths were reversible with approved anti-HER2 therapies including trastuzumab (Her-

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 prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $259; Individual International: $499; Institutional Domestic: $319; Institutional International $559. Contact subscriptions@harborsidepress.com.

Baylor College of Medicine in Houston, said that these preliminary findings have limited clinical utility at present. “But if you are a patient with one of these mutations, it is important for you to know. Now that Bose et al have identified these mutations, it is possible that they will be found in other types of cancer, heightening their importance.”

a multi-institutional phase II trial has been initiated. Patients with stage IV, HER2-negative breast cancer will be screened by sequencing DNA from their cancer, and those who have somatic HER2 mutations will be treated with neratinib. Tumor response to neratinib will be measured by RECIST criteria. Press conference moderator C. Kent Osborne, MD, Professor of Medicine and Director of both the Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center at

Formal discussant of the trial, Maccon M. Keane, MD, Consultant Oncologist at Galway University Hospitals, Galway, Ireland, raised the issue of whether adding trastuzumab to neratinib could improve outcomes. Dr. Bose said that in tissue culture, no benefit was observed for adding trastuzumab to neratinib. “But we don’t know what the situation will be in actual patients,” Dr. Bose commented. If the phase II study shows that targeting the mutations with neratinib improves outcomes, it is more likely that genomic sequencing of HER2 will move to the clinic, Dr. Bose said. Although genomic sequencing is not yet used to guide breast cancer treatment, it is being used increasingly in lung cancer and other cancers. n

Disclosure: Drs. Bose, Osborne, and Keane reported no potential conflicts of interest.

References 1. Bose R, Kavuri SM, Searleman AC, et al: Activating HER2 mutations in HER2 gene amplification negative breast cancers. 2012 San Antonio Breast Cancer Symposium. Abstract S5-6. Presented December 7, 2012. 2. Bose R, Kavuri SM, Searleman AC, et al: Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discovery. December 7, 2012 (early release online).

Correspondence: Address general inquiries to Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume 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.

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PAGE 5

ASH Annual Meeting Hematology

Ibrutinib in Mantle Cell Lymphoma Yields ‘Unprecedented’ Response Rates By Caroline Helwick

he investigational agent ibrutinib demonstrated “unprecedented” single-agent activity in relapsed or refractory mantle cell lymphoma, according to the lead author of an international phase II study reported at the Annual Meeting of the American Society of Hematology (ASH).1

EXPERT POINT OF VIEW

Durable Responses “The responses have been durable and the median duration of response has not been reached,” reported Michael Wang, MD, Associate Professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, Houston. “The response improved with longer See Page 61 follow-up, demonstrating the phenomenon of ‘incremental response.’” Ibrutinib is an inhibitor of Bruton’s tyrosine kinase, which is a critical kinase for lymphoma cell survival and prolifer-

Michael Wang, MD

ation. Bruton’s tyrosine kinase inhibitors block signaling and induce apoptosis. “Ibrutinib produced the highest response rate ever observed with a single drug in the history of relapsed mantle cell lymphoma,” Dr. Wang told attendees. “Patients with all characteristics benefited across the board.”

Study Details The PCYC-1104-CA study is an ongoing international multicenter open-label phase II single-agent trial of ibrutinib in patients with relapsed or refractory mantle cell lymphoma. Patients are being treated orally with ibrutinib at 560

Ibrutinib in Other Hematologic Tumors

t the 2012 ASH Annual Meeting, researchers also reported preliminary results for ibrutinib in diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. A multicenter phase II study in 70 heavily pretreated patients with relapsed or refractory diffuse large B-cell lymphoma in two genetically distinct subtypes— the activated B-cell subtype and the germinal center subtype—found an overall response rate of 23%.1 Responses were primarily in the activated B-cell subtype (41%), including five complete responses and seven partial responses. Investigators suggested that the use of the acivated B-cell molecular subtype could serve as a biomarker for enrichment of patients in future trials. In relapsed follicular lymphoma, a phase I study in 16 heavily pretreated patients showed the overall response rate to be 44%, including three complete responses.2 In optimally See Page 61 dosed patients, response rates rose to 55% and median progression-free survival was 13.4 months. In relapsed/refractory multiple myeloma, signals of biologic and clinical activity were observed for ibrutinib.2 Reductions in paraprotein ≥ 50% were seen in three patients, and one patient responded when dexamethasone was added. Decreases in several biomarkers of bone metabolism, angiogenesis, and chemotaxis were associated with treatment. n References 1. Wilson WH, Gerecitano J, Goy A, et al: The Bruton’s tyrosine kinase inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma: Interim results of a multicenter, open-label, phase 2 study. 2012 ASH Annual Meeting. Abstract 686. Presented December 10, 2012. 2. Fowler N, Advani R, Sharman J, et al: The Bruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765) is active and tolerated in relapsed follicular lymphoma. 2012 ASH Annual Meeting. Abstract 156. Presented December 9, 2012.

artin Dreyling, MD, Professor of Medicine at Ludwig Maximilians University in Munich and Coordinator of the European Mantle Cell Lymphoma Network, commented on the data emerging for ibrutinib in lymphoma. “Ibrutinib is the molecule of the year at ASH,” he told The ASCO Post. “With other molecular compounds in relapsed mantle cell lymphoma, the response rate is about 30%. With lenalidomide (Revlimid), bortezomib (Velcade), and temsirolimus (Torisel), we see median progression-free survival rates of around 6 months. In contrast, in this phase II study (PCYC1104-CA), ibrutinib achieved an overall response rate of about 70%, and more than 20% of patients had complete responses, which increased over time. The difference in response is outrageous,” he said. As for ibrutinib in relapsed diffuse large B-cell Martin Dreyling, MD lymphoma, Dr. Dreyling said the drug’s performance was “not overwhelmingly impressive” in the group as a whole. However, the response rate doubled in the activated B-cell subtype, for a rate of 41% that “has never been achieved with monotherapy thus far.” “Inhibition of the B-cell receptor pathway is a revolution. It will change our understanding of how to treat lymphomas,” Dr. Dreyling concluded. n Disclosure: Dr. Dreyling reported no potential conflicts of interest.

mg per day until disease progression. At data cutoff in September 2012, the study population included 115 patients (110 evaluable) with mantle cell lymphoma (cyclin D1–positive or t[11;14]), 65 of whom were of whom

64% for patients with bulky disease, 65% for patients with refractory disease, 70% for those not disease-refractory, 66% for patients with at least three prior regimens, 76% for patients with prior lenalidomide (Revlimid), and 74% for

Ibrutinib in Mantle Cell Lymphoma ■■ For the treatment of advanced mantle cell lymphoma, the novel Bruton’s

tyrosine kinase inhibitor ibrutinib produced responses in 68% of patients; median progression-free survival has not been reached among responders.

■■ Response rates increased with longer duration of treatment. ■■ Ibrutinib also showed activity in relapsed follicular lymphoma and diffuse large B-cell lymphoma.

were either totally naive to bortezomib (Velcade) or had received fewer than two cycles of bortezomib (“bortezomibnaive”), and 50 of whom had received at least two cycles of the agent. Subjects were allowed to have received up to five prior lines of treatment. The overall response rate to singleagent ibrutinib was 68% for the total study population, 65% among bortezomib-naive patients, and 72% for patients exposed to at least two cycles of bortezomib. The complete response rates in these cohorts were 21%, 23%, and 22%, respectively, Dr. Wang reported. By patient characteristics, all subgroups benefited. Response rates were

those with a high-risk score.

Longer Follow-up Longer follow-up on the initial 51 patients demonstrated that responses increased over time. The increase in response and complete response rates, respectively, from the earlier analysis at 3.7 months to a median of 14.7 months, was as follows: in all patients, 69% and 16% initially, and now 75% and 39%; in bortezomib-naive patients, 71% and 16% initially, and now 77% and 40%; in bortezomib-exposed patients, 65% and 15% initially and now 71% and 38%. “We saw the overall complete recontinued on page 10

NEW INDICATION: ZYTIGA® (abiraterone acetate) is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

ADT = androgen-deprivation therapy.

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in study 1) or NYHA Class II to IV heart failure (in study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated

with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

I N T R O D U C I N G More than 20,000 patients with mCRPC have received ZYTIGA® (post-chemotherapy with docetaxel) to date.†1

MECHANISM OF ACTION ZYTIGA® is a CYP17 (17 -hydroxylase/C17, 20-lyase) inhibitor that inhibits androgen production at 3 sources: the testes, adrenal glands, and the prostate tumor tissue itself.

NEW EFFICACY DATA —In a recent Phase 3 clinical trial in patients with mCRPC who had progressed on ADT and had not received chemotherapy.* Efficacy was also demonstrated in a Phase 3 trial of patients who had received prior chemotherapy containing docetaxel.*

ZytigaOne™ is your single source for personalized access services for you and your patients: Visit www.zytigaone.com or call 1-855-998-4421. *Study Designs: ZYTIGA®, in combination with prednisone, was evaluated in 2 Phase 3, randomized, double-blind, placebo-controlled, multicenter trials in patients with mCRPC. Study 1 enrolled patients who received prior chemotherapy containing docetaxel (N = 1,195), whereas Study 2 enrolled patients who had not received prior chemotherapy (N = 1,088). In both studies, patients were using a luteinizing hormone-releasing hormone agonist or were previously treated with orchiectomy. In the active treatment arms, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the control arms, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In Study 1, the primary efficacy endpoint was overall survival. In Study 2, the coprimary efficacy endpoints were overall survival and radiographic progression-free survival. † Estimate based on sales and use data from May 2011 to November 2012. Reference: 1. Data on file. Janssen Biotech, Inc.

www.zytigahcp.com Please see adjacent pages for brief summary of full Prescribing Information.

K08Z121176

Adverse Reactions—The most common adverse reactions (≥ 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on its use with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors or inducers on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution during treatment with ZYTIGA®. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 12/12 08Z12264B

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. • Increased ZYTIGA Exposures with Food [see Warnings and Precautions]. 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 clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castrationresistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

ZYTIGA® (abiraterone acetate) Tablets Table 1: Adverse Reactions due to ZYTIGA in Study 1 System/Organ Class Adverse reaction Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 Muscle discomfort3 General disorders Edema4 Vascular disorders Hot ﬂush Hypertension Gastrointestinal disorders Diarrhea Dyspepsia Infections and infestations Urinary tract infection Upper respiratory tract infection Respiratory, thoracic and mediastinal disorders Cough Renal and urinary disorders Urinary frequency Nocturia Injury, poisoning and procedural complications Fractures5 Cardiac disorders Arrhythmia6 Chest pain or chest discomfort7 Cardiac failure8

ZYTIGA with Prednisone (N=791) Grade 3-4 All Grades1 % %

Placebo with Prednisone (N=394) All Grades Grade 3-4 % %

29.5 26.2

4.2 3.0

23.4 23.1

4.1 2.3

26.7

1.9

18.3

0.8

19.0 8.5

0.3 1.3

16.8 6.9

0.3 0.3

17.6 6.1

0.6 0

13.5 3.3

1.3 0

11.5 5.4

2.1 0

7.1 2.5

0.5 0

10.6

7.6

7.2 6.2

0.3 0

5.1 4.1

0.3 0

5.9

1.4

2.3

7.2 3.8 2.3

1.1 0.5 1.9

4.6 2.8 1.0

1.0 0 0.3

1 Adverse

events graded according to CTCAE version 3.0 terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial ﬁbrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial ﬂutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 2 Includes 3 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Laboratory Abnormality Hypertriglyceridemia High AST Hypokalemia Hypophosphatemia High ALT High Total Bilirubin

Abiraterone (N=791) All Grades Grade 3-4 (%) (%) 62.5 0.4 30.6 2.1 28.3 5.3 23.8 7.2 11.1 1.4 6.6 0.1

Placebo (N=394) All Grades Grade 3-4 (%) (%) 53.0 0 36.3 1.5 19.8 1.0 15.7 5.8 10.4 0.8 4.6 0

Study 2: Metastatic CRPC Prior to Chemotherapy Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥ 2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Prednisone (N=542) Grade 3-4 System/Organ Class All Grades1 Adverse reaction % % General disorders Fatigue 39.1 2.2 Edema2 25.1 0.4 Pyrexia 8.7 0.6 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 Groin pain 6.6 0.4 Gastrointestinal disorders Constipation 23.1 0.4 Diarrhea 21.6 0.9 Dyspepsia 11.1 0.0 Vascular disorders Hot ﬂush 22.3 0.2 Hypertension 21.6 3.9 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 Dyspnea 11.8 2.4 Psychiatric disorders Insomnia 13.5 0.2 Injury, poisoning and procedural complications Contusion 13.3 0.0 Falls 5.9 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 Nasopharyngitis 10.7 0.0 Renal and urinary disorders Hematuria 10.3 1.3 Skin and subcutaneous tissue disorders Rash 8.1 0.0 1 Adverse

events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Placebo with Prednisone (N=540) All Grades Grade 3-4 % % 34.3 20.7 5.9

1.7 1.1 0.2

25.2 4.1

2.0 0.7

19.1 17.8 5.0

0.6 0.9 0.2

18.1 13.1

0.0 3.0

13.5 9.6

0.2 0.9

11.3

0.0

9.1 3.3

0.0 0.0

8.0 8.1

0.0 0.0

5.6

0.6

3.7

0.0

ZYTIGA® (abiraterone acetate) Tablets

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Storage and Handling: Store at 20oC to 25oC (68oF to 77oF); excursions permitted in the range from 15oC to 30oC (59oF to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Speciﬁc Populations].

Table 4: Laboratory Abnormalities in > 15% of Patients in the ZYTIGA Arm of Study 2 Laboratory Abnormality Hematology Lymphopenia Chemistry Hyperglycemia1 High ALT High AST Hypernatremia Hypokalemia 1Based

Abiraterone (N = 542) Grade 1-4 Grade 3-4 % %

Placebo (N = 540) Grade 1-4 Grade 3-4 % %

38.2

8.7

31.7

7.4

56.6 41.9 37.3 32.8 17.2

6.5 6.1 3.1 0.4 2.8

50.9 29.1 28.7 25.0 10.2

5.2 0.7 1.1 0.2 1.7

on non-fasting blood draws

Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA 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 ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, 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 ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: December 2012 2000005445 K08Z121174A

The ASCO Post | FEBRUARY 1, 2013

PAGE 10

ASH Annual Meeting Maintenance in Myeloma continued from page 1

thalidomide [Thalomid]), which was followed by 2 years of maintenance therapy with VT (bortezomib and

duction clearly points to synergy for this combination, he added. “But more striking is the diverging of the curve that we observe during the maintenance approach. After maintenance, when both groups are off treatment, the curves tend to continue to part.” “There is evidence that continuous treatment can delay clonal evolution, whereas we see faster clonal evolution and relapse without maintenance,” he explained.

Survival Benefit Antonio Palumbo, MD

thalidomide). This was compared to a control arm receiving induction with three drugs—VMP (bortezomib, melphalan, and prednisone)—without maintenance therapy. Patients received nine 5-week cycles of induction. The 58-center study included 511 patients older than 65 years and patients ≤ 65 who were not transplanteligible. The median age was 71.

Risk Reduction After a median follow-up of 54 months, the risk of progression was reduced by 42% in the experimental arm, and the time to next treatment was reduced by 48%, Dr. Palumbo reported. Median progression-free survival was 24.8 months with VMP, increasing to 35.3 months with VMPT-VT, and the 5-year progression-free survival rate was 13% vs 29%, respectively (HR = 0.58; P < .0001). Median time to next treatment was 27.8 vs 46.6 months, respectively. “We are now able to deliver treatment that can keep disease under control for 4 years, and we can maintain disease in an asymptomatic state,” he commented. The addition of the immunomodulatory drug to bortezomib during in-

Ibrutinib in MCL continued from page 5

sponse rate increase to 39%, which we have termed the ‘phenomenon of incremental response,’” Dr. Wang said. “We saw this in bortezomib-exposed and bortezomib-naive patients. This is higher than the complete response rates we see in other subtypes of lymphoma, including [historically] in mantle cell lymphoma. It is an unprecedented single-agent response rate.”

EXPERT POINT OF VIEW

ommenting on Dr. Palumbo’s presentation at the ASH meeting, Sagar Lonial, MD, Professor of Hematology and Medical Oncology at the Winship Cancer Center at Emory University, Atlanta, noted that while a survival benefit has been associated with maintenance lenalidomide (Revlimid) after transplant, the value of maintenance for transplant-ineligible patients has been “an open question.” “Most trials have shown improvements in proSagar Lonial, MD gression-free survival but not in overall survival,” he noted. “What Dr. Palumbo showed at ASH is that the response rate and depth of response for the group receiving maintenance therapy not only improved progression-free survival but, for the first time, was actually associated with an overall survival benefit,” Dr. Lonial emphasized. “One could argue that the four-drug induction regimen (bortezomib [Velcade], melphalan, prednisone, thalidomide [Thalomid]) may have been better than VMP (bortezomib, melphalan, and prednisone), or it may have been that the maintenance therapy (bortezomib and thalidomide) provided the benefit. But I think there is enough writing on the wall,” he concluded, “to suggest that visiting the question of maintenance therapy, particularly for high-risk myeloma patients, might be important for older patients as well as younger ones.” Dr. Lonial added that the availability of subcutaneous bortezomib should ameliorate concerns over peripheral neuropathy with maintenance bortezomib. “When we tend to dose in the maintenance setting, we give it weekly or every other week, and I think those approaches offer the opportunity for much less toxicity,” he said. n

Furthermore, an overall survival advantage emerged with the four-drug induction plus maintenance therapy. Five-year overall survival rates were 61% with VMPT-VT, compared with 51% for the control arm, producing a hazard ratio of 0.70 (P = .01). Median overall survival has not been reached in the experimental arm, while it is 60.6 months in the control arm. “If we look at the landmark analysis, which evaluates survival after induction and from the start of maintenance, the hazard ratio is even better—0.63 =�� .006),” he added. Four-year over(P �� all survival from the start of maintenance was 67% with VMPT-VT vs 58% with VMP; median overall survival has not been reached with VMPTVT and was 54.2 months with VMP. Most of the survival benefit seems to accrue during the maintenance period, he emphasized. “In the subgroup analysis, we observed that this schema is excellent for patients aged 65 to 75 (HR = 0.60; P = .009), but the benefit is not so evident in those over the age of 75 =� �� .36),” �� possibly be(HR = 0.76; P �� cause the regimen is more toxic, he said. Older patients were more likely to discontinue treatment, and they received a lower dose intensity. The benefit of the experimental regimen was also more notable among patients with International Staging System (ISS) stages I and

II, rather than III, and in patients who obtained a complete response, compared with those with lesser responses. The study did not show a survival benefit for the novel regimen from the time of first relapse. In those patients, 3-year overall survival rates were about 47% per arm and median overall survival time was 27 months. In conclusion, Dr. Palumbo suggested that the use of two drugs during maintenance may be more important than the four-drug induction regimen. “A proteasome inhibitor in conjunction with an immumodulatory drug, taking advantage of the synergistic effect, basically doubled the progres-

sion-free survival and time to next treatment,” he said, “and more importantly, we were able to keep patients in an asymptomatic condition for up to 4 years.” n

He added that the time to response was “very fast, after two cycles usually,” though the average time to achieve a complete response was 5.5 months (ranging from 1.7 to 16.4 months). Median progression-free survival was 13.9 months for the whole population; for responders, it has not been reached, whereas the average nonresponder showed disease progression in less than 7 months. Similarly, the median duration of response has not been reached and

responses have been dramatic in some patients, he noted. Ibrutinib is well tolerated. Treatmentemergent adverse events were consistent with the safety data previously reported for this investigational agent. Grade 3 and 4 events occurred in fewer than 5% of patients. Approximately 10% of patients experienced grade�� 1 or 2 confusion, epistaxis, petechiae, and ecchymosis. In conclusion, Dr. Wang let his enthusiasm for this agent be known. “I look

forward to the future with excitement, caution, and confidence,” he said. n

Disclosure: Dr. Lonial has served as a consultant or on the scientific advisory board for Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb, and Sanofi-Aventis.

Disclosure: Dr. Palumbo is a consultant for and has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millennium, and Onyx.

References 1. Palumbo A, Bringhen S, Rossi D, et al: Overall survival benefit for bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide versus bortezomib-melphalan-prednisone in newly diagnosed multiple myeloma patients. 2012 ASH Annual Meeting. Abstract 200. Presented December 9, 2012.

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

Reference 1. Wang M, Rule S, Martin P, et al: Interim results of an international, multicenter, phase 2 study of Bruton’s tyrosine kinase inhibitor, ibrutinib (PCI-32765), in relapsed or refractory mantle cell lymphoma. 2012 ASH Annual Meeting. Abstract 904. Presented December 11, 2012.

NOW FDA APPROVED new phase III trial data

The evolution continues. See the new data at www.ALIMTAupdate.com

ALIMTA is available in 100 mg and 500 mg vials. PM79999

The ASCO Post | FEBRUARY 1, 2013

PAGE 12

ASH Annual Meeting Hematology

Inotuzumab Moves Forward in Relapsed/Refractory ALL By Alice Goodman

ingle-agent inotuzumab ozogamicin achieved an encouraging overall response rate of 57% in the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL) in a phase II trial reported at the 54th Annual Meeting of the American Society of Hematology (ASH). Response was independent of monthly or weekly schedule and correlated with clearance of leukemia cells from the bone marrow.

Susan M. O’Brien, MD

No difference was observed in response between the weekly and monthly schedule of administration, though the weekly schedule will be preferred going forward in clinical trials because of less toxicity, said lead author See Page 61 Susan M. O’Brien, MD, Ashbel Smith Professor of Medicine, Professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston.

Clear Benefit “When we compare inotuzumab data with any regimen or investigational agent in our MD Anderson database, no matter which cohort we look at, there is a clear benefit for inotuzumab in relapsed/refractory ALL,” she stated. Additional studies of inotuzumab include a pivotal trial of the weekly schedule vs the best standard of care in relapsed/refractory ALL, and a study of inotuzumab in combination with low-intensity chemotherapy in elderly patients with ALL.

CD22 B-cell–specific antigen expression is seen in > 90% of patients with ALL, she explained. Inotuzumab is an antibody-antigen complex that binds to CD22 cells, releasing calicheamicin inside the tumor cell. Calicheamicin is a potent cytotoxic agent that binds to DNA, inducing doublestranded DNA breaks leading to apoptosis of the cell.

Study Data At the ASH meeting, Dr. O’Brien reported results with inotuzumab in patients with refractory or relapsed CD22-positive ALL (N = 89). The first 10 patients were aged 18 or older, and then the trial was opened to children. Two schedules were studied: weekly and monthly, with the same total dose for both schedules. Patients could receive up to eight cycles. Median age was 39 years, and about 28% were over age 60; 10% had an ECOG performance status of 2 or higher; 11% had prior allogeneic stem cell transplantation; one-third were receiving third-line or higher salvage therapy; and about 25% had high-risk cytogenetics. More than 90% of patients expressed CD22 antigen. An overall response rate of 57% was similar in the two arms (weekly vs monthly schedule). The complete remission rate (eradication of all clinical and/or radiologic evidence of disease) was 18% in both arms; CRp rate (complete response except for platelets < 100 × 109/L) was 29% in the monthly arm and 30% in the weekly arm. CRi (complete response without recovery of neutrophils or platelet counts) was 10% in both arms. Resistance occurred in 39% and 38% of the two arms, respectively, and there were two deaths in each arm in less than 4 weeks. Cytogenetic complete response was seen in 89% and 90% of patients. Overall, 63% and 70%, respectively, were determined to be minimal residual disease–negative. Median progression-free survival

Inotuzumab in Acute Lymphoblastic Leukemia ■■ The investigational antibody-antigen complex inotuzumab ozogamicin has

achieved encouraging responses in phase II trials of relapsed/refractory ALL.

■■ The compound will move forward in clinical trials.

EXPERT POINT OF VIEW

or years, adults with acute lymphoblastic leukemia (ALL) have been treated with intensive, multiagent, cytotoxic chemotherapy involving multiple rounds of treatment, derived from regimens that are highly effective in children. Although the survival of children with ALL hovers around 90%, less than 50% of adults have long-term survival with this approach, and many experience relapsed disease, explained Amir T. Fathi, MD, Instructor of Medicine and Medical Oncology at Dana-Farber/Harvard Cancer Center and Massachusetts General Hospital in Boston. “Therefore, there has been an urgent need for new treatments for adults with ALL. Novel and targeted therapies are now emerging that appear to be Amir T. Fathi, MD highly effective. The investigational antibody-drug conjugates are antibody-based therapies that hold promise for treatment of ALL in adults. Studies have shown impressive rates of response with single-agent therapy in those with relapsed /refractory ALL,” Dr. Fathi stated.

Novel Mechanisms “Inotuzumab is an anti-CD22 humanized antibody-drug conjugate with significant response rare in relapsed/refractory ALL, and is among a growing list of targeted therapies that mediate their effect through an immunologic mechanism,” he continued. “Another novel and targeted agent, blinotumumab, belonging to a class of compounds called bi-specific T-cell engagers (BiTE), has also demonstrated significant promise in results from phase II studies,” he added. “These drugs use novel mechanisms to attack lymphoblasts in ALL by targeting proteins on the surface of these cells. I suspect that such targeted agents will become an integral part of therapy for adults with ALL in the near future, which is great news for our patients who are in need of more effective therapies. Nevertheless, we will need additional data and advanced phase studies to further assess clinical benefit in this population of patients with high-risk ALL, and these studies are ongoing,” Dr. Fathi said. n Disclosure: Dr. Fathi has served in an advisory capacity for Seattle Genetics.

was 4.9 months, with a progressionfree survival rate of 21% at 1�� year. Duration of complete response was a median of 7 months, and some patients are still responding at 27 months, Dr. O’Brien said. Median overall survival is 5.6 months; 20% are alive at 1 year, with no difference between the treatment arms. Median overall survival was 8.8 months for those in first salvage, 4.3 months for those in second salvage, and 7.4 months for those in third or more salvage. “We found the best data in first salvage, not surprisingly,” she stated.

Clinical Toxicity Although infusion reactions and liver function abnormalities were generally grade 1/2 in both arms, they were significantly more frequent in

the monthly schedule (where the full dose was given as one large infusion, rather than spaced out over 3 weeks). Thus, the weekly schedule was chosen to move forward into the forthcoming pivotal trial. The investigators found that older age, at least two salvage regimens, and Philadelphia chromosome–positive status were associated with slightly lower response rates. n

Disclosure: Dr. O’Brien reported no potential conflicts of interest.

Reference 1. O’Brien S, Thomas D, Jorgensen J, et al: Experience with 2 dose schedules of inotuzumab ozogamicin, single-dose, and weekly in refractory-relapsed acute lymphocytic leukemia. 2012 Annual Meeting of ASH. Abstract 671. Presented December 10, 2012.

ASCOPost.com | FEBRUARY 1, 2013

PAGE 13

San Antonio Breast Cancer Symposium Breast Cancer

Primary Endpoint Not Met for Eribulin vs Capecitabine in Breast Cancer By Caroline Helwick

hile a global phase III trial failed to meet its primary endpoint in showing an overall or progression-free survival benefit for eribulin (Halavan) in metastatic breast cancer, a trend toward greater efficacy than capecitabine (Xeloda) was observed, researchers reported at the 2012 San Antonio Breast Cancer Symposium.1 Eribulin is a nontaxane microtubule dynamics inhibitor.

Peter A. Kaufman, MD

Novel Mechanism “We did not show a statistically significant superiority of eribulin over capecitabine, which was our goal, but eribulin demonstrated a trend favoring an overall survival benefit over capecitabine,” said Peter A. Kaufman, MD, Associate Professor of Medicine at Dartmouth-Hitchcock Norris Cotton Cancer Center in Lebanon, New Hampshire. Dr. Kaufman noted that eribulin is the only chemotherapeutic agent that has demonstrated a significant survival benefit in heavily pretreated metastatic breast cancer patients. The drug’s novel mechanism of action is distinct from most other tubulin-targeted agents.

The earlier EMBRACE trial did show a 2.5-month survival benefit over standard treatment as selected by the treating physician, leading to the FDA’s approval of the drug in November 2010, for patients with metastatic disease who have received at least two prior chemotherapy regimens with anthracyclines and taxanes.

Current Study Study 301 examined whether eribulin would be effective for patients less heavily pretreated, with a standardized control arm, capecitabine. Half of the 1,102 patients had received only one prior regimen for advanced disease. Patients were randomly assigned to receive eribulin mesylate at 1.4 mg/ m2 on days 1 and 8 every 21 days or capecitabine at 1,250 mg/m2 twice daily on days 1 to 14, every 21 days. The coprimary endpoints were overall survival and progression-free survival. Dr. Kaufman reported that median overall survival was 15.9 months with eribulin and 14.5 months with capecitabine, for a 12% reduction in risk that was not statistically significant (P = .056). The statistical plan for the study determined the P values for superiority to be ≤ .0372 for overall survival and ≤ .01 for progression-free survival. Overall survival rates per year were 64.4% with eribulin vs 58.0% with capecitabine at 1 year (P = .035); 32.8% vs 29.8%, respectively, at 2 years =� �� .324); and 17.8% vs 14.5%, re(P �� spectively, at 3 years (P = .175). “There was an early separation of

EXPERT POINT OF VIEW

isa Carey, MD, Preyer Distinguished Professor in Breast Cancer Research at the University of North Carolina, Chapel Hill, said the study should not be interpreted as negative for eribulin. “Most of the patients in this study were being treated second-line. EMBRACE was a totally different circumstance, as it enrolled heavily pretreated patients, and the comparison was eribulin vs whatever the physician still had in his or her grab bag. Here, in [study 301], eribulin was compared Lisa Carey, MD to a well-established second-line therapy, and that made a difference,” she noted. “I am not troubled by the fact that it did not prove superior to capecitabine. The results show instead that eribulin is a reasonable drug. I like having multiple options for my patients,” she said. n Disclosure: Dr. Carey reported no potential conflicts of interest.

Treating Earlier with Eribulin

ribulin is also being evaluated for use earlier in patients with breast cancer, in both the metastatic and adjuvant settings, in three studies described at the San Antonio meeting. In a phase II study of eribulin as first-line treatment for locally recurrent or metastatic HER2-negative breast cancer in 48 patients, response rates were 27% overall, 29% for the estrogen receptor–positive subset, and 30% for the triple-negative subset; disease control rates were 75%, 83%, and 60%, respectively.1 Overall, 30 patients (62%) experienced a grade 3/4 treatment-related or treatment-emergent adverse event, most commonly alopecia, neutropenia, and fatigue. The most common grade�� 3/4 toxicity was neutropenia, which occurred in 50% of patients. In a phase II trial of 40 HER2-positive patients with locally recurrent or metastatic disease, eribulin given concurrently with trastuzumab produced responses in 55% of patients, and the disease control rate was 92%.2 Duration of response in the 22 responders was 204 days. For all treated patients, median progression-free survival was 9.2 months. In the adjuvant setting, investigators are testing the benefit of adding eribulin following dose-dense doxorubicin and cyclophosphamide.3 Fifty-five patients were enrolled, but the investigators determined that the regimen conferred an unacceptable risk for neutropenia. The study was amended to include a cohort who will follow a regimented growth factor protocol, to improve the feasibility of the treatment. n References 1. Vahdat L, Schwartzberg L, Gluck S, et al: Results of a phase 2, multicenter, single-arm study of eribulin lmesylate as first-line therapy for locally recurrent or metastatic HER2-negative breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract P1-12-02. Presented December 11, 2012. 2. Vahdat L, Schwartzberg L, Wilks S, et al: Eribulin mesylate + trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer: Results from a phase 2, multicenter, single-arm study. 2012 San Antonio Breast Cancer Symposium. Abstract P5-20-04. Presented December 13, 2012. 3. Cadoo K, Fornier M, Lake DE, et al: Adjuvant treatment of early-stage breast cancer with eribulin mesylate following dose-dense doxorubicin and cyclophosphamide: Preliminary results from a phase 2, single-arm feasibility study. 2012 San Antonio Breast Cancer Symposium. Abstract P1-13-11. Presented December 11, 2012.

the curve and a trend, but it’s not statistically significant,” he said. Median progression-free survival was 4.1 months with eribulin and 4.2 months with capecitabine (P = .305), with no difference between independent and investigator reviews. The clinical benefit rates and drug exposure were similar for the two drugs by both review processes.

Subset Analyses Prespecified exploratory analyses suggested that particular patient subgroups may derive greater therapeutic benefit with eribulin. Trends favoring eribulin were observed in patients with triple-negative disease, estrogen receptor–negative disease, and HER2-negative disease, but further studies would be required to confirm any benefit in

these subgroups. The adverse event profiles of the two drugs were consistent with their previously known side effects. Compared with capecitabine recipients, patients in the eribulin group had a higher incidence of neutropenia (54% vs 16%), but febrile neutropenia was “acceptably low” among eribulin recipients (2% vs < 1%). In contrast, hand-foot syndrome occurred far more frequently in the capecitabine group (45% vs < 1%). The researchers are currently compiling data from the quality-of-life analysis, which should help guide future studies of eribulin in metastatic breast cancer, Dr. Kaufman said. “Although we did not meet our primary endpoints, this is still the first study demonstrating the activity of continued on page 14

The ASCO Post | FEBRUARY 1, 2013

PAGE 14

FDA Update

Dune Medical Devices Receives FDA Approval for the MarginProbe System

une Medical Devices, Inc, announced that the FDA has granted Premarket Approval to the MarginProbe System, the company’s breakthrough intraoperative tissue assessment tool for early-stage breast cancer surgery. The technology significantly improves surgeons’ ability to intraoperatively identify “cancer on the margin” and significantly reduce pathologically positive margins following a patient’s initial lumpectomy surgery. FDA approval of the MarginProbe

Eribulin vs Capecitabine

System was based on a prospective, multicenter, randomized, doublearm study of 664 patients evaluating the effectiveness of MarginProbe in identifying cancerous tissue along the margins of removed breast tissue dur-

S:6.75”

ing initial lumpectomy procedures. MarginProbe, which uses electromag-

netic “signatures” to identify healthy and cancerous tissue, was found to be over three times more effective in finding cancer on the margin during lumpectomy, compared to traditional intraoperative imaging and palpation

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

NOW APPROVED

continued from page 13

eribulin in earlier lines of treatment of metastatic breast cancer,” Dr. Kaufman said. “Eribulin is an active therapy in this setting, and overall it has potentially comparable activity to capecitabine, which is a widely used treatment in this patient population.” n Disclosure: Dr. Kaufman has received a research grant and acted as a consultant for Eisai.

Reference 1. Kaufman PA, Awada A, Twelves C, et al: A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. 2012 San Antonio Breast Cancer Symposium. Abstract S66. Presented December 7, 2012.

Eribulin in Metastatic Breast Cancer ■■ Eribulin was compared to

capecitabine in patients with advanced breast cancer, mostly in the second-line setting.

■■ The study did not meet

its coprimary endpoints of improved overall or progression-free survival, but a trend favoring eribulin was observed for overall survival.

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

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 BOXED 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 COMETRIQtreated 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. ADDITIONAL IMPORTANT SAFETY INFORMATION Gastrointestinal (GI) perforations (3%) and GI fistulas (1%), all serious, were reported with COMETRIQ, including 1 (<1%) fatal GI fistula. Non-GI fistulas including tracheal/esophageal were reported (4%), including 2 (1%) fatal events. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events

was higher with COMETRIQ (3%) than with placebo (1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Increased incidence of thrombotic events (venous thromboembolism: 6% vs 3%; arterial thromboembolism: 2% vs 0%) was reported with COMETRIQ vs placebo, respectively. Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication. Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ ≥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. Increased incidence of treatment-emergent hypertension, stage 1 or 2 (modified JNC† criteria), was identified with COMETRIQ (61% vs 30% with placebo). 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.

†Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

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T:1

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FDA Update

assessment. This enabled surgeons to significantly reduce the number of patients with positive margins following initial surgery.

the operating room has been limited. Frequently, early-stage breast cancers are detected by mammography. This can make the process of achieving negative margins more challenging,” said Susan K. Boolbol, MD, an investigator for the pivotal clinical S:6.75” trial and Chief of Breast Surgery at Beth Israel Medical Center. “Fol-

Reduces Need for Repeat Surgery “Up to this point our ability to assess the microscopic margin status in

lowing their breast cancer surgery, telling a patient that they need more surgery can be an emotional issue for doctors and patients. This may result in tremendous anxiety and frustration. I believe that the MarginProbe System can help advance the field of breast surgery.” It is estimated that 30% to 60% of

patients with early-stage breast cancer who have an initial lumpectomy procedure will undergo a repeat surgery. This is because cancerous cells are found to be present on the rim or edge of the removed tissue, increasing the possibility that cancer still remains in the breast. continued on page 16

COMETRIQ demonstrated significant efficacy in a phase 3 trial (N=330) in metastatic MTC patients with radiographically confirmed disease progression.* Progression-free survival (PFS) COMETRIQ (n=219) Placebo (n=111) HR=0.28 95% CI: 0.19, 0.40 P<0.0001

1.0 0.9 0.8 PFS Probability

7.5”

15”

ASCOPost.com | FEBRUARY 1, 2013

0.7 0.6 0.5 0.4

4.0

0.3

11.2

months

0.2 0.1 0

12 2

2 0

21 22

Months

Patients at risk: COMETRIQ Placebo

219 111

121 35

78 11

55 6

31 3

1 0

> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) —Median PFS was 11.2 months with COMETRIQ vs 4.0 months with placebo > Objective response rate (ORR) was 27% with COMETRIQ vs 0% with placebo (P<0.0001) —Median duration of tumor 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 alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Palmar-plantar erythrodysesthesia syndrome (PPES) occurred (50%) 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 was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome, compared with 0 patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

COMETRIQ.com

Please see brief summary of full Prescribing Information, including Boxed Warning, on next page.

B:11.25”

Osteonecrosis of the jaw (ONJ) occurred with COMETRIQ (1%). 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 therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for ≥28 days prior to scheduled surgery, if possible.

Reversible posterior leukoencephalopathy syndrome (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. Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. The COMETRIQ dose was reduced in 79% of patients vs 9% for placebo.

S:9.75”

Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

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: ORR and overall survival (OS). OS data are not yet mature.

The ASCO Post | FEBRUARY 1, 2013

PAGE 16

FDA Update

MarginProbe Receives Premarket Approval continued from page 15

Susan Scanlan, breast cancer survivor and Chair of the National Council of Women’s Organizations said, “When I was first diagnosed with breast cancer I decided to undergo a lumpectomy, but like many others, I

was told I had cancer on the margin following the procedure. The mental distress of having to go back for a repeat surgery undermined my confidence. I believe MarginProbe offers women the additional peace of mind that they can move on to the next step in fighting the disease and put breast cancer in their rearview mirror.”

“The MarginProbe System was developed to address one of the longest standing unmet medical needs in the breast cancer surgical community,” said Daniel Levangie, Chief Executive Officer of Dune Medical Devices. “We have received resounding support from clinicians, advocacy organizations and patients alike, who have rec-

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

ognized the value of MarginProbe and intra-operative, real-time detection of cancer on the margin to potentially improve patient outcomes.” MarginProbe has been available in Europe since 2008 and is now available in select locations throughout the United States with national availability expected in early 2013. n

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

ASCOPost.com | FEBRUARY 1, 2013

PAGE 17

FDA Update

Ezatiostat Gets Orphan Designation for Treatment of Myelodysplastic Syndrome

elik, Inc, announced that its product candidate, ezatiostat hydrochloride (Telintra), has been granted orphan drug designation by the FDA for the treatment of myelodysplastic

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

syndromes (MDS). Ezatiostat is an investigational agent in development for the treatment of MDS and idiopathic chronic neutropenia. The drug is a novel inhibitor of the

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

enzyme glutathione S-transferase P1-1, leading to activation of Jun kinase, a key regulator of cellular growth and differentiation of blood precursor cells. Ezatiostat has been shown to cause

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]

clinically significant and sustained reduction in red blood cell transfusions, transfusion independence, and multilineage responses in patients with multidysplastic syndromes. The results of four clinical trials of ezatiostat in MDS have been reported in peer-reviewed scientific journals. Orphan designation grants potential US market exclusivity to a drug for the treatment of a specified condition for a period of 7 years following FDA marketing approval. Additional potential benefits of orphan designation include development grants, tax credits related to clinical trial expenses, protocol development assistance and exemption from FDA user fees. The U.S. Orphan Drug Act aims to encourage the development of drugs for the diagnosis, prevention and treatment of medical conditions affecting fewer than 200,000 people in the United States. n

Watch future issues of

The ASCO Post for comprehensive coverage of these important meetings:

■■ 2013 Gastrointestinal

Cancers Symposium January 24–26, 2013 San Francisco, California

■■ 2013 Genitourinary

Cancers Symposium February 14–16, 2013 Orlando, Florida

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | FEBRUARY 1, 2013

PAGE 18

ASH Annual Meeting Hematology

PET-negative Scan after Short-course Chemotherapy Identifies Early Hodgkin Lymphoma Patients Who Can Forgo Radiation By Alice Goodman

ositron-emission tomography (PET)-directed therapy is promising for early-stage Hodgkin lymphoma, according to results of the UK NCRI RAPID trial presented at the 54th Annual Meeting of the American Society of Hematology (ASH).1 The use of PET scan enabled the identification of a population of patients See Page 61 with early-stage Hodgkin lymphoma (stages IA and IIA) who have an excellent prognosis following three cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and who can potentially be spared from having to undergo radiotherapy, avoiding its toxicity.

tolerability, and most importantly avoiding late toxicity of radiotherapy, Dr. Radford continued. “It is crucial with this approach to have experienced reviewers of the PET images,” he stated. “We obtained these results in the setting of quality-controlled PET acquisition, with a central review of PET images at a Core Lab and with a conservative definition of PET-negative. We need longer followup to establish the impact of a PETdirected approach on 10- and 20-year survival and cause of death.” The RAPID study was a noninferiority trial that enrolled 602 patients (321 male and 281 female) with stage IA (33%) and IIA (67%) Hodgkin lymphoma. Sixty-two percent of these patients had a favorable prognosis according to European Organisation for Research and Treatment of Cancer (EORTC) criteria.

Key Findings

John Radford, MD

“In early-stage Hodgkin lymphoma, abbreviated chemotherapy followed by involved-field radiation therapy is standard of care, but some patients are probably cured by chemotherapy alone. We found that the prognosis was excellent without further treatment in the 75% of patients who became PETnegative after three cycles of ABVD,” said John Radford, MD, Professor of Medical Oncology at the University of Manchester, United Kingdom.

Advantages of PET-based Strategy A PET-directed approach based on centrally reviewed PET images has several advantages, among them reduced treatment time and costs, improved

Between 2003 to 2010, all patients received three cycles of ABVD. Of these 571 underwent a PET scan. Scans were PET-negative (score of 1 or 2 using the Deauville Criteria for PET scans [see box]) in 426 patients (74.7%); 420 were randomly assigned to involvedfield radiotherapy or no involved-field radiotherapy. PET-positive patients received a fourth cycle of ABVD plus involved-field radiotherapy. At a median follow-up of 48.6 months, 194 patients (92.8%) in the PET-negative involved-field radiotherapy arm and 190 (90%) in the PETnegative no-radiotherapy arm were alive with no progressive disease, compared with 125 patients (85.9%) in the PET-positive arm. In an intent-to-treat analysis of 420 patients assigned to one of the three arms, 3-year progression-free survival was 94.5% in the PET-negative involved-field radiotherapy arm vs 90.8% in the PET-negative no-radiotherapy arm.

PET-guided Approach in Early Hodgkin Lymphoma ■■ In patients with early-stage Hodgkin lymphoma and a negative PET after three cycles of ABVD, prognosis is excellent without further treatment.

■■ The 3-year progression-free survival is slightly higher in this setting among PET-negative patients given involved-field radiotherapy (93.8% vs 90.7%).

EXPERT POINT OF VIEW

ommenting on the UK NCRI RAPID trial data presented at the ASH Annual Meeting, Martin Dreyling, MD, Professor of Medicine and Head of the Lymphoma Program at the University Hospital Grosshaden, Ludwig Maximilian University, Munich, Germany, stated, “This is a straightforward study suggesting that PET-negative patients with complete response to chemotherapy do not need to be treated with radiotherapy. A larger meta-analysis1 confirms the results of the RAPID trial. The meta-analysis of three trials with a total of 655 patients found that radiotherapy was improving outcome especially in Martin Dreyling, MD patients with early-stage disease with only an interim partial response to chemotherapy. The authors concluded that their data supported the concept that in early responders one might consider skipping the radiation consolidation.” n Disclosure: Dr. Dreyling reported no potential conflicts of interest.

Reference 1. Hay A, Klimm B, Chen BE, et al: Treatment of stage I-IIA non-bulky Hodgkin’s lymphoma: An individual patient-data comparison of German Hodgkin Study Group (GHSD) HD10 and HD11 combined-modality therapy (CMT) and NCIC clinical trials group (NCIC CTG) HD6 ABVD alone. 2012 Annual Meeting of ASH. Abstract 548. Presented December 10, 2012.

A per-protocol analysis excluded 28 patients who did not get allocated involved-field radiotherapy and 2 patients allocated to the no-radiotherapy arm who did get radiotherapy. In this analysis of 392 patients who received allocated treatment, 3-year progression-free survival was 97% for those PET-negative patients treated with involved-field radiotherapy vs 90.7% of those who had no further treatment, and 85.9% for the PET-positive patients.

Survival Analysis “Both progression-free survival analyses are within the noninferiority margin,” Dr. Radford said, suggesting that PET-negative patients after three cycles of ABVD can be safely treated without involved-field radiotherapy. Overall survival at 3 years was 97% in the PET-negative group treated with involved-field radiotherapy, 99.5% in the PET-negative group who had no further treatment, and 93.9% in PETpositive patients who got involvedfield radiotherapy. The PET score after 3 cycles of ABVD, was more predictive than favorable or unfavorable prognosis

based on pretreatment risk factors, he told listeners. “In both univariate and multivariate analysis, PET score was highly predictive of outcome.” n Disclosure: Dr. Radford reported no potential conflicts of interest.

Reference 1. Radford J, Barrington S, Counsell N, et al: Involved field radiotherapy versus no further treatment in patients with clinical stages IA and IIA Hodgkin lymphoma and a ‘negative’ PET scan after 3 cycles ABVD: Results of the UK NCRI RAPID trial. 2012 Annual Meeting of ASH. Abstract 547. Presented December 10, 2012.

Deauville 5-Point Criteria for PET Scans 1. No uptake 2. Uptake ≤ mediastinum 3. Uptake > mediastinum but ≤ liver 4. Uptake moderately more than liver uptake, at any site 5. Markedly increased uptake at any site and new site of disease Source: André M, et al: Advances in Hematology 2011.

STIVARGAÂŽ for Metastatic Colorectal Cancer (mCRC):

Expanding Treatment. Extending Survival. â&#x20AC;˘ Median overall survival: 6.4 months with STIVARGA vs 5.0 months with placebo; HR, 0.77; 95% CI, 0.64-0.94; P =0.01021

Indication STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild-type, an anti-EGFR therapy. Important Safety Information WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

Please see brief summary of full Prescribing Information, including the Boxed Warning, on last pages.

Important Safety Information (Continued) Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in 0.3% of 1100 STIVARGA®treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis. Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (grades 1-5) was 21% in STIVARGA-treated patients compared to 8% in placebo-treated patients in Study 1. Fatal hemorrhage occurred in 4 of 500 (0.8%) STIVARGA-treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin. Dermatological Toxicity: STIVARGA caused an increased incidence of hand-foot skin reaction (HFSR) (also known as palmar-plantar erythrodysesthesia [PPE]) and rash, frequently requiring dose modification. The overall incidence of HFSR (45% vs 7%) and the incidence of grade 3 HFSR (17% vs 0) were increased in STIVARGAtreated patients compared to placebo-treated patients in Study 1. The overall incidence of rash (26% vs 4%) and the incidence of grade 3 rash (6% vs <1%) were higher in STIVARGA-treated patients in Study 1. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of dermatologic toxicity. Hypertension: STIVARGA caused an increased incidence of hypertension (30% of STIVARGA-treated patients vs 8% of placebo-treated patients in Study 1). Hypertensive crisis occurred in 0.18% of 1100 STIVARGA-treated patients across all clinical trials. Do not initiate STIVARGA until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks

of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension. Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (1.2% for STIVARGA-treated patients vs 0.4% of placebotreated patients). Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 of 1100 STIVARGA-treated patients across all clinical trials. Confirm the diagnosis of RPLS with MRI and discontinue STIVARGA in patients who develop RPLS. Gastrointestinal Perforation or Fistula: Gastrointestinal perforation or fistula occurred in 0.6% of 1100 patients treated with STIVARGA across clinical trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula. Wound Healing Complications: Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume STIVARGA after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence. Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. Use effective contraception during treatment and up to 2 months after completion of therapy. 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. Nursing Mothers: Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from STIVARGA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Most Frequently Observed Adverse Drug Reactions in Metastatic Colorectal Cancer (mCRC) (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

Please see brief summary of full Prescribing Information, including the Boxed Warning, on last pages. Reference: 1. STIVARGA Prescribing Information. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2012.

23% reduction in the risk of death* Overall survival (OS)1 100

STIVARGA (n=505) Placebo (n=255)

Survival Probability (%)

Hazard ratio, 0.77 (95% CI, 0.64-0.94; P =0.0102)

Median: 6.4 months (95% CI, 5.8-7.3) with STIVARGA vs 5.0 months (95% CI, 4.4-5.8) with placebo

0 0 Patients at Risk STIVARGA + BSC Placebo + BSC

452 221

352 150

33 9

7 3

Months From Randomization 187 75

93 32

The CORRECT trial was an international, multicenter, randomized (2:1), doubleblind, placebo-controlled phase 3 trial in 760 patients with previously treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival.1

*Based on hazard ratio.

• T here were 275 deaths out of 505 patients with STIVARGA (55%) vs 157 deaths out of 255 patients with placebo (62%)1 • S TIVARGA improved OS in the CORRECT study, which included patients with historically collected KRAS status (n=729)1 — Mutated KRAS = 59%; wild-type KRAS = 41%

WARNING: HEPATOTOXICITY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

www.STIVARGA-US.com

6 West Belt, Wayne, NJ 07470 USA © 2013 Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ STIVARGA is co-promoted in the USA by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. Bayer® and the Bayer Cross® are registered trademarks of Bayer. 900-10-002-12 01/13

The ASCO Post | FEBRUARY 1, 2013

PAGE 22

Announcements

Pediatric Cancer Foundation Names Four Recipients of 2012 Award, Each to Receive Grant for Research

lex’s Lemonade Stand Foundation, a nonprofit group dedicated to finding cures for all children with cancer, has named four researchers 2012 recipients of the “A” Award.

Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory; Roland Walter, MD, PhD, of the Fred Hutchinson Cancer Research Center; Myron Ignatius, PhD, of Massachu-

setts General, and Grant Challen, PhD, of Washington University were chosen as the 2012 recipients of the grant which totals $375,000 for each over the course of 3 years. The doctors’

Stivarga (regorafenib) tablets, oral initial U.S. approval: 2012 BRIEF SUMMARY oF pREScRIBIng InFoRMAtIon conSULt pAcKAgE InSERt FoR FULL pREScRIBIng InFoRMAtIon WarNiNg: HEPatOtOXiCitY Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function prior to and during treatment. interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence [see Dosage and Administration (2.2), Warnings and Precautions (5.1)]. 1 iNDiCatiONS aND USagE Stivarga® is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. 4 None

CONtraiNDiCatiONS

research will focus on various leukemias, with the exception of Dr. Ignatius who will examine rhabdomyosarcoma The grant designed to jump-start the careers of promising scientists in

The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously treated metastatic colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The mean duration of therapy was 12 weeks for patients receiving Stivarga and 8 weeks for patients receiving placebo. Due to adverse reactions, 61% of the patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Stivarga-treated patients compared to 1.2% of patients who received placebo. Skin toxicity (HFSR/PPE or rash) was the most common cause of permanent drug discontinuation. The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are asthenia/ fatigue, decreased appetite and food intake, HFSR/PPE, diarrhea, mucositis, weight loss, infection, hypertension and dysphonia. The most serious adverse drug reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation. Table 1 compares the incidence of adverse reactions (≥10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1). table 1: Adverse drug reactions (≥10%) reported in patients treated with Stivarga and reported more commonly than in patients receiving placebo

5 WarNiNgS aND PrECaUtiONS 5.1 Hepatotoxicity Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1100 Stivarga-treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. Obtain liver function tests (ALT, AST and bilirubin) before initiation of Stivarga and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline. Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration (2.2)].

Stivarga (n=500) adverse reactions

5.2 Hemorrhage Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% in Stivarga-treated patients compared to 8% in placebo-treated patients in Study 1. Fatal hemorrhage occurred in 4 of 500 (0.8%) of Stivarga-treated patients and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)].

Placebo (n=253)

grade

all %

≥3 %

all %

≥3 %

general disorders and administration site conditions Asthenia/fatigue Pain Fever

64 29 28

15 3 2

46 21 15

9 2 0

Metabolism and nutrition disorders Decreased appetite and food intake

Skin and subcutaneous tissue disorders HFSR/PPE Rash

45 26

17 6

7 4

0 <1

gastrointestinal disorders Diarrhea Mucositis

43 33

8 4

17 5

2 0

5.3 Dermatological toxicity Stivarga caused an increased incidence of hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE) and rash frequently requiring dose modification. The overall incidence of HFSR (45% versus 7%) and the incidence of Grade 3 HFSR (17% versus 0) were increased in Stivarga-treated patients in Study 1. The overall incidence of rash (26% versus 4%) and the incidence of Grade 3 rash (6% versus <1%) were higher in Stivarga-treated patients in Study 1 [see Adverse Reactions (6.1)]. The onset of dermatologic toxicity occurred in the first cycle of treatment in most patients. Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief.

investigations Weight loss

infections and infestations Infection

vascular disorders Hypertension Hemorrhage*

30 21

8 2

8 8

<1 <1

5.4 Hypertension Stivarga caused an increased incidence of hypertension (30% of Stivarga-treated patients vs. 8% of placebo-treated patients in Study 1) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.18% of 1100 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients. Do not initiate Stivarga until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Stivarga for severe or uncontrolled hypertension [see Dosage and Administration (2.2)].

respiratory, thoracic and mediastinal disorders Dysphonia

Nervous system disorders Headache

5.5 Cardiac ischemia and infarction Stivarga increased the incidence of myocardial ischemia and infarction (1.2% for Stivarga-treated patients vs. 0.4% of placebo-treated patients) [see Adverse Reactions (6.1)]. Withhold Stivarga in patients who develop new or acute onset cardiac ischemia or infarction. Resume Stivarga only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia. 5.6 reversible Posterior Leukoencephalopathy Syndrome (rPLS) RPLS (also known as posterior reversible encephalopathy syndrome) occurred in one of 1100 Stivargatreated patients across all clinical trials. Confirm the diagnosis of RPLS with MRI and discontinue Stivarga in patients who develop RPLS.

fatal outcomes observed Other clinically important adverse reactions observed more commonly in less than 10% of Stivarga-treated patients and at a higher incidence than in placebo-treated patients included the following: alopecia (7.6% vs. 1.6%), taste disorder (7.6% vs. 2.4%), musculoskeletal stiffness (6.0% vs. 2.0%), dry mouth (4.8% vs. 2.0%), hypothyroidism (4.2% vs. 0.4%), tremor (2.0% vs. 0.0), gastroesophageal reflux (1.4% vs. 0.0), and gastrointestinal fistula (0.8% vs. 0.4%). Keratoacanthoma/squamous cell carcinoma of the skin occurred in 0.09% of 1100 Stivarga-treated patients across open-label or placebo-controlled clinical trials. *

Laboratory Abnormalities Laboratory abnormalities observed in Study 1 are shown in Table 2. table 2: Laboratory test abnormalities reported in Study 1 Stivarga plus BSC (n=500*)

5.7 gastrointestinal Perforation or Fistula Gastrointestinal perforation or fistula occurred in 0.6% of 1100 patients treated with Stivarga across clinical trials. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula.

Laboratory Parameter

5.8 Wound Healing Complications No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, treatment with regorafenib should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on clinical judgment of adequate wound healing. Regorafenib should be discontinued in patients with wound dehiscence. 5.9 Embryo-Fetal toxicity Stivarga can cause fetal harm when administered to a pregnant woman. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 6 aDvErSE rEaCtiONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hepatotoxicity [See Warnings and Precautions (5.1)] • Hemorrhage [See Warnings and Precautions (5.2)] • Dermatological Toxicity [See Warnings and Precautions (5.3)] • Hypertension [See Warnings and Precautions (5.4)] • Cardiac Ischemia and Infarction [See Warnings and Precautions (5.5)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [See Warnings and Precautions (5.6)] • Gastrointestinal Perforation or Fistula [See Warnings and Precautions (5.7)] 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 rate observed in practice.

Placebo plus BSC (n=253*)

all %

grade** 3 %

4 %

all %

grade** 3 %

4 %

Blood and lymphatic system disorders Anemia Thrombocytopenia Neutropenia Lymphopenia

79 41 3 54

5 2 1 9

1 <1 0 0

66 17 0 34

3 <1 0 3

0 0 0 0

Metabolism and nutrition disorders Hypocalcemia Hypokalemia Hyponatremia Hypophosphatemia

59 26 30 57

1 4 7 31

<1 0 1 1

18 8 22 11

1 <1 4 4

0 0 0 0

Hepatobiliary disorders Hyperbilirubinemia Increased AST Increased ALT

45 65 45

10 5 5

3 1 1

17 46 30

5 4 3

3 1 <1

renal and urinary disorders Proteinuria

investigations Increased INR *** Increased Lipase Increased Amylase

24 46 26

4 9 2

N/A 2 <1

17 19 17

2 3 2

N/A 2 <1

% based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo) ** Common Terminology Criteria for Adverse Events (CTCAE), v3.0 *** International normalized ratio: No Grade 4 denoted in CTCAE, v3.0 *

ASCOPost.com | FEBRUARY 1, 2013 2013

PAGE 23

Announcements

Christopher Vakoc, MD, PhD

Roland Walter, MD, PhD

Myron Ignatius, PhD

Grant Challen, PhD

7 DrUg iNtEraCtiONS 7.1 Effect of Strong CYP3a4 inducers on regorafenib Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) [see Clinical Pharmacology (12.3)].

8.8 Females and Males of reproductive Potential Contraception Use effective contraception during treatment and up to 2 months after completion of therapy.

7.2 Effect of Strong CYP3a4 inhibitors on regorafenib Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)].

10 OvErDOSagE The highest dose of Stivarga studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no specific antidote for Stivarga overdose. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization.

8 USE iN SPECiFiC POPULatiONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)] Risk Summary Based on its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Stivarga in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. 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 In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC). In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. In a repeat dose study with daily administration of regorafenib to pregnant rats during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) with dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/ kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis. In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dosedependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies. 8.3 Nursing Mothers It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Stivarga, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established. In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate. 8.5 geriatric Use Of the total number of subjects in clinical studies of Stivarga, 39% were 65 and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients. 8.6 Hepatic impairment No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions (5.1)]. Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) as it has not been studied in this population. 8.7 renal impairment No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min/1.73m2) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min/1.73m2). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease.

Infertility There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology (13.1)].

13 NONCLiNiCaL tOXiCOLOgY 13.1 Carcinogenesis, Mutagenesis, impairment of Fertility Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells. Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans. 13.2 animal toxicology and/or Pharmacology In a chronic 26 week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals. 17 PatiENt COUNSELiNg iNFOrMatiON See FDA-Approved Patient Labeling (Patient Information). inform your patients of the following: • Stivarga may cause severe or life-threatening liver damage. Inform patients that they will need to undergo monitoring for liver damage and to immediately report any signs or symptoms of severe liver damage to their health care provider. • Stivarga can cause severe bleeding. Advise patients to contact their health care provider for any episode of bleeding. • Stivarga can cause hand-foot skin reactions or rash elsewhere. Advise patients to contact their health care provider if they experience skin changes associated with redness, pain, blisters, bleeding, or swelling. • Stivarga can cause or exacerbate existing hypertension. Advise patients they will need to undergo blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • Stivarga increased the risk for myocardial ischemia and infarction. Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, or feel dizzy or like passing out. • Contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, severe diarrhea (frequent or loose bowel movements), or dehydration. • Stivarga may complicate wound healing. Advise patients to inform their health care provider if they plan to undergo a surgical procedure or had recent surgery. • Inform patients that regorafenib can cause fetal harm. Advise women of reproductive potential and men of the need for effective contraception during Stivarga treatment and for up to 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her health care provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with Stivarga. • Advise nursing mothers that it is not known whether regorafenib is present in breast milk and discuss whether to discontinue nursing or to discontinue regorafenib. • Inform patients to take any missed dose on the same day, as soon as they remember, and that they must not take two doses on the same day to make up for a dose missed on the previous day. • Inform patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Any remaining tablets should be discarded 28 days after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle.

Manufactured in Germany Distributed and marketed by:

the pediatric cancer field will provide each researcher with $375,000 for his research. The ‘A’ Award, created in 2009, seeks to find the best and brightest young researchers and encourage them to build lifelong careers in the pediatric cancer field. “Since its inception, Alex’s Lemonade Stand Foundation has been dedicated to finding cures for all kids with cancer,” said Jay Scott, Co-Executive Director of the Foundation. “Through promising projects like [those of these researchers], we know that we are on the right course to not only finding those cures, but bettering the lives of children facing cancer both now and in the long term.” n

Samuel M. Silver, Elected as a Master of ACP

amuel M. Silver, MD, PhD has been elected as a Master of the American College of Physicians (ACP). Mastership is conferred upon a select number of candidates following election by ACP’s Awards Committee and Board of Regents.

Samuel M. Silver, MD, PhD

Dr. Silver is Assistant Dean for Research and Professor of Internal Medicine at the University of Michigan in Ann Arbor, Michigan. Additionally he holds several leadership roles within the National Comprehensive Cancer Network (NCCN), including Vice Chair of the NCCN Board of Directors, Chair of the NCCN Governance Committee, Member of the NCCN Executive Committee, and Member of the NCCN Guidelines Steering Committee. Mastership of ACP (MACP) is presented to physicians who are considered distinguished in the practice of internal medicine. The Mastership will be presented on April 11, 2013 at the ACP’s Convocation ceremony, in San Francisco, California.n

The ASCO Post | FEBRUARY 1, 2013

PAGE 24

Journal Spotlight Genitourinary Oncology

Postoperative Radiation Therapy Extends Progression-free Survival in Men with High-risk Prostate Cancer By Alice Goodman

ostoperative irradiation significantly improves biochemical progression-free survival and local control compared with a “wait-and-see” approach in men with high-risk prostate cancer, according to more than a decade of long-term follow-up in the European Organisation for Research and Treatment of Cancer [EORTC] 22911 trial. These findings, recently published online in The Lancet,1 confirm See Page 61 previously reported 5-year results of the trial. An exploratory analysis suggested that postoperative irradiation might improve clinical progression-free survival in men younger than age 70 years and in those with positive surgical margins, although a detrimental effect was suggested in men aged 70 years or older.

trast, patients aged 70 and older appear not to have a benefit. “Within the framework of a multimodal approach, the urologist should explain to the patient before radical prostatectomy that immediate irradiation could be applied if the patient has high-risk features, such as extracapsular extension, positive margins, and seminal vesicle involvement. Should the patient not agree, irradiation should probably be postponed until [prostate-specific antigen increase] becomes minimally detectable,” Dr. Bolla added.

■■ The benefit of postoperative radiation seems to be confined to men under

inclusion criteria. The study was done with contemporary radiation techniques at the time it was initiated. Radiation therapy was given within 16 weeks of surgery at a dose of 50 Gy to the prostate bed in 25 fractions over 5 weeks; a 10-Gy boost was given in 5 fractions over 1-week to a reduced volume. Patients assigned to the wait-and-see arm were treated at biochemical or clinical relapse with irradiation or another treatment. At a median follow-up of 10.6 years, the rate of biochemical progression was 39.4% in men who received radiation following surgery vs 61.8% in men assigned to the wait-and-see ap<�� .0001). Locoregional reproach (P �� lapse occurred in 8.4% of the postoperative irradiation group vs 17.3% of the wait-and-see group. However, the difference in clinical progression-free survival at 5 years of follow-up favoring postoperative irradiation was not maintained after 10 years, and both groups had similar rates of distant metastasis (about 11%) and overall survival (76.9% for postoperative irradiation vs 80.7% for the wait-and-see policy). The 10-year cumulative rate of prostate cancer–related mortality was 3.9% for postoperative irradiation vs 5.4% for the wait-and-see approach.

■■ Issues that remain to be resolved include optimal timing of postoperative

Unresolved Issues

Study Design EORTC 22911 randomly assigned 1,005 men to either a wait-and-see policy (n = 503) or postoperative radiation (n = 502). There was no consistent policy in the wait-and-see group, since not all men received radi-

Postoperative Radiation Therapy in Prostate Cancer ■■ Long-term follow-up of a large, randomized, phase III study in prostate

cancer confirmed that postoperative radiation for high-risk disease extends progression-free survival in men with extracapsular invasion, positive margins, and seminal vesicle involvement compared with a “wait-and-see” approach. the age of 70 years, and it may even harm older men.

radiation, optimal radiation technique, and the role of androgen deprivation therapy in combination with radiation in the salvage setting.

According to lead author Michel Bolla, MD, Centre Hospitalier Universitaire A Michallon, Grenoble, France, these results suggest that younger patients (ie, under age 70) and those with positive surgical margins derive significant benefit from postoperative radiation in terms of biochemical progression-free survival and local control and perhaps in clinical progression-free survival. In con-

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ation therapy at disease progression. The study population included men who were aged 75 or younger and had undergone radical prostatectomy. The prostate specimens had at least one of the following features denoting high risk: extracapsular extension, positive surgical margins, or seminal vesicle involvement. About 98% had no nodal involvement, and nodal involvement was not considered in the

In an accompanying editorial,2 Jason A. Efstathiou, MD, DPhil, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, noted that the long-term results of this study and other large trials still support the role of adjuvant irradiation in men with prostate cancer, especially those younger than 70 years, with high-risk features such as extracapsular extension, seminal vesicle involvement, and, most importantly, positive margins with acceptable long-term morbidity. However, he suggested there are unre-

Jason A. Efstathiou, MD, DPhil

solved issues in this setting that await results of other trials. These remaining issues include questions about the optimal timing of irradiation (adjuvant vs early salvage), and whether there is a benefit of more aggressive therapy in the salvage setting, such as androgen deprivation therapy in combination with irradiation and/or extending the radiation field to include the pelvic nodes and prostate bed. These questions are being explored in the RADICALS-HD, RAVES, GETUG-17, EORTC 22043, RTOG 9601, and RTOG 0534 trials. Dr. Efstathiou emphasized the need for a multidisciplinary approach when surgery alone has probably not been curative. “In this setting, prospective data still support postoperative radiation. The onus is on the uro-oncology team [surgical, radiation, and medical] to discuss postoperative radiation with the patient, address optimal timing of initiation when it is used, and to provide justification when it is not.”n Disclosure: Dr. Bolla and Dr. Efstathiou reported no potential conflicts of interest.

References 1. Bolla M, van Poppel H, Tombal B, et al: Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: Long-term results of a randomized controlled trial (EORTC 22911). Lancet 380(9858): 2018-2027, 2012. 2. Efstathiou JA: Postoperative radiation for prostate cancer. Lancet 380(9858): 1974-1976, 2012.

website at ASCOPost.com

XGEVA速 (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA速 is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. Please see the following pages for Important Safety Information.

XGEVA®, THE FIRST AND ONLY RANK LIGAND INHIBITOR TO PREVENT SREs

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 Hypocalcemia

Osteonecrosis of the Jaw (ONJ)

• XGEVA® can cause severe hypocalcemia. 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 hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• 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.

• 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.

• 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.

www.XGEVA.com

SUPERIORITY XGEVA® delayed the median time to ﬁrst SRE in a prespeciﬁed integrated analysis across 3 head-to-head studies vs zoledronic acid1

PERCENTAGE OF PATIENTS WITHOUT SRE

Time to first SRE, evaluated in more than 5,600 patients1,2 XGEVA® 120 mg Q4W (n = 2,862) zoledronic acid 4 mg Q4W (n = 2,861)

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

HR = 0.83 (95% CI: 0.76–0.90) P < 0.0001†

0 0

Reduction in risk of ﬁrst SRE in 3 individual studies • Breast cancer: 18% vs zoledronic acid (P = 0.010, superiority)3 • Prostate cancer: 18% vs zoledronic acid (P = 0.008, superiority)3 • Other solid tumors* or multiple myeloma: 16% vs zoledronic acid (P < 0.001, noninferiority; P = 0.060, NS for superiority)3 – Subanalysis of other solid tumors*: 19% vs zoledronic acid (P = 0.034, superiority)2 – XGEVA® is not indicated for the prevention of SREs in patients with multiple myeloma *Excluding breast and prostate cancer. † P value for superiority.

STUDY MONTH Data from three 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), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. 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.3

SUBCUTANEOUS INJECTION

NO DOSE ADJUSTMENTS

PRECISE ACTION

XGEVA® is not cleared by the kidneys and does not require dose adjustments, regardless of renal function3-8

XGEVA® acts precisely to bind XGEVA® is administered once to RANK Ligand, a key mediator every 4 weeks as a single, 120 mg of bone resorption, to inhibit subcutaneous injection3 osteoclast activity3

Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.3

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. During post approval use, severe symptomatic hypocalcemia, including fatal cases has been identiﬁed.

Please see brief summary of Prescribing Information on the following page.

REFERENCES: 1. Lipton A, Siena S, Rader M, et al. Comparison of denosumab versus zoledronic acid for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials. Ann Oncol. 2010;21(suppl 8):viii380. Abstract 1249P and poster. 2. Data on ﬁle, Amgen. 3. XGEVA® (denosumab) prescribing information, Amgen. 4. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066. 5. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2:645-653. 6. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493-507. 7. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010;24:23-39. 8. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50:793-807.

T:9.5â&#x20AC;?

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 25Â°C/77Â°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: None. WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. 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.

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 immunogenicity. Using an electrochemiluminescent bridging immunoassay, less receive care by a dentist or an oral surgeon. In these patients, extensive dental than 1% (7/2758) of patients with osseous metastases treated with denosumab surgery to treat ONJ may exacerbate the condition. doses ranging from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 weeks for up to PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant 3 years tested positive for binding antibodies. No patient with positive binding woman. Based on ďŹ ndings in animals, Xgeva is expected to result in adverse antibodies tested positive for neutralizing antibodies as assessed using a reproductive effects. In utero denosumab exposure in cynomolgus monkeys chemiluminescent cell-based in vitro biological assay. There was no evidence resulted in increased fetal loss, stillbirths, and postnatal mortality, along with of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical response associated evidence of absent peripheral lymph nodes, abnormal bone growth and with binding antibody development. The incidence of antibody formation is decreased neonatal growth (see Use in SpeciďŹ c Populations). There are no highly dependent on the sensitivity and speciďŹ city of the assay. Additionally, adequate and well controlled studies with Xgeva in pregnant women. Women the observed incidence of a positive antibody (including neutralizing antibody) should be advised not to become pregnant when taking Xgeva. If this drug is test result may be inďŹ&#x201A;uenced by several factors, including assay methodology, used during pregnancy, or if the patient becomes pregnant while taking this drug, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab the patient should be apprised of the potential hazard to the fetus. with the incidence of antibodies to other products may be misleading. ADVERSE REACTIONS: The following adverse reactions are discussed below DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted and elsewhere in the labeling: with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva t )ZQPDBMDFNJB TFF 8BSOJOHT BOE 1SFDBVUJPOT

was administered in combination with standard anticancer treatment. Serum t 0TUFPOFDSPTJT PG UIF +BX TFF 8BSOJOHT BOE 1SFDBVUJPOT) denosumab concentrations at 1 and 3 months and reductions in the bone turnover The most common adverse reactions in patients receiving Xgeva (per-patient marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, were similar in patients with and without prior intravenous bisphosphonate therapy. and nausea (see Table 1). The most common serious adverse reaction in patients There was no evidence that various anticancer treatments affected denosumab receiving Xgeva was dyspnea. The most common adverse reactions resulting in systemic exposure and pharmacodynamic effect. Serum denosumab concentrations discontinuation of Xgeva were osteonecrosis and hypocalcemia. at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone Clinical Trials Experience. Because clinical trials are conducted under widely therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar varying conditions, adverse reaction rates observed in the clinical trials of a drug between patients receiving concomitant chemotherapy and/or hormone cannot be directly compared to rates in other clinical trials and may not reďŹ&#x201A;ect the therapy (see Clinical Pharmacology [12.2] in full Prescribing Information). rates observed in practice. The safety of Xgeva was evaluated in three randomized, USE IN SPECIFIC POPULATIONS: double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Information) in which a total of 2841 patients with bone metastasis from prostate Xgeva can cause fetal harm when administered to a pregnant woman based cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple on ďŹ ndings in animals. In utero denosumab exposure in cynomolgus monkeys myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were resulted in increased fetal loss, stillbirths, and postnatal mortality, along with 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 evidence of absent lymph nodes, abnormal bone growth and decreased every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium neonatal growth. There are no adequate and well-controlled studies with Xgeva (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance in pregnant women. Women should be advised not to become pregnant when 30 mL/min or greater. Patients who had received IV bisphosphonates were taking Xgeva. If this drug is used during pregnancy, or if the patient becomes excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an pregnant while taking this drug, the patient should be apprised of the potential active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, hazard to the fetus. Women who become pregnant during Xgeva treatment are or any planned invasive dental procedure. During the study, serum chemistries encouraged to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or including calcium and phosphorus were monitored every 4 weeks. Calcium and their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 â&#x20AC;&#x201C; 41) and median duration on-study was 13 months (range: 0.1 â&#x20AC;&#x201C; 41). Of patients who received 9HFWB XFSF GFNBMF &JHIUZ mWF QFSDFOU XFSF 8IJUF )JTQBOJD -BUJOP Asian, and 3% Black. The median age was 63 years (range: 18 â&#x20AC;&#x201C; 93). SeventyďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.

DOUS2X0319_T_4Pg Tabloid_Update_Aug_12_BS_r8.indd 1

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 beneďŹ ts in continuing or discontinuing treatment with Xgeva.

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab 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 of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information). OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2Â°C to 8Â°C (36Â°F to 46Â°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25Â°C/77Â°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: t 4ZNQUPNT PG IZQPDBMDFNJB JODMVEJOH QBSFTUIFTJBT PS NVTDMF TUJGGOFTT twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) t 4ZNQUPNT PG 0/+ JODMVEJOH QBJO OVNCOFTT TXFMMJOH PG PS ESBJOBHF GSPN UIF jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) t 1FSTJTUFOU QBJO PS TMPX IFBMJOH PG UIF NPVUI PS KBX BGUFS EFOUBM TVSHFSZ (see Warnings and Precautions) t 1SFHOBODZ PS OVSTJOH (see Warnings and Precautions and Use in SpeciďŹ c Populations) Advise patients of the need for: t 1SPQFS PSBM IZHJFOF BOE SPVUJOF EFOUBM DBSF t *OGPSNJOH UIFJS EFOUJTU UIBU UIFZ BSF SFDFJWJOH 9HFWB t "WPJEJOH JOWBTJWF EFOUBM QSPDFEVSFT EVSJOH USFBUNFOU XJUI 9HFWB Advise patients that denosumab is also marketed as ProliaÂŽ. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ÂŠ2012 Amgen Inc. All rights reserved. Printed in USA.

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Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied Severity (Trials 1, 2, and 3) in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?). Xgeva Zoledronic Acid In cynomolgus monkeys dosed subcutaneously with denosumab throughout Body System n = 2841 n = 2836 pregnancy at a pharmacologically active dose, there was increased fetal loss during % % gestation, stillbirths, and postnatal mortality. Other ďŹ ndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal GASTROINTESTINAL bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and Nausea 31 32 tooth malalignment; and decreased neonatal growth. At birth out to one month of Diarrhea 20 19 age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects GENERAL on bone quality and strength returned to normal; there were no adverse effects Fatigue/ Asthenia 45 46 on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes INVESTIGATIONS were present, though small; and minimal to moderate mineralization in multiple )ZQPDBMDFNJBb 18 9 tissues was seen in one recovery animal. There was no evidence of maternal 32 20 )ZQPQIPTQIBUFNJBb harm prior to labor; adverse maternal effects occurred infrequently during labor. NEUROLOGICAL Maternal mammary gland development was normal. There was no fetal NOAEL (no )FBEBDIF 13 14 observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of RESPIRATORY denosumab) also caused fetal lymph node agenesis and led to postnatal impairment Dyspnea 21 18 of dentition and bone growth. Pregnant RANKL knockout mice showed altered Cough 15 15 maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials Nursing Mothers. It is not known whether Xgeva is excreted into human milk. 1, 2, and 3, and meeting one of the following criteria: Measurable concentrations of denosumab were present in the maternal milk t "U MFBTU HSFBUFS JODJEFODF JO 9HFWB USFBUFE QBUJFOUT PS of cynomolgus monkeys up to 1 month after the last dose of denosumab t #FUXFFO HSPVQ EJGGFSFODF FJUIFS EJSFDUJPO PG MFTT UIBO BOE NPSF UIBO (â&#x2030;¤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and 5% greater incidence in patients treated with zoledronic acid compared to because of the potential for serious adverse reactions in nursing infants from placebo (US Prescribing Information for zoledronic acid) Xgeva, a decision should be made whether to discontinue nursing or discontinue b Laboratory-derived and below the central laboratory lower limit of normal the drug, taking into account the importance of the drug to the mother. Maternal [8.3 â&#x20AC;&#x201C; 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL (0.71 â&#x20AC;&#x201C; 0.9 mmol/L) for phosphorus] signaling pathway that have shown altered maturation of the maternal mammary Severe Mineral/Electrolyte Abnormalities HMBOE MFBEJOH UP JNQBJSFE MBDUBUJPO QPTUQBSUVN )PXFWFS JO DZOPNPMHVT t 4FWFSF IZQPDBMDFNJB DPSSFDUFE TFSVN DBMDJVN MFTT UIBO NH E- PS MFTT monkeys treated with denosumab throughout pregnancy, maternal mammary than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% gland development was normal, with no impaired lactation. Mammary gland of patients treated with zoledronic acid. Of patients who experienced severe histopathology at 6 months of age was normal in female offspring exposed to hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia denosumab in utero; however, development and lactation have not been fully and 16% experienced 3 or more episodes (see Warnings and Precautions and evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information). Use in SpeciďŹ c Populations). Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and t 4FWFSF IZQPQIPTQIBUFNJB TFSVN QIPTQIPSVT MFTT UIBO NH E- PS MFTT UIBO effectiveness of Xgeva in pediatric patients have not been established. Treatment 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of with Xgeva may impair bone growth in children with open growth plates and patients treated with zoledronic acid. may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target Osteonecrosis of the Jaw of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in at doses â&#x2030;¤ 10 mg/kg was associated with inhibition of bone growth and tooth 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic eruption. Adolescent primates treated with denosumab at doses 5 and 25 times acid group (see Warnings and Precautions). When events occurring during an (10 and 50 mg/kg dose) higher than the recommended human dose of extended treatment phase of approximately 4 months in each trial are included, 120 mg administered once every 4 weeks, based on body weight (mg/kg), had the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Postmarketing Experience. Because postmarketing reactions are reported decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and voluntarily from a population of uncertain size, it is not always possible to reliably mesenteric lymph nodes. Some bone abnormalities recovered once exposure estimate their frequency or establish a causal relationship to drug exposure. was ceased following birth; however, axillary and inguinal lymph nodes remained The following adverse reactions have been identiďŹ ed during post approval absent 6 months post-birth (see Use in Pregnancy). use of Xgeva: Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) t )ZQPDBMDFNJB Severe symptomatic hypocalcemia, including fatal cases. were 65 years of age or older. No overall differences in safety or efďŹ cacy were Immunogenicity. As with all therapeutic proteins, there is potential for observed between these patients and younger patients.

ASCOPost.com | FEBRUARY 1, 2013

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Direct from ASCO

Philanthropy Spotlight Coalition of Cancer Cooperative Groups Celebrates 10 Years of Clinical Trial Participation Awards

or any community practice, participation in a clinical trial can be a time-consuming, intense commitment. But this commitment is integral to the advancement of new methods and therapies, which is why the Coalition of Cancer Cooperative Groups has exactly one mission: increasing clinical trial participation. Ten years ago, the Coalition partnered with the Conquer Cancer Foundation of the American Society of Clinical Oncology and ASCO to support the Clinical Trials Participation Awards, which are presented to highquality community-based practices participating in clinical trials. 2012 marked the 10th consecutive year that the Coalition has supported the awards.

Shared Commitment to Clinical Trials The Coalition of Cancer Cooperative Groups was established in 1997 to address its members’ shared goal of improving the cancer clinical trials system by improving patient awareness of cancer clinical trials, facilitating access, and promoting participation. Today, the Coalition comprises members from 10 National Cancer Institute–sponsored Cooperative Groups, the country’s leading patient advocacy organizations, and thousands of oncology and cancer research specialists. Several years later, in 2001, ASCO formed the Clinical Trials Task Force as part of its strategic planning process to recommend initiatives to increase clinical trial awareness and participation by physicians. Establishing the Clinical Trials Participation Awards was one of

the recommendations of this task force. The awards recognize the commitment of community practices who contribute to the growing body of clinical oncology data through participating in clinical trials. Since the first award was granted in 2003, over 100 awards have been presented to deserving community practices, and for all 10 years, this program has been generously supported by the Coalition of Cancer Cooperative Groups. Each year, starting in January, ASCO solicits award nominees from each of the National Cancer Institute (NCI) Cooperative Groups, as well as from each of the following major community-based oncology research networks. All nominated practices are then invited to formally submit an application, which is then peer-reviewed by the Clinical Trials Participation Award Review and Selection Subcommittee of the Conquer Cancer Foundation. Winners are those practices determined to have high-quality, community-based research programs with investigators in good standing, and high accrual by site, by individual investigator, or of underserved populations. The awards are presented annually at the ASCO Annual Meeting.

A Tradition of Partnership The Clinical Trial Participation Awards are not the only instance where the Coalition has partnered with the Conquer Cancer Foundation. Collectively, the Cooperative Groups treat more than half of all patients participating in clinical trials in the United States, and in 2007, Cancer Coopera-

Conquer Cancer Foundation Grant Recipients Supported by Kidney Cancer Association (2006-2012) ■■ Henk Verheul, MD, PhD

(2006 YIA) VU University Medical Center

■■ Patricia Tang, MD (2007 YIA) Princess Margaret Hospital

■■ Kevin Courtney, MD, PhD

(2008 YIA) University of Texas Southwestern Medical Center

■■ Aymen Elfiky, MD (2008 YIA) Dana-Farber Cancer Institute

■■ Stephen Keefe, MD (2009 YIA) University of Pennsylvania

■■ Aditya Bardia, MBBS, MPH

(2010 YIA) Massachusetts General Hospital

■■ Thai Ho, MD, PhD (2011 YIA) The University of Texas, M.D. Anderson Cancer Center

■■ Martin Voss, MD (2012 YIA)

Memorial Sloan-Kettering Cancer Center

2012 Clinical Trials Participation Award recipients

tive Groups became the first group to receive an American Society of Clinical Oncology Distinguished Service Award for Scientific Leadership, recognizing the “team science” achievements of the Cooperative Groups in designing and conducting cancer clinical trials. ASCO has also collaborated with the Coalition to present, along with the Oncology Nursing Society, a clinical trials workshop designed to help oncologists and their health-care and practice management teams evaluate, integrate, and conduct successful clinical trials in the community practice setting, and a Summit Series on Clinical Trials highlighting some of the major issues that relate to cancer clinical trials. A nonprofit organization founded in 1997, the Coalition’s mission is to improve the quality of life and survival of cancer patients by increasing participation in cancer clinical trials. The Coalition has created and made available a suite of programs and services designed to increase the understanding of cancer clinical trials and boost participation. Since the Coalition’s founding, patient participation in Cooperative Group trials has gone up by about 30%. “We are extremely grateful for the support of the Coalition of Cancer Cooperative Groups,” says Nancy R. Daly, MS, MPH, Executive Director of the Conquer Cancer Foundation. “Clinical trials are the cornerstone of oncology research. Our shared commitment to increased participation in clinical trials will one day deliver better, more well-executed trials that bring significant advances for patients and their caregivers. Together, we will all realize the Conquer Cancer Foundation’s ultimate vision: creating a world that’s free from the fear of cancer.”

Applications for the 2013 Clinical Trial Participation Awards will be available shortly. To learn more, please visit http://www.conquercancerfoundation.org/cancer-professionals/grants-awards/clinicaltrials-participation-award. To learn more about the Coalition of Cancer Cooperative Groups, visit http:// www.cancertrialshelp.org. To learn more about the Conquer Cancer Foundation and to make a donation in support of our Grants and Awards Program, visit www. conquercancerfoundation.org. n © 2013. American Society of Clinical Oncology. All rights reserved.

Clinical Trials Participation Award: 2012 Recipients ■■ Altru Cancer Center of Altru Health System Grant Forks, North Dakota

■■ Billings Clinic Billings, Montana

■■ Derrick L. Davis Forsyth Regional Cancer Center Winston Salem, North Carolina

■■ LRGHealthcare-Lakes Region General Hospital Laconia, New Hampshire

■■ Northwest Medical Specialties Tacoma, Washington

■■ West Michigan Cancer Center Kalamazoo, Michigan

The ASCO Post | FEBRUARY 1, 2013

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New England Journal of Medicine Article Reports Inferior Outcome in Using Alternative Treatments to Counter Mechlorethamine Shortage

SCO Immediate Past President Michael P. Link, MD, recently coauthored a perspectives piece in The New England Journal of Medicine on the impact of drug shortages on children with cancer. The paper, “The Impact of Drug Shortages on Children with Cancer — The Example of Mechlorethamine,” describes the impact of using alternative treatments to counter shortages of the drug mechlorethamine (Mustargen), also known as nitrogen mustard. Mechlorethamine was one of the first anticancer agents created and has been used in a 12-week chemotherapy regimen for treating children and adults with Hodgkin lymphoma that includes vinblastine, doxorubicin, vincristine, bleomycin, etoposide, and prednisone. When mechlorethamine went into shortage in 2009, it was substituted with cyclophospha-

mide in the regimen.

Greater Event-free Survival with Mechlorethamine A retrospective analysis through the Pediatric Hodgkin Lymphoma Consortium compared the probability of event-free survival among 181 patients who were treated with the original regimen including mechlorethamine with 40 patients treated with the modified regimen including cyclophosphamide. The study found that 88% of patients treated with the established regimen with mechlorethamine were expected to be eventfree survivors at 2 years, compared to

only 75% of those treated with the cyclophosphamide-containing regimen. The article noted: Almost 80% of children and adolescents with cancer can be cured with current therapy. Most of the curative treatment regimens are based on chemotherapeutic agents that have been available for decades, but some of these have recently been in short supply. These shortages are likely to have devastating effects on patients with cancer and must be prevented. For many of these agents, no adequate substitute drugs are available. Our results suggest that even promising substitute regimens should be

examined carefully before adoption; what might appear to be a suitable alternative regimen may result in an inferior outcome—an intolerable situation for young people with curable diseases.

ASCO is currently in the process of surveying its members to gauge how shortages are impacting their practice and will continue to monitor the situation. Please continue to visit ascoaction.asco.org for the latest news on drug shortages, research and cancer policy. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO Decision Aids Intersect Evidence-based Guidelines, Productive Patient Communication

magine this common clinical scenario: A 64-year-old woman presents with a new abnormality on a mammogram. A core needle biopsy and subsequent partial mastectomy reveal a 1.8-cm invasive ductal carcinoma. Sentinel lymph nodes are negative for cancer. The tumor is moderately differentiated and is estrogen receptor–positive, progesterone receptor–positive, and HER2-negative. Oncotype DX testing reveals a recurrence score of 12 (low risk). The patient completes postlumpectomy radiation and now presents to your clinic to discuss adjuvant antiestrogen strategies. What are the treatment options? How do you present them clearly to your patient? And how do you ensure that she is a partner in decision-making? ASCO Decision Aids (asco.org/ clinicaltools) can facilitate these discussions. These tools are based on the science in ASCO’s evidence-based clinical practice guidelines and incorporate the best practices of decision aid development (see Additional Readings).

They allow the clinician to display and explain information on risk and benefits, and help the patient think about his or her own values and preferences. Research suggests that the use of decision aids increases patient knowledge without increasing anxiety, and can increase patient satisfaction.

Streamlining the Decisionmaking Process Decision aids can streamline the decision-making process and their use frequently leads to a finalized decision about care. “When I have used the ASCO Adjuvant Endocrine Therapy Decision Aid with women in my practice, it has cut down on the number of times I’ve received follow-up phone calls,” said Michael A. Danso, MD, of Virginia Oncology Associates and ASCO Practice Guidelines Implementation Network (PGIN) Co-Chair. In the scenario above, the patient has more than one treatment option (outlined in the ASCO Guideline Update on Adjuvant Endocrine Ther-

apy for Women with Hormone Receptor–Positive Breast Cancer). The options carry benefits and risks and none is clearly superior—a frequent

nician in explaining them. Decision aids help to bridge this gap and lead to shared decision-making. For example, the ASCO Decision

[Decision aids allow] me to give my patients a more complete picture of the treatment regimen, potential benefits and risks, including an excellent summary table on potential chemotherapy toxicities. —James N. Frame, MD

experience in oncology. Patients in this situation may experience feelings of uncertainty, difficulty identifying the best option, and concern they will regret their choice (“decisional conflict”). Although clinical practice guidelines and clinical trials may guide the clinician, guidelines and study results are typically not written with a patient audience in mind, and circumstances may constrain the cli-

Aid for this scenario includes data showing potential benefits and risks or harms of tamoxifen, aromatase inhibitors, or a sequential combination. It appeals to a variety of learning styles, including visual and auditory. Graphics are formatted to quickly and comprehensibly communicate data in text and pictographs. After the visit, the patient can use the Decision Aid’s worksheet (based on the

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Direct from ASCO

Ottawa Personal Decision Guide), to reflect on the discussion, plan next steps (such as seeking support from others), and make the best choice for him or herself. ASCO Decision Aids are available for adjuvant endocrine therapy and risk reduction in breast cancer, and adjuvant treatment and treatment of advanced disease in non–small cell lung cancer. “This information allows me to give my patients a more complete picture of the treatment regimen, potential benefits and risks, including an excellent summary table on potential chemotherapy toxicities,” said James N. Frame, MD, of Charleston Area Medical Center and PGIN CoChair, who uses the ASCO Decision Aid on the treatment of advanced non-small cell lung cancer in his practice. n Originally printed in ASCO Connection. © 2013 American Society of Clinical Oncology. (“ASCO Decision Aids Intersect Evidence-Based Guidelines, Productive Patient Communication.” ASCO Connection, November 2012: 36-37) All rights reserved.

Health Insurance Issues for Young Cancer Survivors

he latest addition to Cancer. Net’s video series for young adults, Moving Forward: Perspectives from Survivors and Doctors, deals with the health insurance issues young adult cancer survivors may face. This video series is a collaboration between Cancer. Net and LIVESTRONG. Each set of videos in the series features an ASCO member and a young adult cancer survivor See Page 61 discussing issues that young survivors may encounter after treatment; watch them all at www.cancer.net/movingforward. n © 2013. American Society of Clinical Oncology. All rights reserved.

Additional Readings 1. O’Brien MA, Whelan TJ, VillasisKeever M, et al. Are cancer-related decision aids effective? A systematic review and meta-analysis. J Clin Oncol 6:974985, 2009. 2. O’Connor A, Jacobsen MJ, Stacey D. An evidence-based approach to man-

aging women’s decisional conflict. J Obstet Gynecol Neonatal Nurs 31;570-581, 2002. 3. Barry MJ, Edgman-Levitan S. Shared decision making—pinnacle of patient-centered care. N Engl J Med 366:780-781, 2012. 4. Fagerlin A, Zikmund-Fisher BJ,

Ubel PA. Helping patients decide: Ten steps to better risk communication. J Natl Cancer Inst 103:1436-1443, 2011. 5. Stacey D, Bennett CL, Barry MJ, et al. Decision aids for people facing health treatment or screening decisions. Cochrane Database Syst Rev 10:CD001431, 2011.

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Direct from ASCO

ASCO’s CancerProgress.Net: Where We’ve Come From, Where We Are, and Where We’re Going By Kirsten Goldberg

he British science historian James Burke once wrote, “If you don’t know where you’ve come from, you don’t know where you are.” To tell the story of where we are in the treatment of people with cancer and how we got there, ASCO launched an ambitious history project in 2011 with a new website, CancerProgress.Net (http://www.cancerprogress.net/). CancerProgress.Net is a resource for anyone with an interest in the progress that has been made and continues to be made against cancer. The site demonstrates the significant progress that has been made in cancer treatment, diagnosis, detection, and prevention in the past 50 years—within the lifetimes of many current ASCO members, some of whom have taken part in creating this history. Yet it also demonstrates that much work remains to be done in reducing cancer incidence and mortality. “Clinical research has played a major part in the advances in the last few decades in cancer treatment,” said Robert Sticca, MD, of University of North Dakota School of Medicine and Health Sciences and an executive editor of CancerProgress.Net. “Without the research funded through national cooperative group trials, I don’t think we would have made many of the advances we’ve made.”

Robert Sticca, MD

Interactive Timeline The central feature of the site is an interactive timeline of major milestones in cancer treatment, prevention, and detection, covering 17 different cancer types. Three can-

Ghassan K. Abou-Alfa, MD

David H. Ilson, MD, PhD, of Memorial Sloan-Kettering (stomach); and Everett E. Vokes, MD, of University of Chicago (head and neck). Last December, ASCO added a new section to CancerProgress.Net dedicated to the most important clinical cancer advances from the past year, based on ASCO’s annual Clinical Cancer Advances report. The report complements ASCO’s Blueprint for Accelerating Progress Against Cancer, also featured on the site, which lays out ASCO’s vision for a revitalized research system that delivers more effective and personalized cancer therapies, faster.

David H. Ilson, MD, PhD

cer timelines were added to the site in 2012: liver, stomach, and head and neck cancer. The new timelines were curated by CancerProgress. Net specialty editors Ghassan K. Abou-Alfa, MD, of Memorial SloanKettering Cancer Center (liver);

Everett E. Vokes, MD

Engaging Visitors The site was recently expanded to feature the voices of patients and advocates, who speak to the value of cancer research and the specific and personal impact it has had in their lives. These compelling video

interviews have become instantly popular. The site also includes video interviews with oncologists that help bring the story of cancer research progress alive. “CancerProgress.Net is an engaging resource providing an overview of how far we’ve come in the past several decades, and the important work we have left to do,” said Howard Sandler, MD, of Cedars-Sinai Medical Center and an executive editor of CancerProgress. Net. “The story of this progress shows just how urgent it is that we continue the momentum with sustained public and private support for clinical cancer research.” To help users delve even more deeply into the progress made in recent decades, the site editors last year added links to primary research articles associated with the advances chronicled on the interactive website. In addition, visitors can use the site’s data visualizer to examine cancer statistics. ASCO created CancerProgress. Net to mark the 40th anniversary of the National Cancer Act of 1971, which led to major new investments in cancer research and significant increases in cancer survival. n © 2013. American Society of Clinical Oncology. All rights reserved.

The Conquer Cancer Foundation Announces Its Sustaining Donor Program

ou can help the Conquer Cancer Foundation fulfill its mission of creating a world free from the fear of cancer when you make a monthly gift today. When you become a sustaining donor to the Foundation, your monthly gift will provide a reliable stream of support that is so vital to ensuring that the Foundation can continue to support superlative cancer researchers all over the world. Whether you choose to support bi-

lingual patient resources like Cancer. Net or the training and education of oncologists here and abroad, you can feel confident that your investment is

truly making a difference. And, we continue to be acknowledged from

Charity Navigator for outstanding transparency, accountability, and stewardship of our funds; the Foundation holds their highest score, a four-star ranking. Here is how it works: ■■ You determine the amount of your monthly donation. You can alter or stop it at any time by calling the Foundation. ■■ Your credit card is charged on the 15th of each month, and you’ll receive an email confirmation when charged. ■■ Each January, you will receive an

annual giving statement from the previous tax year, which can be used for tax purposes. In order to participate in our sustaining donor program, we invite you to visit the website at www. ConquerCancerFoundation.org and select “Yes, automatically repeat this donation every month.” Of course, we encourage you to call us at 571-4831700—a member of the Foundation staff would be happy to assist you. n © 2013. American Society of Clinical Oncology. All rights reserved.

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Perspective

Cost of Cancer Drugs continued from page 1

bled, from $4,500 to about $10,000 per month.3 It has been suggested that “profiteering” (making profit by unethical methods, such as raising prices after natural disasters) could be applied to this recent trend, where life-threatening disease is the natural disaster. Pharmaceutical companies contend the higher prices are necessary to support investment in research and development. The often-cited cost of bringing anticancer drugs to FDA approval is $1 billion. This figure may be inflated to include ancillary expenses, salaries, bonuses, and other indirect costs not related to research and development. This trend of increasing drug prices is not unique to targeted new molecules but also applies to novel or reformulated chemotherapy drugs. How are anticancer drug prices set? Quite arbitrarily, it appears, by pharmaceutical companies that charge “what the market will bear.” As new agents are approved by the FDA, pharmaceutical companies seem to analyze the market response to the most similar previous agent, and then set the price of the new drug about 15% to 20% higher. In a free market, the hope is that the drug price settles according to its real benefit. But there seems to be little correlation between the actual benefit of a new drug and its price, based on standardized objective measures like cost-efficacy ratios, prolongation of patient life in years, or quality-adjusted life-year.4

Self-inflicted Wounds An interesting phenomenon involves laws that explicitly prohibit

Medicare from negotiating lower drug prices (although the Department of Veterans Affairs can, and actually does pay about 50% of the prices paid by Medicare). These laws may have resulted from interest-group pressures to protect the profits of pharmaceutical companies at the expense of our health care. Most other countries pay significantly lower prices for cancer drugs. For example, the prices of drugs to treat chronic myeloid leukemia in the rest of the world are 25% to 50% those a patient pays in the United States. This seems unfair to our U.S. health-care system and equally unfair to our patients, who often shoulder the burden of such costs (about 20% of the price of drugs, which may come out to about one-quarter of

on rational discussions of their costbenefit as well as both individual and societal costs.

Value-based Pricing We propose that experts in particular tumors convene and discuss the prices of new cancer drugs once they are FDA-approved. Discussions should involve governmental health agencies, Medicare, FDA, expert oncologists, insurance companies, pharmaceutical companies, and other interested parties. Only then can we come up with acceptable solutions that provide financial profit to pharmaceutical companies but safeguard the economic infrastructure of the U.S. health-care system and avoid undue financial bur-

We propose that experts in particular tumors convene and discuss the prices of new cancer drugs once they are FDA-approved.… Only then can we come up with acceptable solutions…and avoid undue financial burden on patients with cancer. —Hagop M. Kantarjian, MD, and Leonard Zwelling, MD, MBA

a household income). Is it any wonder that the most common cause of personal bankruptcy in the United States is medical bills? Allowing the free market to set drug prices has spiraled the cost of cancer care out of control. However, our self-inflicted wounds can be easily remedied through new legislation that allows U.S. health-care agencies better leverage on drug prices and health-care costs. More reasonable prices of new anticancer agents need to be based

den on patients with cancer. Any of several methodologies can be employed to derive a reasonable price for a new anticancer agent. Simple measures of efficacy could be based on the amount of time a new drug prolongs life. For example, if survival is prolonged by more than 6 months and/or by more than one-third of the patient’s life expectancy (eg, 12–18+ months or 30–40+ months), this would be considered extremely effective and would put the drug price in a higher range—for example,

over $50,000 per year, but not more than $75,000. A drug that prolongs survival by 3 to 6 months and/or by 25% to 33% of life expectancy (eg, 12–16 months or 30– 37 months) would be considered beneficial and priced modestly—perhaps between $30,000 to 50,000 per year. Finally drugs that demonstrate “statistically significant survival benefits” of 2 months or less and less than 25% prolongation of life expectancy would be considered to have minimal efficacy and priced below $30,000 a year. This proposal would present a true value-based pricing system. The better the drug, the more the drug company can make. Is this not the American way? n Disclosure: Drs. Kantarjian and Zwelling reported no potential conflicts of interest.

References 1. National Health Expenditure Projections 2011-2020. Available at http://www. cms.gov/Research-Statistics-Data-andSystems/Statistics-Trends-and-Reports/ NationalHealthExpendData/Downloads/ Proj2011PDF.pdf. Accessed October 2012. 2. 2012 Annual Report of the Board of Trustees of the Federal Hospital Insurance and Federal Supplementary Medical Insurance Trust Funds. Available at https://www. cms.gov/ReportsTrustFunds/downloads/ tr2012.pdf. Accessed October 26, 2012. 3. Fojo T, Grady C: How much is life worth: Cetuximab, non-small cell lung cancer, and the $440 billion Question. J Natl Cancer Inst 101:1044-1048, 2009. 4. Hillner B, Smith T: Efficacy does not necessarily translate to cost effectiveness: A case study in the challenges associated with 21st-century cancer drug pricing. J Clin Oncol 27:2111-2113, 2009.

Don’t Miss These Important Reports in this Issue of The ASCO Post Neal Meropol, MD, on Patient Expectations in Clinical Trials see page 38

Eduardo Bruera, MD, FAAHPM, on Patients’ Understanding of Prognosis see page 44

Kevin P. Weinfurt, MD, on Communicating with Patients and Informed Consent see page 38

James F. Holland, MD, on Clinical Research in the Early Days of Chemotherapy see page 52

Visit The ASCO Post online at ASCOPost.com

V. Craig Jordan, OBE, PhD, DSc, Sir Richard Peto, FRS, and other experts on Tamoxifen Therapy and the ATLAS Study see page 59

6.7 months median PFS with INLYTA vs 4.7 months with sorafenib INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Gastrointestinal perforation and fistula, including death, have occurred. Blood pressure should be well controlled prior to initiating INLYTA. Use with caution in patients at risk for gastrointestinal perforation Monitor for hypertension and treat as needed. For persistent or fistula. Monitor for symptoms of gastrointestinal perforation or hypertension, despite use of antihypertensive medications, reduce fistula periodically throughout treatment. the dose. Discontinue INLYTA if hypertension is severe and persistent Hypothyroidism requiring thyroid hormone replacement has been despite use of antihypertensive therapy and dose reduction of reported. Monitor thyroid function before initiation of, and periodically INLYTA, and discontinuation should be considered if there is throughout, treatment. evidence of hypertensive crisis. Stop INLYTA at least 24 hours prior to scheduled surgery. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue who have a history of these events. Hemorrhagic events, including fatal events, have been reported. treatment. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

INLYTA

for the treatment of advanced RCC after failure of one prior systemic therapy

PROOF OF SUPERIOR EFFICACY VERSUS SORAFENIB IN 2nd-LINE mRCC

IT MATTERS. Superior progression-free survival (PFS) vs sorafenib HR=0.67 (95% CI: 0.54, 0.81); P<.0001

Proportion progression-free

1.0 0.9

INLYTA (n=361)

6.7months (95% CI: 6.3, 8.6)

0.8

[43% longer median PFS]

0.7 0.6 0.5 0.4 0.3

Sorafenib (n=362)

4.7months (95% CI: 4.6, 5.6)

0.2 0.1 0.0

Time (months) Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 twice daily) with dose adjustments allowed in both groups.1

More than doubled objective response rate1 19.4% vs 9.4% with sorafenib –95% Cl: 15.4, 23.9 and 6.6, 12.9, respectively –Risk ratio: 2.06 (95% CI: 1.41, 3.00) All responses were partial responses per RECIST criteria

INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3 in vitro and in preclinical models Preclinical activity does not necessarily correlate with clinical outcomes

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Please see brief summary on the following page.

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimens). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident [see Adverse Reactions]. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to *10 U/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. 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. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

AXU470817

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA 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 INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (*20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in *10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in *10% of Patients Who Received INLYTA or Sorafenib INLYTA

Sorafenib

(N=359)

Adverse Reaction

(N=355)

All Gradesb

Grade 3/4

All Gradesb

Grade 3/4

% 55 40 39 34 32 31 27 25 24 21 20 19 15 15 15 15 15 14 14 13 13 11 11 10 10 7 4 2

% 11 16 11 5 3 0 5 2 3 5 1 <1 1 1 2 1 3 2 1 1 <1 3 0 0 0 0 0 0

% 53 29 32 29 22 14 51 21 17 14 20 8 17 12 11 12 12 11 11 14 32 7 8 11 2 12 32 10

% 7 11 5 4 1 0 16 1 1 3 1 0 1 1 1 <1 3 1 0 1 4 2 0 0 0 0 0 <1

Diarrhea Hypertension Fatigue Decreased appetite Nausea Dysphonia Palmar-plantar erythrodysesthesia syndrome Weight decreased Vomiting Asthenia Constipation Hypothyroidism Cough Mucosal inﬂammation Arthralgia Stomatitis Dyspnea Abdominal pain Headache Pain in extremity Rash Proteinuria Dysgeusia Dry skin Dyspepsia Pruritus Alopecia Erythema

Percentages are treatment-emergent, all-causality events National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0

a b

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic attack (1%), and RPLS (<1%). The following table presents the most common laboratory abnormalities reported in *10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in *10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality Hematology Hemoglobin decreased Lymphocytes (absolute) decreased Platelets decreased White blood cells decreased Chemistry Creatinine increased Bicarbonate decreased Hypocalcemia ALP increased Hyperglycemia Lipase increased Amylase increased ALT increased AST increased Hypernatremia Hypoalbuminemia Hyperkalemia Hypoglycemia Hyponatremia Hypophosphatemia

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

336 314 336 336 336 338 338 331 331 338 337 333 336 338 336

55 44 39 30 28 27 25 22 20 17 15 15 11 13 13

0 <1 1 1 2 5 2 <1 <1 1 <1 3 <1 4 2

318 291 319 319 319 319 319 313 311 319 319 314 319 319 318

41 43 59 34 23 46 33 22 25 13 18 10 8 11 49

<1 0 2 1 2 15 2 2 1 1 1 3 <1 2 16

DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (*15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at *0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib 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 INLYTA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at *15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at *5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were *65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were *65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min )creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at *15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and *1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at *5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (*15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. 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). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only Issued: February 2012 Reference: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.

a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib).

May 2012

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PAGE 37

In the Clinic Head and Neck Cancer

Cabozantinib in Metastatic Medullary Thyroid Cancer By Matthew Stenger

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

Indication On November 29, 2012, cabozantinib (Cometriq) was approved for the treatment of patients with progressive metastatic medullary thyroid cancer.1 Approval was based on results of an international trial in which 330 patients with metastatic medullary thyroid cancer were randomly assigned to receive oral cabozantinib at 140 mg (n = 219) or placebo (n = 111) daily until disease progression or intolerable toxicity.2 Patients were required to have progressive disease within 14 months prior to entry. Overall, patients had a median age of 55 years (23% ≥ 65 years), 67% were male, 90% were white, 54% had ECOG performance status of 0, and 92% had undergone thyroidectomy; 25% had received two or more prior systemic therapies and 21% had prior tyrosine kinase inhibitor treatment. Placebo patients could not cross over to cabozantinib at progression. Median progression-free survival was 11.2 months in the cabozantinib group and 4.0 months in the placebo group, representing a significant 72% reduction in risk of progression (hazard ratio [HR] = 0.28, P < .0001). The overall response rate was 27% (all partial responses)

OF NOTE Cabozantinib is a small-molecule inhibitor of multiple tyrosine kinases involved in normal cellular function as well as in oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. <� �� .0001), and median revs 0% (P �� sponse duration was 14.7 months. No significant difference in overall survival was observed between the groups at a planned interim analysis or in an updated survival analysis requested by FDA.

How It Works Cabozantinib is a small-molecule inhibitor of the activity of multiple tyrosine kinases—RET, MET, VEGFR-1, -2, and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. These kinases are involved in both normal cellular function and in oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

How It Is Given Cabozantinib is given at a dosage of 140 mg once daily. Patients should not eat for least 2 hours before and 1 hour after taking the medication. There are no specific contraindications to cabozantinib use. Cabozantinib is a CYP3A4 substrate, and concomitant use of strong CYP3A4 inhibitors (eg, ritonavir, idinavir, clarithromycin, ketoconazole,

cardial infarction, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, osteonecrosis of the jaw, and reversible posterior leukoencephalopathy syndrome. Patients should have blood pressure and urine protein monitored regularly and should be monitored for signs and symptoms of bleeding.

Safety Profile Adverse events occurring in at least 30% of cabozantinib patients and at an incidence at least 5% greater than in placebo patients included diarrhea (63% vs 33%), stomatitis (51% vs 6%), palmar-plantar erythrodysesthesia syndrome (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs

Cabozantinib in Metastatic Thyroid Cancer ■■ Cabozantinib (Cometriq) has been approved for the treatment of patients with progressive metastatic medullary thyroid cancer.

■■ The drug is given at 140 mg once daily, at least 2 hours after and 1 hour before eating.

itraconazole) or CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John’s wort) should be avoided. The cabozantinib daily dose should be reduced by 40 mg if concomitant use of strong inhibitors is required (or increased by 40 mg if concomitant use of strong inducers is required) and returned to the prior dose 2 to 3 days after stopping treatment with the inhibitor (or inducer). Patients with moderate or severe hepatic impairment should not receive cabozantinib. Treatment should be withheld for grade 4 hematologic toxicity, grade 3 or higher nonhematologic adverse reactions, or intolerable grade 2 adverse reactions. Upon resolution/improvement of adverse reactions, the dose should be reduced by 40 mg; treatment should be stopped in patients unable to tolerate a retrial of a 60-mg daily dose. Overall, dose reduction was required in 79% of patients in the clinical trial. Treatment should be permanently discontinued for any of the following: visceral perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic event (eg, myo-

21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), and hypertension (33% vs 4%). Grade 3 or 4 adverse events that occurred in at least 8% of cabozantinib patients and at an incidence at least 2% greater than that in patients receiving placebo were diarrhea (16% vs 2%), palmar-plantar erythrodysesthesia syndrome (13% vs 0%), fatigue (9% vs 3%), and hypertension (8% vs 0%). Nearly all cabozantinib patients experienced elevated blood pressure, and 61% vs 30% of placebo patients had overt hypertension (based on Joint National Committee staging criteria). No patients developed malignant hypertension. The most common laboratory abnormalities of any grade (≥�� 35%) in cabozantinib patients were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%), increased alkaline phosphatase (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), and thrombocytopenia (35% vs 4%). The most common grade 3 or 4 abnormalities were lymphopenia (16% vs 11%), hypocalcemia (12% vs 3%), increased ALT (6% vs 2%), and hy-

OF NOTE The most common adverse events with cabozantinib therapy include diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, and hypertension. pokalemia (4% vs 3%). Serious adverse events attributed to cabozantinib included pancreatitis in 3 patients, fatal hemorrhage in 2, fatal perforation/fistula in 2, osteonecrosis of the jaw in 1, reversible posterior leukoencephalopathy syndrome in 1, and nephrotic syndrome in 1. Cabozantinib carries a boxed warning for perforations and fistulas. Gastrointestinal perforations occurred in 3% of patients receiving cabozantinib and fistula formation occurred in 1%. Severe and sometimes fatal hemorrhage, including hemoptysis and gastrointestinal hemorrhage, occurred in 3%. Cabozantinib has warnings/precautions for thrombotic events, wound complications, hypertension, osteonecrosis of the jaw, palmar-plantar erythrodysesthesia syndrome, proteinuria, reversible posterior leukoencephalopathy syndrome, and embryofetal toxicity. n References 1. U.S. Food and Drug Administration: Cabozantinib. Available at http://www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm330213.htm. Accessed January 9, 2013. 2. COMETRIQTM (cabozantinib capsules) prescribing information. Exelixis, Inc, November 2012. Available at http:// www.accessdata.fda.gov/drugsatfda_ docs/label/2012/203756lbl.pdf. Accessed January 9, 2013.

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).

The ASCO Post | FEBRUARY 1, 2013

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JCO Spotlight

Expectations of Benefit continued from page 1

attitude toward a future event—eg, “I am 90% confident that I will be one of the people who respond to the experimental treatment.” Patients in the “belief ” (or “confidence”) group (n = 56) were asked, “How confident are you that the experimental therapy will control your cancer (0% to 100%)?” Those in the “frequency” group (n = 55) were asked, “If 100 people were to participate in this study, how many could be expected to have their cancer controlled as a result of the experimental therapy?” Those in the combination group (n�� =�� 60) first answered the “belief ” question, discussed the answer with the interviewer, and then were asked the “frequency” question; the answer to the latter was the response of interest in this group, with the investigators hypothesizing that discussion of the first response would lower expectations as reflected in the response to the frequency question. Overall, patients had a mean age of 60 years. Most were men (58%), white (82.5%), married/partnered (74%), living with others (89%), and participating in a clinical trial for the first time (68%). Almost all (95%) had ECOG performance status of 0 or 1. Most patients had some college (22%) or were college graduates

EXPERT POINT OF VIEW By Kevin P. Weinfurt, PhD

ur work suggests three specific recommendations for researchers and care providers who are discussing with patients the possibility of enrolling in a phase I clinical trial. First, we should always communicate the likelihood of benefit in terms of the number of participants expected to derive benefit from among a total population—eg, fewer than 3 out of every 100 people. Whether this is done in words or graphics, the important point is that a frequency-type concept should be used, because it is the most sincere statement about what we know. We don’t know the chance that this particular patient will benefit, but we can calculate a historical rate of benefit from prior studies. Second, if we are interested in checking the potential participant’s understanding of the chance of benefit, we should query the person using the same frequency-type concept used to

(43%). Monthly income level brackets with more than 10% of the population were $2,000 to $2,999 (16%), $3,000 to $3,999 (11%), $5,000 to $5,999 (11%), and $8,000 or more (19%). Sixty-seven percent of pa-

communicate the chance of benefit. For example, we might ask, “On average, how many patients enrolled in phase�� I�� clinical trials have had their cancer controlled?” with responses ranging from “0 out of 100” to “100 out of 100.” Third, if we hear a patient expressing high expectations of direct personal benefit from participating in a phase� �� I�� trial, we should not immediately conclude that the patient does not understand the nature of the phase�� I�� trial. In our research, the overwhelming number of patients who said such things were trying to voice a positive attitude for various reasons, not to describe their understanding. It is possible for a person to express hope for the best while still planning for the worst; thus, clinicians and researchers might attend more to the behaviors of the person than to their stated expectations to determine whether the person seems to appreciate his or her situtients were enrolled in phase I trials, and 33% in phase II trials.

Higher Expectations in ‘Confidence’ Group Expectation of benefit differed

EXPERT POINT OF VIEW By Neal J. Meropol, MD

critical component of informed consent is an understanding of the potential risks and benefits of investigational treatments. In the context of early-phase oncology trials, concern has been raised about whether this understanding is adequate, since patients tend to express high expectations about their treatment outcomes. Our group has sought to obtain empirical data about what patients actually intend when they state an expectation of benefit that exceeds historical results and their own physicians’ estimations. Whereas some medical ethicists have argued that such expressions represent a failure of the consent process, we have found that when patients are asked, “What is the chance you will benefit?” they are not necessarily providing a population frequency estimate with their

response. What, then, are patients expressing, and is this a problem? There is substantial normative pressure for patients with cancer to be “optimistic,” yet little is known about whether such attitudes are beneficial (or harmful) in the setting of earlyphase clinical trials, where a poor disease outcome is common. We are hoping to answer this question through longitudinal study of psychological outcomes among patients taking part in early-phase trials. The informed consent process in oncology is characterized by a high level of uncertainty regarding harms and benefits, and hence requires a particularly sensitive approach by clinical researchers who wish to ensure understanding but avoid dashing hope. What is too much optimism? The answer requires attention not only to what patients “know,” but also

Neal J. Meropol, MD

what they “mean.” n

Disclosure: Dr. Meropol reported no potential conflicts of interest. He is coauthor of the article by Weinfurt KP et al,4 cited in the accompanying article.

Dr. Meropol is Chief, Division of Hematology and Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, and Associate Director for Clinical Research, Case Comprehensive Cancer Center, Cleveland, Ohio.

Kevin P. Weinfurt, PhD

ation. Instead of trying to dissuade patients from expressing hope or positive attitude, we might work with them to make sure they are planning for all possible outcomes. n Disclosure: Dr. Weinfurt reported no potential conflicts of interest.

Dr. Weinfurt is Professor, Department of Psychiatry and Behavioral Sciences and Department of Psychology and Neuroscience, Duke Clinical Research Institute, Durham, North Carolina

significantly by question type (P < .001). The confidence group exhibited a mean expectation of benefit of 64.4�� ± �� 22.3, significantly higher than the 51.6 ± 25.9 (P = .01) and 43.1 ± 27.1 (P < .001) values in the combination and frequency groups, respectively. Contrary to the investigators’ hypothesis, expectation reflected in the combination group’s response to the frequency question was (nonsignificantly) higher than that in the frequency group. Mean expectations were slightly but nonsignificantly higher among participants in phase II trials (56.5 vs 51.7). A noteworthy finding was that 34% of patients in the confidence group selected an answer of 50, a clustering not observed in the other groups. Expectations of patients in the confidence and frequency groups were also analyzed according to patient characteristics elicited using various survey measures. Patient aptitude for numbers was assessed using the Subjective Numeracy Scale and a single item assessing understanding of a statement of aggregate probability. The Quality of Informed Consent measure was used to assess understanding of elements of informed consent in clinical research. The Life Orientation Test-Revised

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JCO Spotlight

measured patients’ optimism, and the Daily Spiritual Experiences Scale and Organizational Religousness– Short Form were used as measures of patients’ spirituality and religiousness.

Associated Factors On these analyses, patients with higher belief-type expectations tended to prefer information expressed in nonquantitative terms (r = –0.19, 95% confidence interval [CI]�� = –�� 0.19 to –0.36, on the numeracy preference subscale), had poorer knowledge about research/objective understanding of informed consent information (r = –0.21, 95% CI = –0.38 to –0.03, on Quality of Informed Consent objective score), greater dispositional optimism (r = 0.20, 95% CI = 0.01 to 0.37, on Life Orientation Test-Revised measure), and reported more spiritual thoughts and feelings in daily life (r = 0.22, 95% CI = 0.03 to 0.38, on Daily Spiritual Experiences scale). The only factor correlated with higher frequency-type expectations was poorer knowledge about research/ objective understanding of informed consent information (r = –0.27, 95% CI = 0.27 to –0.51, on Quality of Informed Consent objective score). As noted by the investigators, the finding that belief-type questions elicit a higher expectation of benefit from an experimental treat-

ment (ie, greater confidence in a good personal outcome) may reflect a patient’s taking the opportunity to voice optimism about outcome. For example, patients may believe that personal feelings of confidence are less vulnerable to being called inaccurate than are knowledge claims

verbatim characteristics of information during disclosure, or trying to voice an optimistic attitude rather than express true understanding of the chances of success. More research is needed on the relative impact of factors leading to misestimation of frequency-type probabilities.”

[T]hese findings ... suggest the need to continue investigations of how best to advance the science of medicine while maintaining respect for patients who participate in these trials. about what proportion of patients are likely to benefit from treatment. Many patients value optimism, and a belief-type probability statement affords greater opportunity to express that optimism.

Ethical Implications It was also the case that expectations elicited by frequency-type questions were higher than would be expected based on the chance of benefit suggested by historical data. As noted by the investigators, the ethical implications of such “therapeutic misestimation” depend on the reasons for the misestimation: “Such reasons might include difficulty understanding quantitative information during the consent process, encoding the gist of rather than the

With regard to the patients’ high belief-type expectations, the investigators stated, “[O]ur findings shift the focus of ethical concern in informed consent for clinical trials to issues other than disclosure, such as whether it is morally acceptable for patients to be optimistic, whether such optimism is beneficial, or whether it represents a cognitive bias that makes patients vulnerable and diminishes the quality of their informed consent.” They noted that they currently are conducting studies to address these issues. As concluded by the investigators, “[T]hese findings show that the process of obtaining genuinely informed consent in early-phase clinical trials is more complex than has been understood previously, and they

suggest the need to continue investigations of how best to advance the science of medicine while maintaining respect for patients who participate in these trials.” n See page 44 for a related recently published trial.

Disclosure: Among the authors of the JCO report, Dr. Herbert I. Hurwitz has been a consultant for Genentech/Roche, sanofi-aventis, Regeneron Pharmaceuticals, and Bayer Pharmaceuticals; has received honoraria from Genentech/Roche and Bayer; and has received research funding from Genentech/Roche, sanofi-aventis, BristolMyers Squibb, Tracon Pharmaceuticals, and Ascenta Therapeutics. None of the other authors reported any potential conflicts of interest.

References 1. Meropol NJ, Weinfurt KP, Burnett CB, et al: Perceptions of patients and physicians regarding phase I cancer clinical trials: Implications for physicianpatient communication. J Clin Oncol 21:2589-2596, 2003. 2. Daugherty C, Ratain MJ, Grochowski E, et al: Perceptions of cancer patients and their physicians involved in phase I trials. J Clin Oncol 13:10621072, 1995. 3. Cox AC, Fallowfield LJ, Jenkins VA: Communication and informed consent in phase 1 trials: A review of the literature. Support Care Cancer 14:303-309, 2006. 4. Weinfurt KP, Seils DM, Lin L, et al: Research participants’ high expectations of benefit in early-phase oncology trials: Are we asking the right question? J Clin Oncol 30:4396-4400, 2012.

Patients Receiving Higher-intensity Chemotherapy for ALL Are at Greater Risk for Cognitive Deficits, Researchers Report By Charlotte Bath

mitting cranial irradiation from the treatment regimen for acute lymphoblastic leukemia (ALL) See Page 61 may help preserve global cognitive abilities. “Treatment with chemotherapy alone is not without risks,” however, noted researchers from St. Jude Children’s Research Hospital in Memphis. “The St. Jude Total Therapy XV study evaluated whether intensification of systemic drugs that affect control of ALL in the central nervous system, together with optimal intrathecal treatment, would allow for complete omission of prophylactic cranial irradiation without

compromising overall survival,” the researchers explained. The treatment results “remain excellent with a 10year overall survival 86.0% for standard/high-risk patients,” but cognitive outcomes had not been systematically investigated or reported.

Cognitive Outcomes Focus of Current Study For the current study, patients were assessed 120 weeks after completion of consolidation therapy (n = 243).1 “The entire sample performed well on global measures of cognitive ability without evidence of excess impairment on measures of intellectual functioning, academic abilities, and learning and memory,” the researchers wrote.

“Problems with sustained attention emerged as the most prominent deficit, with below-average performance in approximately 40% of the sample irrespective of sex, age at treatment, or treatment intensity.”

Main Results Compared with patients receiving lower-intensity therapy, those who got higher-intensity chemotherapy were at greater risk for below-average performance as measured by processing speed (27.14% vs 6.25%, P = .009) and academic abilities (math reasoning: 18.60% vs 3.90%, P = .008; word reading: 20.00% vs 2.60%, P = .007; spelling: 27.91% vs 3.90%, P = .001). In addition, higher-intensity chemotherapy

was associated with a higher incidence of of parent-reported hyperactivity (23.00% vs 9.84%, P = .018) and learning problems (35.00% vs 16.39%, P = .005). “These results warrant additional follow-up with potential therapeutic interventions,” according to the authors. They called for caregiver education and interventions to address both early attention deficits and cognitive late effects. n References 1. Conklin HM, et al: Cognitive outcomes following contemporary treatment without cranial irradiation for childhood acute lymphoblastic leukemia. J Natl Cancer Inst 104:1386–1395, 2012.

For the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. 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.

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.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients

Adverse Reactions The most common adverse drug reactions (â&#x2030;Ľ 5%) reported in patients receiving

Important Safety Information

Reference: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. ÂŠ 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012I-076-6397 9/12 XTANDI is a registered trademark of Astellas Pharma Inc. Astellas and the flying star logo are trademarks of Astellas Pharma US, Inc.

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AND... • 37% reduction in risk of death vs placebo

(P < 0.0001; HR = 0.63 [95% CI, 0.53, 0.75])1

• XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1 – In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1

• Oral, once-daily dosing1 • The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1

AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, 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.

Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of

• Seven patients (0.9%) out of 800 treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1 • The most common adverse reactions (≥ 10%) in patients treated with XTANDI were asthenia/fatigue, peripheral edema, back pain, arthralgia, musculoskeletal pain, diarrhea, hot flush, headache, and upper respiratory tract infection1

XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for brief summary of Full Prescribing Information.

Learn more at XtandiHCP.com

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; FEBRUARY 1, 2013

PAGE 42

JCO Spotlight

Cisplatin Linked to Significantly Increased Risk of Venous Thromboembolism By Charlotte Bath

atients with advanced solid tumors treated with cisplatin-based chemotherapy had a significantly increased risk of venous thromboembolic

events, according to a meta-analysis of 38 randomized phaseÂ II and III trials evaluating cisplatin-based vs nonâ&#x20AC;&#x201C;cisplatin-based chemotherapy. The trials

involved a total of 8,216 patients with various solid tumors. The incidence of venous thromboembolic events was 1.92% (95%

CIÂ =Â 1.07â&#x20AC;&#x201C;2.76) in patients treated with cisplatin-based chemotherapy and 0.79% (95% CI = 0.45â&#x20AC;&#x201C;1.13) in patients treated with nonâ&#x20AC;&#x201C;cisplatin-based

(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 9.0 44.4 9.3 Asthenic Conditionsa 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.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; FEBRUARY 1, 2013

PAGE 43

JCO Spotlight

regimens, Sonia Seng, MD, of Southcoast Centers for Cancer Care, Fairhaven, Massachusetts, and co-investigators reported in the Journal of Clinical Oncology.1 Patients given cisplatin-based chemotherapy had a significantly increased risk of venous thromboembolic events (relative risk [RR] = 1.67;

95% CI = 1.25â&#x20AC;&#x201C;2.23; P = .01). The authors noted that the finding of a 1.67-fold increase in the risk of venous thromboembolic events with cisplatin, â&#x20AC;&#x153;should be viewed in the context of a recent meta-analysis suggesting a 1.33fold increased risk of [such events] with bevacizumab [Avastin], an antivascular

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\@

endothelial growth factor receptor antibody, which has been used for decades less frequently than cisplatin to treat a fraction of the malignancies.â&#x20AC;?

Subgroup Analysis Exploratory subgroup analysis showed that the highest relative risk of

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

venous thromboembolic events was among patients who received a weekly equivalent cisplatin dose >Â 30 mg/m2 (2.71; 95% CI = 1.17â&#x20AC;&#x201C;6.30; P = .02). â&#x20AC;&#x153;Although the lack of a linear increase in RR with increasing dose does not support a dose-response relationship,

Our study adds further support to calls for prospective trials of cisplatinbased chemotherapy administered with prophylactic anticoagulation. a threshold effect cannot be ruled out,â&#x20AC;? the researchers wrote. To explore whether the excess risk or venous thromboembolic events was unique to cisplatin or common to all platinum agents, patients in the control arm were categorized according to whether their drug regimen included another platinum agent such as carboplatin or oxaliplatin. â&#x20AC;&#x153;Interestingly, the effect size was greater in the analysis comparing cisplatin-based chemotherapy with regimens containing other platinum agents (RR = 1.96; 95% CI = 1.38â&#x20AC;&#x201C;2.78; P=.01) vs the analysis comparing cisplatin-based chemotherapy with nonplatinum regimens (RR = 1.22; 95% CI = 0.74â&#x20AC;&#x201C;2.00; P = .43); however, there was no significant difference between these subgroups,â&#x20AC;? the investigators stated. The incidence of venous thromboembolic events was highest among patients with gastric/esophageal cancer, followed by patients with pancreatic and small cell lung cancer, although the differences among tumor types were not statistically significant. â&#x20AC;&#x153;Given the morbidity and mortality associated with [venous thromboembolic events] in patients with cancer, our study adds further support to calls for prospective trials of cisplatin-based chemotherapy administered with prophylactic anticoagulation,â&#x20AC;? the authors concluded. n Reference 1. Seng S, Liu Z, Chiu SK, et al: Risk of venous thromboembolism in patients with cancer treated with cisplatin: A systematic review and meta-analysis. J Clin Oncol 30:4416-4426, 2012.

The ASCO Post | FEBRUARY 1, 2013

PAGE 44

Journal Spotlight Issues in Oncology

Most Patients Do Not Report that Cure Is Highly Unlikely with Chemotherapy for Advanced Cancer By Matthew Stenger

hemotherapy for metastatic lung or colorectal cancer can provide palliation and modestly prolong life, but is not curative. In a study recently reported in The New England Journal of Medicine, Jane C. Weeks, MD, of Dana-Farber Cancer Insitute, and colleagues found that the majority of patients with such disease did not report

physician told them not to have chemotherapy were not asked these questions, and the questions were not included in surveys administered to surrogates of deceased patients. For each of the measures of cure, life extension, and symptom relief, patients with colorectal cancer thought that chemotherapy was more likely to be effective than did those with lung cancer (P < .01 for all comparisons). Both groups of patients thought that chemotherapy was more likely to extend life than to achieve cure (P < .01 for both).

Associated Factors

Jane C. Weeks, MD

understanding that that their chemotherapy was highly unlikely to cure them.1 Inaccurate belief about chemotherapy in this setting was more likely among nonwhite patients and among patients with favorable ratings of physician communication.

Study Details The study involved 1,193 patients participating in the Cancer Care Outcomes Research and Surveillance (CanCORS) study who were alive 4 months after diagnosis and who had received chemotherapy for newly diagnosed metastatic lung (n = 710) or colorectal (n�� =�� 483) cancer. Professional interviewers surveyed patients (or surrogates if patients were too ill to be interviewed or had died) 4 to 7 months after diagnosis regarding personal characteristics, decision-making, experience of care, and outcomes. Patients were asked, “After talking with your doctors about chemotherapy, how likely did you think it was that chemotherapy would cure your cancer.” Response options were “very likely,” “somewhat likely,” “a little likely,” “not at all likely,” and “don’t know.” Patients were also asked the same question with “help you live longer” (life extension) and “help you with problems you were having because of your cancer” (symptom relief) substituted for “cure your cancer.” Patients who reported not discussing chemotherapy with a physician or whose

Overall, 69% of patients with lung cancer and 81% of patients with colorectal cancer did not respond that chemotherapy was “not at all likely” to achieve cure. Multivariate analysis showed that patients with colorectal cancer were almost twice as likely to have an inaccurate expectation compared with patients with lung cancer (odds ratio [OR] = 1.75, P < .001). Inaccurate expectation was more likely among patients of nonwhite race or ethnic group compared with white patients, including approximately three times more likely among Hispanic patients (OR = 2.82, 95% confidence interval [CI] = 1.51– 5.27) and black patients (OR = 2.93, 95% CI = 1.80–4.78) and four times more likely among Asian/Pacific Islander patients (OR = 4.32, 95% CI = <�� .001 for overall com2.19–8.49; P �� parison). Factors associated with inaccurate expectations of cure included receipt of care outside of an integrated health-care network and reporting of poorer physician communication. Physician communication was scored as 0 to 100 (poorer to better) by transforming the sum of five items

EXPERT POINT OF VIEW By Eduardo Bruera, MD, FAAHPM

he study by Weeks and colleagues is an important one that shows quite unexpected results. There are three main possible reasons for the very low rate of accurate reporting by the patients: (1) Physicians are not communicating prognosis adequately. (2) Patients are unable to understand the information provided by their physicians—eg, the use of terms such as “response” or “tumor shrinkage” might be interpreted as associated with cure in some cases. (3) Patients are in denial—ie, after receiving appropriate information and understanding it cognitively, many patients are unable to cope emotionally and proceed to deny the information. It is likely that all three mechanisms are present Eduardo Bruera, MD, FAAHPM in this population, and in some cases more than one mechanism may be present in a given patient. Future research needs to “personalize” the causes for inaccurate statements of prognosis. For the first two mechanisms, better communication techniques may be very helpful. For the third mechanism, compassionate care and respect for the patient’s chosen coping mechanism will be important, even though it may be distressing for clinicians and family. n Disclosure: Dr. Bruera reported no potential conflicts of interest.

Dr. Bruera is Department Chair, Department of Palliative Care and Rehabilitation Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

derived from the Consumer Assessment of Healthcare Providers and Systems—ie, “How often did your doctors (1) listen carefully to you, (2) explain things in a way you could understand, (3) give you as much information as you wanted about your cancer treatments (including potential benefits and side effects), (4) encourage you to ask all the cancer-related questions you had, and (5) treat you with courtesy and respect?” Compared with patients rating physician communication as 80 to 99, those rating it as 0 to 79 were 37% (OR = 1.37, 95% CI = 0.93–2.02) more likely to believe that chemo-

Patient Expectations about Chemotherapy ■■ More than two-thirds of patients report inaccurate expectations of cure from chemotherapy.

■■ Factors associated with inaccurate expectation of cure were nonwhite race, colorectal vs lung cancer, treatment outside an integrated network, and worse-rated physician communication.

■■ No significant association of inaccurate expectation of cure was found for education level, functional status, or patient’s role in decision-making.

therapy could be curative. Compared with those giving physician communication a rating of 100, those rating it < 80 were nearly twice as likely to believe chemotherapy might cure their cancer (OR = 1.90, 95% CI = =�� .002 for overall com1.33–2.72; P �� parison). None of the other factors assessed in the multivariate analysis, including education level, functional status, and patient’s role in decision-making, were significantly associated with misunderstanding of the curative potential of chemotherapy. Patients in age brackets older than 21 to 54 years were more likely to have inaccurate expectations, but the overall trend was not significant (P = .06).

Further Analyses In a sensitivity analysis, the effect of care in an integrated health-care network in reducing likelihood of inaccurate expectation of cure was stronger in patients with colorectal cancer than in those with lung cancer (OR = 0.51, P = .02). In an analysis

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Journal Spotlight

restricted to patients with data on treatment duration, there was no significant interaction between completing the survey after finishing chemotherapy and expectation of cure. An analysis in which “don’t know” and “refused to answer” were categorized along with “not at all likely” as correct answers to the question about cure showed very similar results, except that the reduced likelihood of misunderstanding associated with receipt of care in an integrated healthcare network was no longer significant (OR = 0.80, P = .17). In a model in which only “very likely” was considered an inaccurate response to the cure question, results were similar to those in the primary model except for a strong inverse correlation between education level and likelihood of inaccurate expectation. Patients with a high school education or some college were 31% less likely to have inaccurate expectation compared with patients with less than high school education (OR = 0.69, 95% CI = 0.48–0.98) and those with a college degree were 51% less likely compared with those with a less than

high school education (OR = 0.49, 95% CI = 0.32–0.77; P = .009 for overall comparison).

Do Patients Know but Not Say? As noted by the investigators, the study does not provide information on what physicians told patients

difference not explained by education or income, strongly suggests that cultural factors influence patients’ beliefs, the nature of physician-patient communication about prognosis and care, or both.” The finding that patients reporting better physician communication also were more likely to have inac-

Efforts to incorporate earlier and more effective end-of-life care must address honestly and unambiguously patients’ unrealistic expectations about the outcomes of chemotherapy. about chemotherapy or examine the roles of physicians and patients in forming expectations about treatment. It also cannot show whether patients may have understood the true likelihood of cure but responded to or decided to respond to the question in a manner that did not reflect that understanding. In this regard, the authors stated, “The strikingly high rate of inaccurate responses among nonwhite patients in our cohort, a

curate expectations “suggests that patients perceive physicians as better communicators when they convey a more optimistic view of chemotherapy.” Similarly, the finding that treatment within integrated networks was associated with a modest increase in recognition that chemotherapy is not curative “suggests that providers may be able to improve patients’ understanding if they feel it is part of their professional role.”

The authors concluded, “In an era of greater measurement and accountability in health care, we need to recognize that oncologists who communicate honestly with their patients, a marker of a high quality of care, may be at risk for lower patient ratings. Our results suggest the need for targeted education to help all physicians learn to communicate honestly while also maintaining patients’ trust and regard. Efforts to incorporate earlier and more effective end-of-life care must address honestly and unambiguously patients’ unrealistic expectations about the outcomes of chemotherapy.” n See page 1 for a related recently published study on patient expectations in clinical trials.

Disclosure: Among the authors of the NEJM study, Drs. Jane Weeks, Paul Catalano, Matthew Finkelman, and Nancy Keating, reported receiving grant support (via their institution) from the National Cancer Institute.

Reference 1. Weeks JC, Catalano PJ, Cronin A, et al: Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med 367:1616-1625, 2012.

Helping Patients Prepare for Cancer Treatment Decisions

nder the stress of a cancer diagnosis and overwhelmed with the influx of information, patients often report that they feel unprepared to engage fully in the discussion with their health-care provider around a critical treatment decision. Consequently, the Cancer Support Community—an international nonprofit providing support, education, and hope to people affected by cancer— has developed Open to Options, a free treatment decision support program that helps patients identify and prioritize questions and concerns to share with their health-care team during a pivotal medical visit in which a treatment decision may be made. By helping the patient better prepare for these discussions, Open to Options enables the health-care provider to focus in on the key questions and concerns a pa-

Visit

tient may bring to the appointment. Physicians and patients alike report that this creates a more productive and focused appointment resulting in a personalized and appropriate treatment decision. Open to Options professional counselors help patients create a written personalized list of prioritized questions and concerns that can be brought to an upcoming medical appointment or sent to the health-care provider in advance. No medical advice is given nor do the Open to Options counselors help patients weigh one treatment option against another.

Pilot Program An Open to Options pilot program was funded by the Centers for Disease Control and Prevention and developed by the Cancer Support Community,

Jeffrey Belkora, PhD

the Education Network to Advance Cancer Clinical Trials, and Jeffrey Belkora, PhD, Assistant Professor, Department of Surgery and Philip R. Lee Institute for Health Policy Studies, and UCSF Director, Decision Services, UCSF Breast Care Center, San Francisco. Patients participating in the pilot program reported feeling: ■■ Less anxious about their upcoming

doctor appointment ■■ More positive about what was accomplished in the appointment ■■ Better about the treatment decision that was made ■■ More informed and aware of whether a clinical trial might be a good treatment option for them The free service is available by appointment through a toll-free cancer support helpline in English and Spanish for any type of cancer at any stage of the patient journey, and at select Cancer Support Community centers nationwide. For more information, including helpline hours and local centers where the service is currently offered, visit the Cancer Support Community website at www.cancersupportcommunity.org/open2options or call 1-888-793-9355. n

website at ASCOPost.com

The ASCO Post | FEBRUARY 1, 2013

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2013 Oncology Meetings February Highlights of ASH® Miami, FL and San Francisco, CA February 1-2 • Miami, Florida, and San Francisco, California For more information: www.hematology.org/meetings Optimizing Outcomes in Colorectal Cancer February 7 • Boston, Massachusetts For more information: www. omedlive.com Interventional Pulmonology in Cancer Patients: An Intensive Hands-on Course February 7-9 • Houston, Texas For more information: www.mdanderson.org/conferences Advances in Orbital Oncology and Oculofacial Plastic Surgery February 8-9 • Houston, Texas For more information: www.mdanderson.org/conferences Integrative Medicine Program’s 1st Annual Integrative Oncology Healthcare Professional Training Conference February 8-9 • Houston, Texas For more information: www.mdanderson.org/conferences Methods in Cancer Research Workshop February 9-13 • Al Ahsa, Saudi Arabia For more information: mcrw.kacst.edu.sa ASCO-MECC Palliative Care Workshop February 10-13 • Muscat, Oman For more information: www.asco.org/palliativecare

cancer-stem-cells/ Quantitative Real-time PCR: Applications for Molecular Diagnostics February 11-12 • San Francisco, California For more information: www.triconference.com/ Quantitative-Pcr/ Molecular Med Tri-Con 2013 February 11-15 • San Francisco, California For more information: www.triconference.com

American Psychosocial Oncology Society 10th Annual Conference February 14-16 • Huntington Beach, California For more information: www.apos-society.org 2013 Genitourinary Cancers Symposium February 14-16 • Orlando, Florida For more information: www.gucasymposium.org North Carolina Oncology Association & South Carolina Oncology Society Joint Membership Conference February 14-16 • Greenville, South Carolina For more information: www.ncoa-northcarolina.com

Genomics in Medicine: Individualized Care for Improved Outcomes February 11-12 • San Francisco, California For more information: www.triconference.com/genomicspersonalized-medicine

Scripps Cancer Center’s 33rd Annual Clinical Hematology and Oncology Conference February 16-19 • San Diego, California For more information: www.scripps.org/events/clinicalhematology-and-oncologyfebruary-16-2013

Second Annual Targeting Cancer Stem Cells: Promising New Therapeutics for Oncology February 11-12 • San Francisco, California For more information: www.triconference.com/targeting-

NCOA & SCOS Joint Membership Conference February 22-23 • Greenville, South Carolina For more information: www.ncoanorthcarolina.com

2013 Multidisciplinary Head and Neck Cancer Update February 22-23 • Weston, Florida For more information: www.clevelandclinicmeded.com 2nd Novel Cancer Therapeutics Summit February 25-26 • Las Vegas, Nevada For more information: www.gtcbio.com

March Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial Sloan-Kettering Cancer Center March 1-5, 2013 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse International Congress on Targeted Anticancer Therapies March 4-6 • Paris, France For more information: www.tatcongress.org/tat13-home. html 24th Annual Cancer Progress Conference March 5-6 • New York, New York For more information: www.cancerprogressbyDH.com Inaugural Prostate Cancer Research and Translation Symposium March 6-7 • Winston-Salem, North Carolina For more information: northwestahec.wfubmc.edu NCCN 18th Annual Conference: Advancing the Standard of Cancer Care March 14-17 • Hollywood, Florida For more information: www.nccn.org

April IGCS Regional Meeting on Gynecologic Cancers April 11-13 • Bali, Indonesia For more information: www2.kenes. com/igcs2013 66th Urological Society of Australia and New Zealand Annual Scientific Meeting April 13-16 • Melbourne, Australia For more information: www.usanz2013.com/ 3rd ITLT Essen 2013 Interdisciplinary Treatment of Liver Tumors April 18-20 • Essen, Germany For more information: www.itlt.org 7th Conference on Experimental and Translational Oncology April 20-24 • Portoroz, Slovenia For more information: www.ceto.si Highlights of ASH® in Latin America April 25-26 • Santiago, Chile For more information: www.hematology.org/meetings

May 5th IMPAKT Breast Cancer Conference May 2-4 • Brussels, Belgium For more information: www.esmo. org Precision Medicines in Breast Cancer May 9-10 • London, United Kingdom For more information: www.precisionmedicines.com

Highlights of ASH® in Asia March 23-24 • Shanghai, China For more information: www. hematology.org/meetings 23rd Annual National Interdisciplinary Breast Cancer Conference March 23-27 • Las Vegas, Nevada For more information: www.breastcare.org/

European Multidisciplinary Conference in Thoracic Oncology May 9-11 • Lugano, Switzerland For more information: www.esmo.org continued on page 51

When hemoglobin fallsâ&#x20AC;Ś

For chemotherapy-induced anemia (CIA) in metastatic patients with Hb < 10 g/dL

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 Q3W6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa CIA 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.3

INDICATION and LIMITATIONS OF USE Aranesp® (darbepoetin alfa) is 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. Aranesp® is not for use: • In patients receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy • In patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure • As a substitute for RBC transfusions in patients requiring immediate correction of anemia Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being.

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

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 • 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, and discontinue upon completion of a chemotherapy course

• ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure • Prescribers and hospitals must enroll in the ESA APPRISE Oncology Program to prescribe or dispense Aranesp® to patients with cancer; to enroll, visit www.esa-apprise.com or call 1-866-284-8089 for assistance Do not use Aranesp® in patients with uncontrolled hypertension; control blood pressure prior to and during treatment. Do not use Aranesp® in patients with pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs. If severe anemia and low reticulocyte count develop during treatment, withhold Aranesp® and evaluate for PRCA. Do not use Aranesp® in patients with history of serious allergic reactions to the product, which may include anaphylaxis, angioedema, bronchospasm, skin rash, and urticaria. Immediately discontinue Aranesp® if such a reaction occurs. Adverse reactions in ≥ 1% of patients treated with Aranesp® in clinical studies were abdominal pain, edema, and thrombovascular events. Please see Aranesp® brief summary on following page for additional safety information, including Boxed WARNINGS. 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

*O BEEJUJPO UP UIF UISPNCPWBTDVMBS BEWFSTF SFBDUJPOT BCEPNJOBM QBJO BOE FEFNB occurred at a higher incidence in patients taking Aranesp compared to patients on QMBDFCP "NPOH BMM QMBDFCP DPOUSPMMFE TUVEJFT BCEPNJOBM QBJO WT BOE FEFNB WT XFSF SFQPSUFE NPSF GSFRVFOUMZ JO QBUJFOUT SFDFJWJOH "SBOFTQ DPNQBSFE UP UIF QMBDFCP HSPVQ *O UIF 4$-$ TUVEZ UIF JODJEFODF PG BCEPNJOBM QBJO WT BOE FEFNB WT JO UIF "SBOFTQ USFBUFE QBUJFOUT compared to those receiving placebo. 1PTUNBSLFUJOH &YQFSJFODF #FDBVTF QPTUNBSLFUJOH SFQPSUJOH PG BEWFSTF SFBDUJPOT JT WPMVOUBSZ BOE GSPN B QPQVMBUJPO PG VODFSUBJO TJ[F JU JT OPU BMXBZT QPTTJCMF UP SFMJBCMZ FTUJNBUF UIFJS GSFRVFODZ PS FTUBCMJTI B DBVTBM SFMBUJPOTIJQ UP ESVH FYQPTVSF The following adverse reactions have been identiямБed during postmarketing use of Aranesp: t 4FJ[VSFT t 13$" t 4FSJPVT BMMFSHJD SFBDUJPOT Immunogenicity "T XJUI BMM UIFSBQFVUJD QSPUFJOT UIFSF JT B QPUFOUJBM GPS JNNVOPHFOJDJUZ /FVUSBMJ[JOH antibodies to darbepoetin alfa that cross-react with endogenous erythropoietin and PUIFS &4"T DBO SFTVMU JO 13$" PS TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT *O DMJOJDBM TUVEJFT UIF QFSDFOUBHF PG QBUJFOUT XJUI BOUJCPEJFT UP "SBOFTQ XBT FYBNJOFE VTJOH UIF #JBDPSF┬о BTTBZ 4FSB GSPN QBUJFOUT XJUI $,% BOE cancer patients were tested. At baseline, prior to Aranesp treatment, binding BOUJCPEJFT XFSF EFUFDUFE JO QBUJFOUT XJUI $,% BOE DBODFS QBUJFOUT %VSJOH "SBOFTQ UIFSBQZ SBOHF UP XFFLT B GPMMPX VQ TBNQMF XBT UBLFO 0OF BEEJUJPOBM QBUJFOU XJUI $,% BOE BEEJUJPOBM DBODFS QBUJFOUT EFWFMPQFE BOUJCPEJFT DBQBCMF PG CJOEJOH "SBOFTQ /POF PG UIF QBUJFOUT IBE BOUJCPEJFT DBQBCMF PG OFVUSBMJ[JOH UIF BDUJWJUZ PG "SBOFTQ PS FOEPHFOPVT FSZUISPQPJFUJO BU CBTFMJOF PS BU FOE PG TUVEZ /P DMJOJDBM TFRVFMBF DPOTJTUFOU XJUI 13$" XFSF BTTPDJBUFE XJUI UIF presence of these antibodies. The incidence of antibody formation is highly dependent on the sensitivity and TQFDJmDJUZ PG UIF BTTBZ "EEJUJPOBMMZ UIF PCTFSWFE JODJEFODF PG BOUJCPEZ JODMVEJOH OFVUSBMJ[JOH BOUJCPEZ QPTJUJWJUZ JO BO BTTBZ NBZ CF JOnVFODFE CZ TFWFSBM GBDUPST including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aranesp with the incidence of antibodies to other products may be misleading.

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

Aranesp overdosage can cause hemoglobin levels above the desired level, which TIPVME CF NBOBHFE XJUI EJTDPOUJOVBUJPO PS SFEVDUJPO PG "SBOFTQ EPTBHF BOE PS XJUI QIMFCPUPNZ BT DMJOJDBMMZ JOEJDBUFE $BTFT PG TFWFSF IZQFSUFOTJPO IBWF CFFO PCTFSWFE GPMMPXJOH PWFSEPTF XJUI &4"T

Aranesp Placebo Aranesp Placebo O O O O

i$FSFCSPWBTDVMBS EJTPSEFSTw FODPNQBTTFT $F/4 IFNPSSIBHFT BOE DFSFCSPWBTDVMBS BDDJEFOUT JTDIFNJD BOE IFNPSSIBHJD &WFOUT JO UIJT DBUFHPSZ NBZ BMTP CF JODMVEFE VOEFS iUISPNCPFNCPMJD BEWFSTF SFBDUJPOT w

Aranesp┬о EBSCFQPFUJO BMGB

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

ASCOPost.com | FEBRUARY 1, 2013

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2013 Oncology Meetings continued from page 46

The Psychological Impact of Cancer for Patients, Carers, and Families May 15 • Milton Keynes, United Kingdom For more information: www8.open.ac.uk/health-and-socialcare/main/research/research-events/ psychological-impact-of-cancer Iowa Oncology Society Spring Membership Conference May 17-18 • West Des Moines, Iowa For more information: www.ios-iowa.com The Bone Marrow Niche, Stem Cells, and Leukemia: Impact of Drugs, Chemicals, and the Environment May 29-31 • New York, New York For more information: www.nyas.org/bonemarrow

T:14”

B:14.25”

S:13”

Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 13th World Congress of the European Association for Palliative Care May 30-June 2 • Prague, Czech Republic For more information: www.eapc-2013.org 2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.asco.org

June

6th International Nasopharyngeal Carcinoma Symposium June 20-22 • Istanbul, Turkey For more information: www.npc2013.org MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com

July 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

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

12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch

Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org

British Gynaecological Cancer Society Annual Scientific Meeting June 20-21 • Belfast, Ireland For more information: bgcsconference.com

11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

September Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org 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

18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas For more information: www.mdanderson.org/conferences 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

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 Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences 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

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 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: http://www. ncri.org.uk/ncriconference/

December 55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org

The ASCO Post | FEBRUARY 1, 2013

PAGE 52

Pioneers in Oncology Oncology Trailblazer James F. Holland, MD, Recalls a Time of Unbridled Scientific Excitement By Ronald Piana

James F. Holland, MD

ames F. Holland, MD, began his journey into oncology when it was still a nascent discipline, working alongside groundbreaking pioneers in the field such as Drs. Emil “Tom” Frei and C. Gordon Zubrod. Dr. Holland recently shared a glimpse of his role in oncology’s formative years with The ASCO Post.

Inspiring Times Please describe the scientific atmosphere when you joined the NCI in 1953. In a word, it was exciting. B-12 had just been synthesized and found active in microgram quantities, which was new for a drug. The very day I joined the NCI they brought over artistic paintings and drawings made by volunteer sailors who had been given LSD, which was also active in microgram quantities. This program was designed to answer an array of psychiatric questions, because investigators could artificially induce psychiatric abnormalities and study them. Up until then, the NCI had locations across the country, but when the Institute was centralized on the National Institutes of Health campus, it generated an intense atmosphere of collective scientific research. Being in the lab next to other equally enthusiastic researchers inspired many fruitful collaborative ventures that changed the course of oncology.

New Era in Chemotherapy What led you to that early place in oncology? When I arrived at the NCI, Dr. G. Burroughs Mider, who was the acting

Clinical Director, introduced me to Lloyd Law, PhD, who had shown that in leukemic mice a combination of drugs given at the same time was better than when given in sequence. Dr. Law and I became wonderful friends, and I learned a lot about science from him. So I continued research in combination therapy, and when it became clear that mercaptopurine and methotrexate were two clinical drugs that were active in childhood leukemia, I put together a protocol with Dr. Law’s approbation. Dr. William Newton, of the Children’s Hospital in Columbus, Ohio, and I were the first researchers to give those two drugs in combination. The strategy was based on the concept that about one-third of patients responded to methotrexate and about one-third responded to mercaptopurine, so theoretically, 1 in 9 might be sensitive to both and conceivably achieve a cure. It was the beginning of a new era in chemotherapy.

Origins of Cooperative Group Research Please share your experience as a member of one of the country’s first collaborative trial groups. After I left the NCI for Roswell Park, Dr. C. Gordon Zubrod recruited

on President Eisenhower, was appointed Chairman of the CCNSC clinical panel. He boomed, “I don’t know anything about chemotherapy, but I know how to knock men’s heads together!” And he did. We used to meet every other month or so with Dr. Ravdin to discuss what kind of clinical research program would be best for the country. One day, Dr. Zubrod stated that the British Medical Research Council had generated a clear treatment program for tuberculosis using a collaborative clinical trial to come up with answers. Setting up cooperative clinical groups seemed like a good idea. Acute leukemia was one of the best malignancies to study because two effective drugs existed, and cancer cells in the peripheral blood and marrow gave ready access to the tumor. The emotional impact of dying children was also a factor. At the time, Dr. Joseph Burchenal was senior to everyone us, so he got to be Acute Leukemia Group A (which became the Children’s Cancer Group) and Tom Frei and I got to be ALG-B. We recruited investigators from the United States, Canada, and Europe, making ALG-B an international organization. This brought in huge numbers of patients. The first cures of childhood leukemia in multi-

There were not nearly so many hurdles to negotiate [when conducting research] in those days.… The laws today that are designed to protect patients, although made in good faith, are amazingly constrictive, making it difficult to launch innovative research efforts. —James F. Holland, MD

Dr. Emil Frei, and the three of us established a continuing collaboration. We published the first collaborative oncology paper in the United States, which appeared in Blood.1 Following that, the Cancer Chemotherapy National Service Center (CCNSC) was established under the impetus of Mary Lasker, led by Dr. Kenneth Endicott, who later became Director of the NCI. It set up a network of cooperative clinical trial groups that evolved across the country under the auspices of the NCI. I. S. Ravdin, MD, who had operated

institutional trials were achieved in the ALG-B using high-dose methotrexate.

Winning the Lasker Award What was it like to accept the Lasker Award, which has become one of the nation’s most prestigious prizes in medical research? First off, I am a strong believer that Mary Lasker was this country’s most important person in cancer research. She felt that cancer awareness needed a boost, so in 1972 the Lasker Award

was given to clinicians who made progress in treating cancer. About 18 of us won the Lasker; Tom Frei won for Hodgkin disease, and I won for acute leukemia. It was a $2,000 prize, which was big-time money then. Actually, I wasn’t there to receive the prize. During the Cold War, Richard Nixon and Leonid Brezhnev tried to put aside the notion of dropping atomic bombs on each other and agreed that finding a cure for cancer would be mutually beneficial. So Brezhnev said he would send a scientist with his family to the United States, and we, in turn, should send a counterpart family to Russia. Dr. Zubrod enlisted me and others to find a candidate, but no one wanted to go. I was leaving Roswell Park at the time, and after the third call from Dr. Zubrod, I asked my wife Jimmie, how about us? She said okay, and off we went with our six kids. I missed the Lasker ceremony, but we had an extraordinary experience for 7 months in the Soviet Union.

Then and Now What is the central difference in the research atmosphere between the 1950s and today? Put simply, there were not nearly so many hurdles to negotiate in those days. My colleagues and I were motivated to cure childhood leukemia, and when we had a good idea, we acted on it. We were freewheeling, but always ethical. The same motivation exists today, but the research process has been frustrated by excessive paperwork and multilevel bureaucratic review. The laws today that are designed to protect patients, although made in good faith, are amazingly constrictive, often making it difficult to launch innovative research efforts. Tell us about your current schedule. I see patients all day long on Monday and Thursday. On the other 3 days, I interact with my laboratory colleagues. We are deeply engrossed in the research that I’ve pursued for 20 years, exploring a virus in human breast cancer that is a “kissing cousin” of the mouse mammary tumor virus, continued on page 53

ASCOPost.com | FEBRUARY 1, 2013

PAGE 53

Announcements

Internationally Renowned Gynecologic Cancer Researcher Joins Ohio State

nternationally renowned uterine cancer researcher and geneticist Paul Goodfellow, MD, PhD, will lead a new team of three researchers devoted to gynecologic oncology research at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Paul Goodfellow, MD, PhD

Dr. Goodfellow comes to Ohio State from Washington University School of Medicine, where he was a professor of surgery, of genetics and of obstetrics and gynecology. “As a geneticist, I’m interested in the genetics of tumor cells, and how gene changes influence how aggressively cancer cells will spread,” said Dr. Goodfellow, who has a doctorate of biology/pediatrics from Queen’s University, Kingston, Canada. Throughout his career, Dr. Goodfellow’s research has made important contributions to improving women’s health care. He also has embraced his role in mentoring gynecologic oncolo-

James F. Holland, MD continued from page 52

the causative agent for breast cancer in mice. Forty percent of American women who present with breast cancer have this virus in their tumor, but not in the normal tissue of the same breast, which thus excludes genetic inheritance. It is acquired. We are working hard to fulfill the criteria that will prove the virus is indeed the cause of these breast cancers. It keeps me busy and out of trouble. n Disclosure: Dr. Holland reported no potential conflicts of interest.

Reference 1. Frei E 3rd, Holland JF, Schneiderman MA, et al: A comparative study of two regimens of combination chemotherapy in acute leukemia. Blood 13:1126-1148, 1958.

gists in basic science and in translational research, helping to develop the next generation of physician scientists. Dr. Goodfellow has a joint appointment within the Division of Gynecologic Oncology of Ohio State’s Comprehensive Cancer Center and within

the Department of Obstetrics and Gynecology at Ohio State’s Wexner Medical Center. While at the Siteman Cancer Center, Washington University School of Medicine, Dr. Goodfellow developed a prominent endometrial research

group that focused on elucidating both the causes and consequences of defective DNA mismatch repair in endometrial cancer. The group’s translational research findings have significantly advanced knowledge about the most common gynecologic cancer. n

The ASCO Post | FEBRUARY 1, 2013

PAGE 54

Patient’s Corner

Social Media Is Helping My Brother Fight Kidney Cancer My brother exhausted his life savings on treatment for his disease. Now, our only recourse is to ask friends—and strangers—for help. By Annie Howell, as told to Jo Cavallo

y brother, Rick Thomas, is a great guy. I’m not just saying that because he’s my brother. He’s funny, warm, and kind to everyone he meets. He became a commercial airline pilot for American Airlines after flying C-5s in the Air Force for 12 years and has always been a responsible person and a diligent saver. He has invested wisely to ensure that his wife Suzette and their three young children, aged 4, 6, and 10, can have financial security. But a diagnosis last February of chromophobe renal cell carcinoma has put all his careful financial planning in jeopardy. Now, in addition to fighting for his life, he is fighting to keep his family financially solvent. Although Rick has employer-sponsored health insurance, he is unable to keep up with the mounting cost of his cancer treatment, some of which is experimental and not covered by insurance. We didn’t expect his kidney cancer to be so aggressive and life-threatening. When his cancerous kidney was removed and biopsied, the pathology report showed that the malignant cells were confined to the grapefruit-size tumor and that the surrounding tissue margins were clear. We all breathed a sigh of relief when Rick’s oncologist said additional treatment wasn’t necessary and that he was likely cancer-free. So it was especially shocking when Rick went for follow-

up 4 months after his surgery and an MRI scan showed tumors growing on his lungs and in the area where the diseased kidney had been.

Emotional and Financial Costs Subsequent radiation treatment and an assortment of oral and intravenous chemotherapies have so far failed to stop the cancer’s progression, and tumors are now present in Rick’s liver, diaphragm, lymph nodes, and

pay for them, my siblings, parents, and I decided to hold a fundraiser to cover Rick’s living and medical expenses. We knew we would have to reach a wide range of donors to hit our target goal of $125,000, which, as it turns out, will just skim the surface of what he’ll need. I began researching online crowdfunding sites, and after getting advice from a tax attorney, I set up a page on GoFundMe.com. I then used so-

The generosity of so many strangers has renewed Rick’s determination to get well and provides him with an enormous sense of relief that his medical bills will be paid. —Annie Howell

pelvis. His prognosis is not great. Still, we are not giving up. He is now on pazopanib (Votrient), and he refuses to think of his life as grains of sand running through the hourglass; he is focused on beating his cancer. Between being unable to work and having to pay for much of his costly treatment out-of-pocket, Rick has used up all his life savings. Fearing that he would reach a point where he still had treatment options but no way to

cial networking sites and services like Facebook and Twitter to get the word out to extended family members, friends, and colleagues about Rick’s illness and his financial need. They sent links to their families and friends, and the response has been overwhelming. After just 3 months, we’ve raised nearly $146,000 from 1,588 donors— a significant portion of the donations coming from the pilot community at American Airlines.

The Kindness of Strangers Taking charge this way is helping me cope with my brother’s illness and makes me feel that I’m contributing to his peace of mind. The generosity of so many strangers in their donations, words of encouragement, and prayers has renewed Rick’s determination to get well and provides him with an enormous sense of relief that his medical bills will be paid and his family’s financial needs will be met. My brother’s illness and the extreme cost of his treatment have given me a new awareness of the economic difficulty many patients in similar circumstances face. We were lucky because we knew how to use social media to mobilize hundreds of people to help our cause. Others, I know, don’t have those networking contacts or social media skills. This experience has been a real lesson about the true goodness of people. To pay forward their generosity, my husband and I have made contributions to the causes of others on GoFundMe. Right now, it’s too painful for me to think of a future that doesn’t include Rick. I have to believe that he will keep fighting, that there will be another drug to try, and that he will survive. n Annie Howell is Executive Vice President of Corporate Communications & Media Relations for Crown Media Family Networks in New York.

Download The ASCO Post iPad App FREE from iTunes today!

In metastatic melanoma

MAKE TREATMENT PERSONAL by testing for the BRAF V600E mutation with the cobas test 速

Test at diagnosis. Test with the cobas 4800 BRAF V600 Mutation Test. 速

Only FDA-approved BRAF PCR diagnostic1 20% more accurate than Sanger Sequencing with fewer false negatives and invalid results1

Indication and Usage: ZELBORAF速 (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. Please see Brief Summary of Prescribing Information and next page for Important Safety Information.

dEcodE metastatic melanoma.

ExtEnd

Significant improvement in OS vs dacarbazine in a randomized Phase III trial of BRAFV600E(+) patients (N=675)* 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

OS=overall survival HR=hazard ratio CI=confidence interval *Patients crossing over to ZELBORAF were censored.2

20 0

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.

OS (months) ZELBORAF (n=337)

†

Dacarbazine (n=338)

Median OS was not reached (NR) for ZELBORAF vs 7.9 months for dacarbazine (95% CI, 9.6 months-NR vs 7.3-9.6 months) 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 cutaneous squamous cell carcinoma and rash 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 Cutaneous squamous cell carcinoma (cuSCC) The incidence of cuSCC, including both SCCs of the skin and keratoacanthomas, was 24%. Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months after therapy. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. 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. 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.

SURVIVAL Updated Significant OS improvement confirmed in an updated analysis3§ OS update at ASCO 20123||¶ 100

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

Percentage surviving

80 60

13.6 9.7

ASCO=American Society of Clinical Oncology

20 0

Patients crossing over to ZELBORAF were censored.3

At the time of updated analysis, 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.3,4

At the time of the ASCO 2012 updated analysis, there were 199 deaths and 166 deaths in the ZELBORAF and dacarbazine arms, respectively.4

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)3,4

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. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

References: 1. cobas® 4800 BRAF V600 Mutation Test Package Insert. Roche Molecular Systems, Inc. August 2011. 2. Center for Drug Evaluation and Research. Clinical review—NDA 202429: ZelborafTM (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 July 23, 2012. 3. 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. Abstract 8502. 4. Data on file. Genentech, Inc.

zelboraf.com

The ASCO Post | FEBRUARY 1, 2013

PAGE 58

Announcements

Leon and Norma Hess Center for Science and Medicine Opens at Mount Sinai

he Leon and Norma Hess Center for Science and Medicine at Mount Sinai in New York officially opened in December, housing significant areas of six of Mount Sinai’s most influential institutes focusing on brain,

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

cancer, heart, children’s health, genomics, and imaging. With a half-million square feet of space, the Hess Center increases the medical center’s research capacity by nearly 30% and is designed to facilitate real-time collaboration be-

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.

tween physicians, investigators, and specialists from across disciplines. “The Hess Center will serve as the focal point of Mount Sinai’s research and clinical programs,” said Kenneth L. Davis, MD, President and CEO of

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* 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 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes 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. Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF*

disorders Cough Injury, poisoning and procedural complications Sunburn

*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.

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

Kenneth L. Davis, MD

The Mount Sinai Medical Center. “The combination of world-class faculty and state-of-the-art equipment and facilities will expand our ability to understand and treat the most challenging medical problems in areas such as cancer, heart disease, and brain and nervous system disorders.”

Expanded Research Capacity The new Hess Center will house both clinical and research facilities of The Tisch Cancer Institute, as well as laboratories for The Friedman Brain Institute, the Cardiovascular Research Institute, the Icahn Institute for Genomics and Multiscale Biology, and the Translational and Molecular Imaging Institute. By expanding Mount Sinai’s research footprint, the Hess Center is expected to draw more than $350�� million in National Institutes of Health funding over its first 5 years. In the new building, clinical space for cancer patients has expanded to 50,000 square feet. A centralized space combining examination and consultation rooms, with easy access to a chemotherapy suite, enhances multidisciplinary care and comfort for patients. Laboratory space incorporates flexible design to host promising areas of research as they emerge. To foster collaboration, the Hess Center’s six full floors of laboratory space are connected to two floors of outpatient clinical space. An open staircase connects all research floors, with shared white boards spanning the walls of each landing. “Cancer today is all about translation: the ability to go from bench to bedside and back again is truly extraordinary,” said Steven Burakoff, MD, and Director of The Tisch Cancer Institute. “Our clinical setup provides multidisciplinary care right in the building: radiation, infusion, imaging, and genomics will be there. We can share ideas with the cardiovascular institute, imaging, neuroscience, genomics, and child health—and be near the patients.” n

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PAGE 59

In the News Breast Cancer

‘Practice-changing’ ATLAS Study Supports 10 vs 5 Years of Tamoxifen Therapy in Women with Breast Cancer By Charlotte Bath

“P

ractice-changing” is the term several physicians and researchers used when asked by the media to describe the results of a study showing that extending tamoxifen therapy from 5 to 10 years for women with estrogen receptor (ER)-positive breast cancer further reduced recurrence and mortality. Results of the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) study, reported at the 2012 San Antonio Breast Cancer Symposium and published simultaneously in The Lancet,1,2 received extensive coverage by the major media and medical press.

Expect Questions from Patients

Christina Davies, MBChB

treatment allocation had little effect on recurrence or mortality rates from 5 to 9 years after diagnosis, but in the second decade following diagnosis, women who had continued tamoxifen treatment beyond 5 years had a 25% lower recurrence rate and a 29% lower breast cancer mortality rate. Details of the study were reported in the January 15 issue of The ASCO Post.5

esults from the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) study “will have a follow-on effect of being able to guide physicians about the advantages of longer than 5 years of therapy for the premenopausal woman,” said V. Craig Jordan, OBE, PhD, DSc, Scientific Director at the Lombardi Comprehensive Cancer Center, Georgetown University, in Washington, DC, in an interview with The ASCO Post. ATLAS found that extending tamoxifen therapy from 5 to 10 years for women with estrogen receptor (ER)-positive breast cancer further reduced recurrence and mortality.

A woman in her 30s or 40s should not be considering 5 years of tamoxifen as chemoprevention, but maybe 10 years, and then stopping and seeing the added benefit of that in her postmenopausal years.

Saved a Lot of Lives

Eric Winer, MD

“It’s going to be practice-changing, in my view, immediately for premenopausal women with breast cancer,” said Eric Winer, MD, Chief of Women’s Cancers at Dana-Farber Cancer Institute in Boston, who was quoted in the Boston Globe Daily Dose blog.3

Sir Richard Peto, FRS

“Certainly, the advice to stop in 5 years should not stand,” the study’s senior author, Sir Richard Peto, FRS, of Oxford University, commented in The New York Times.4 In the ATLAS study, led since its inception in 1995 by Christina Davies, MBChB, of Oxford University, 6,846 women with ER-positive breast cancer who had been taking tamoxifen for 5 years were randomly assigned to continue treatment for another 5 years or stop immediately. This

Over the years, tamoxifen has “saved a lot of women’s lives. That is the important thing,” V. Craig Jordan, OBE, PhD, DSc, told The ASCO Post. Scientific Director at the Lombardi Comprehensive Cancer Center, Georgetown University, in Washington, DC, Dr. Jordan has been a leader in the development of tamoxifen and other selective estrogen receptor modulators (SERMs), but was not directly involved in the ATLAS study. “This has been my life’s work for 40 years. I don’t know anybody else who has been that lucky,” Dr. Jordan said. “I think it is fair to say that tamoxifen has really gone further than our furthest dreams could possibly imagine,” Dr. Jordan continued. “Cancer is so clever” that drug resistance might have been expected after 5 or 10 years, “but we’ve been very lucky because this is a unique agent, so you couldn’t really predict that this was going to happen. The laboratory research with animal models in the 1970s indicated that longer therapy was going to be better, and maybe even that lifetime therapy would be optimal. This was at a time when the only other alternatives were chemotherapies—very aggressive chemotherapies.” During the 1980s and 1990s, concern arose about balancing gains vs side effects, but the use of tamoxifen continued on page 60

— V. Craig Jordan, OBE, PhD, DSc

Tamoxifen Forever? If tamoxifen therapy for 10 years is better than 5 years, would lifelong tamoxifen be even better still? Dr. Jordan said that when he came from the United Kingdom to the United States in the 1980s to pursue research at the University of Wisconsin Comprehensive Cancer Center, “my battle cry, I have to embarrassingly say, was ‘tamoxifen forever,’ because there was no real reason why you should stop it.” Tamoxifen was a relatively new drug then, having become available for the treatment of metastatic breast cancer at the end of 1977, he noted. “We didn’t think in terms of 5 years. We thought in terms of keeping patients on tamoxifen, to see what would actually happen with this safe drug,” he added. Dr. Jordan no longer advocates “tamoxifen forever.” His research found that “very low concentrations of physiological estrogen” can destroy breast cancer cells after years of antihormonal treatment. This finding was supported by results from the Women’s Health Initiative study that postmenopausal hysterectomized women who took estrogen replacement therapy had a decreased incidence of breast cancer. “The estrogen has gone in there and killed off estrogen-deprived cells in the breasts in women in their 60s,” he said. “So you have this long-term beneficial effect. I would put money on there being the same effects from estrogen in a women’s body after long-term tamoxifen has set up and controlled these cells. When the woman’s own estrogen comes back, it kills off the cells, and that’s what causes the decreases in the mortalities.” While the recommendation for tamoxifen use has not yet been extended to 10 years, Dr. Jordan said, “Let’s say it gets from 10 years to 15 years” and “you’re in your 30s and develop ER-positive breast cancer. You now go on and take tamoxifen until your early 50s. Then you stop and continue to get all the benefits through the postmenopausal years.” Given the results of the ATLAS study, “a woman in her 30s or 40s should not be considering 5 years of tamoxifen as chemoprevention, but maybe 10 years, and then stopping and seeing the added benefit of that in her postmenopausal years,” Dr. Jordan said. n

The ASCO Post | FEBRUARY 1, 2013

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In the News

ATLAS Study continued from page 59

for 1 year, 2 years, and 5 years showed continued benefits “and then longterm benefits even after you stop the tamoxifen”—the carry-over effect, Dr. Jordan said. “This really provided enthusiasm for going longer than 5 years with a very safe, very cheap

drug, in very large populations, to find the real answer. That is what we have with ATLAS and will soon have that with aTTom,” he continued. The aTTom (adjuvant Tamoxifen—To offer more?) trial randomly allocated 7,000 women, most with unknown ER status, to continue tamoxifen for 10 years or to stop at 5 years. Results

are expected later this year. “This next year or two is going to be critical,” Dr. Jordan said, as physicians and researchers review the results of ATLAS and aTTom and “compare and contrast” treatment with tamoxifen and aromatase inhibitors for individual patients. “I think leadership from ASCO is absolutely essential here.”

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Oncology News...

‘The Good, the Bad, and the Ugly’ Like 5-year tamoxifen trial results, 10-year results showed an increased incidence of endometrial cancer among postmenopausal women. The cumulative risk of endometrial cancer at 5 to 14 years of follow-up was 3.1% for women who continued tamoxifen beyond 5 years vs 1.6% for those who stopped; and the corresponding mortality rates were 0.4% vs 0.2%. “What we have is a conversation between the laboratory and the clinic See Page 61 to be able to get an understanding of what I’ve always called ‘the good, the bad, and the ugly’ of tamoxifen,” Dr. Jordan said. “Our laboratory studies showing that tamoxifen could encourage the growth of endometrial cancer very quickly got confirmed in clinic. continued on page 61

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The ASCO Post More Breast Cancer News Triple-negative breast cancer see page 3 HER2-negative breast cancer see page 4 Eribulin vs capecitabine in metastatic breast cancer see page 13

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PAGE 61

In the News

ATLAS Study continued from page 60

This presaged the prevention trial, where the definitive study showed, yes, you get a threefold increase in endometrial cancer in postmenopausal women, but the drug is safe in that respect in premenopausal women. What is very, very clear from ATLAS is, irrespective of this side effect in postmenopausal women, the benefits in survivorship far outweigh the risks of dying from endometrial cancer.” The ATLAS study reported that “tamoxifen produces favorable lipid changes” and suggested tamoxifen could provide some protection against ischemic heart disease. Animal studies had shown “that tamoxifen will lower the ‘bad’ cholesterol—the LDL cholesterol—and have no impact on the HDL cholesterol,” Dr. Jordan reported. A Scottish trial found that women who had 5 years of tamoxifen had a decrease in coronary heart disease, but this finding was not replicated in any of the overview analyses, he said. As SERMs became more widely used in clinical practice, Dr. Jordan remained interested in seeing whether lowering LDL would be a positive side effect. “What basically we found is raloxifene [Evista] has an effect an effect on LDL but does not protect from coronary heart disease. At this point, I don’t think we can make a definitive decision about what tamoxifen does with regard to lipid changes. Sir Richard Peto’s data demonstrate that at up to 5 years, there is no positive effect, but he is finding a positive effect for

between 5 and 10 years.” Taking tamoxifen may now be a more favorable option for premenopausal women who should not take aromatase inhibitors or postmenopausal women who cannot tolerate the side effects of aromatase inhibitors. “I think the key lesson here is, you have to take the drug to get the effect,” Dr. Jordan said. For women who stop taking aromatase inhibitors after 1 or 2 years because of the side

according to the New York Times article4], we should go for it, because I think we understand the drug. We can keep mothers alive so they can see their children grow. In societies where the grandmother is integrated in part of the family group, caring for the grandchildren, let’s keep these women alive for 5, 10 years or longer.” He added that “worldwide, the aromatase inhibitors are probably going to stay on the pricey side, but

The control of breast cancer was staggering in the United Kingdom. It dropped like a stone with adjuvant tamoxifen being given to everybody. —V. Craig Jordan, OBE, PhD, DSc,

effects, “tamoxifen now becomes a very good option because 5 years of tamoxifen saves lives. Just 1 or 2 years of tamoxifen or any adjuvant endocrine therapy really doesn’t have a big impact. We have to pay attention to long-term therapies, have operational systems in place to get people to continue taking the drug. Without longterm therapy, you put yourself at risk for a recurrence. That’s the bottom line,” he emphasized.

Cost and Worldwide Impact “Part of the reason for this trial,” Dr. Jordan said, is “Sir Richard Peto has a passion for improving health care on a global basis, and tamoxifen could be a key tool in that effort. If we can gain an enormous healthcare benefit from such an inexpensive drug [less than $200 per year,

Using QR Codes The QR (Quick Response) codes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading. These barcodes can be read by any mobile device with a camera, QR code–reading software, and internet access. Some devices come with the software preinstalled; if not, visit your device’s application store (such as the iTunes Store or the Android Market) and download the software of your choice.

tamoxifen will be used internationally before anything else.” While immunohistochemistry has made it easier to determine the estrogen receptor status of patients, ER testing might not be feasible in economically challenged countries, and tamoxifen may be given to women with breast cancer whose ER status is unknown. This can still produce significant benefits, Dr. Jordan said. “In the United Kingdom, there was a great reluctance in the 1980s to go with the idea that tamoxifen’s action was based on the estrogen receptor,” he continued. That and a lack of sophisticated ER labs “mandated that virtually everybody who received a diagnosis of breast cancer—because there was a thought that it might have some effect in ER-negative cancer—got tamoxi-

fen. This had a dramatic effect,” Dr. Jordan said. “The control of breast cancer was staggering in the United Kingdom. It dropped like a stone with adjuvant tamoxifen being given to everybody.” Longer-term follow-up of the ATLAS study is “almost mandatory” and deserving of government funding, Dr. Jordan stated. “This is a massively important public health issue,” he said. “Money has to be invested so we analyze our data over the next 20 or 30 years.” n Disclosure: Drs. Winer, Peto, and Jordan reported no potential conflicts of interest.

References 1. Davies C, Pan H, Godwin J, et al, for the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. December 5, 2012 (early release online). 2. Davies C, Pan H, Godwin J, et al, for the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group: ATLAS—10 v 5 years of adjuvant tamoxifen in ER+ disease: Effects on outcome in the first and in the second decade after diagnosis. 2012 San Antonio Breast Cancer Symposium. Abstract S1-2. Presented December 5, 2012. 3. Kotz D: Should breast cancer patients have a decade of tamoxifen? Boston Globe. Decem-ber 5, 2012. 4. Pollack A: Bigger role seem for breast cancer drug. New York Times. December 5, 2012. 5. Goodman A: Adjuvant tamoxifen for women with ER-positive breast cancer: 10 years superior to 5 years. ASCO Post. January 15, 2013.

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PAGE 63

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Younger Patients with Family History of Breast Cancer at Similar Risk of Bilateral Disease as Those with BRCA Mutations Women who are diagnosed with breast cancer before age 55 and have a first-degree family history of bilateral disease have risks of contralateral breast cancer similar to women with deleterious mutations of BRCA1 and BRCA 2, according to a study recently published in the Journal of Clinical Oncology, by Anne S. Reiner, MPH, of Memorial Sloan-Kettering Cancer Center, New York, and colleagues. “These results underscore the critical importance of obtaining detailed family histories from all women diagnosed with breast cancer, regardless of BRCA1 and BRCA2 mutation carrier status,” the investigators concluded. “Because women with a family history of bilateral breast cancer have risks of [contralateral breast cancer] similar to those of mutation carriers, these women should receive counseling for preventive measures.” The study involved 594 patients with contralateral breast cancer and 1,119 controls with unilateral breast cancer who tested negative for BRCA1 and BRCA 2 mutations. The women were selected from the WECARE study, a population-based case control study that identifies patients with contralateral or unilateral breast cancer through four cancer registries in the United States and though the Danish Breast Cancer Cooperative Group Registry, supplemented by data from the Danish Cancer Registry. “A first-degree family history of breast cancer was defined as a diagnosis of breast cancer in at least one firstdegree relative (ie, mother, sister, or daughter),” the researchers explained. The investigators estimated age-specific and family history–specific 10-year cumulative absolute risks of contralateral breast cancer.

Risk Rates Family history of breast cancer was associated with an increased risk of contralateral breast cancer, the researchers reported. That risk was highest among women < 45 years with firstdegree relatives who were also affected when they were < 45 years (rate ra-

tio = 2.5; 95% confidence interval [CI] = 1.1–5.3) or among women with firstdegree relatives with bilateral disease (rate ratio = 3.6; 95% CI = 2.0–6.4). Women diagnosed with unilateral breast cancer before age 55 with a firstdegree family history of bilateral disease had a 10-year contralateral breast cancer risk of 15.6%, the investigators stated. This risk is “nearly as high as that of women who are BRCA1 or BRCA2 mutation carriers (15.6% vs 18.4%, respectively),” the researchers reported. “It is important to note that other studies have found higher 10-year rates of [contralateral breast cancer] for BRCA carriers in the 30% to 40% range. However, these studies often differ from the current study by using even younger women or including just BRCA1 carriers. We elected to compare results produced from the same population to take advantage of all similarities including study design and patient case ascertainment,” the investigators noted. Reiner AS, et al: J Clin Oncol, December 26, 2012 (early release online).

Adding Temsirolimus to Letrozole Did Not Improve Survival but Might Benefit Patients under 65 Adding temsirolimus (Torisel) to letrozole did not improve progressionfree survival in patients with aromatase inhibitor–naive, estrogen receptor (ER)-positive advanced breast cancer, but exploratory analysis indicated the combination could benefit postmenopausal patients ≤ 65. In their Journal of Clinical Oncology report, Antonio C. Wolff, MD, of Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, and coauthors noted the need for external confirmation of the benefit seen in the exploratory analysis.

median age of patients was 63 years. In the HORIZON exploratory analysis, patients aged ≤ 65 years receiving letrozole/temsirolimus showed improved progression-free survival over those receiving letrozole/placebo—9.0 vs 5.6 months (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.60–0.93, P = .009). Thus, the investigators performed subpopulation treatment effect pattern plot (STEPP) analyses to further examine possible interaction of age and mTOR inhibition. These analyses showed a consistent benefit in progression-free survival favoring the investigational arm for younger postmenopausal women (P = .003 for interaction). Results were consistent across time (ie, 5-, 6-, 7-, 8-, or 9-month progression-free survival). The HORIZON trial was stopped at the second predefined interim analysis when the Independent Data Monitoring Committee concluded that the study was unlikely to reach its progression-free survival primary endpoint. The study was first reported in abstract/poster form at the 26th Annual San Antonio Breast Cancer Symposium in December 2006, and the data published in the current JCO article correspond to the final data lock from December 2006, with a median

follow-up of 9.5 months and a range of 0 to 27.2 months. The data showed no overall improvement in progressionfree survival among patients receiving letrozole/temsirolimus, although they experienced more toxicities.

Contrasting Results The authors noted that their findings contrast with the progressionfree survival benefit seen in the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study that tested another mTOR inhibitor, everolimus (Afinitor), plus the steroidal aromatase inhibitor exemstane. They speculated that prior exposure to aromatase inhibitors “partly explains the different results observed in these two studies.” Eligibility for BOLERO-2 “required progression on a nonsteroidal [aromatase inhibitor] during or within 12 months of completing adjuvant therapy or within 1 month if in the metastatic setting,” the authors noted, whereas the HORIZON study excluded patients who had taken aromatase inhibitors within 12 months. Alternative reasons given to explain the different outcomes of the two trials included “temsirolimus itself or its dosing, route, and/or schedule of administration” and “intrinsic tu-

Study Details In the phase III HORIZON study, 1,112 patients were randomized to receive first-line oral letrozole at 2.5 mg daily plus temsirolimus at 30 mg daily (5 days every 2 weeks) vs letrozole plus placebo. (The overall study was negative.) “Patients had histologically and/or cytologically confirmed ERpositive breast cancer with evidence of locally advanced or metastatic disease (stage IIIB/C or IV) and one or more measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST),” the investigators reported. The

continued on page 64

The ASCO Post | FEBRUARY 1, 2013

PAGE 64

In the Literature

Emerging Clinical Data continued from page 63

mor factors associated or not with prior [aromatase inhibitor] exposure.”

Learning from Negative Studies “The HORIZON study reminds us that we may learn as much from negative studies as from positive

ones and that it is important to apply results to the clinical population shown to benefit from the intervention,” E. Claire Dees, MD, and Lisa A. Carey, MD, of Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, wrote in an editorial accompanying the article. “It is increasingly clear

that ER-positive disease is heterogeneous,” they concluded, “and that endocrine resistance is a complex problem that will likely require highly translational trials to solve.”

Wolff AC, et al: J Clin Oncol 31:195-202, 2013. Dees EC, Carey LA: J Clin Oncol 31:171173, 2013.

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PROSTATE CANCER No Difference in Toxicity with Proton Radiotherapy vs Less Costly Intensity-modulated Radiotherapy A national sample of Medicare beneficiaries treated for prostate cancer with intensity-modulated radiation therapy or proton radiotherapy found that proton radiotherapy “was rare and expensive and associated with only a modest and transient reduction in genitourinary toxicity,” reported James B. Yu, MD, of Yale University School of Medicine, New Haven, Connecticut, and coauthors in the Journal of the National Cancer Institute. In this retrospective study of 27,647 Medicare beneficiaries aged ≥ 66 years, 27,094 (98%) received intensity-modulated radiotherapy and 553 (2%) received proton radiotherapy for prostate cancer during 20008 and/or 2009. “Although [proton radiotherapy] was associated with a statistically significant reduction in genitourinary toxicity at 6 months compared with [intensity-modulated radiotherapy] (5.9% vs 9.5%; odds ratio [OR] = 0.60, 95% confidence interval [CI] = 0.38–0.96, P = .03), at 12 months post-treatment there was no difference in genitourinary toxicity (18.8% vs 17.5%; OR = 1.08, 95% CI = 0.76–1.54, P = .66). There was no statistically significant difference in gastrointestinal or other toxicity at 6 months or 12 months post-treatment,” the authors wrote.

Explanations and Limitations “Regarding toxicity, it is plausible that differences between [protonbeam and intensity-modulated radiotherapy] would be limited to early genitourinary side effects. In prior studies, the only improvement in radiation dose distribution [for proton vs intensity-modulated radiotherapy] was a reduction in the amount of bladder exposed to low and intermediate levels of radiation,” the researchers noted. “Because the amount of bladder exposed to low doses of radiation predicts early toxicity, the reduction of radiation to the bladder may be responsible for the transient improvement in 6-month toxicity associated with [proton radiotherapy],” they speculated. “Although we excluded patients with a diagnosis of metastatic disease, other staging data were not available. Only

ASCOPost.com | FEBRUARY 1, 2013

PAGE 65

In the Literature

12 months of follow-up were available, so further analyses of longer-term outcomes concerning both toxicity and cancer control are warranted. In addition, patients were not randomized; however, the large pool of controls allowed us to match [proton radiotherapy] patients very closely with respect to observed risk factors,” the researchers reported.

Travel Costs “Patients receiving [proton radiotherapy] were younger, healthier, and from more affluent areas than patients receiving [intensity-modulated radiotherapy],” the investigators stated. Median Medicare reimbursement was $32,428 for proton radiotherapy and $18,575 for intensity-modulated radiotherapy. Proton centers are still relatively rare in the United States, the researchers noted, and many patients traveled substantial distances to undergo proton radiotherapy. Moreover, some patients traveled past one proton radiotherapy center to receive treatment at a more distant proton center. “Because [proton radiotherapy] treatment involves 7 to 9 weeks of daily treatment, such travel often involves relocating for the duration of the treatment, so patients may incur substantial out of-pocket costs,” they continued. “This is perhaps an extreme example of an indirect cost associated with cancer care. Thus, the adoption pattern of [proton radiotherapy] reflects a tiered system of access to cancer care; one level involving most Americans who travel locally for cancer care, and another level where a select group of patients can afford to travel nationally to obtain the treatments that are perceived to be ‘best.’”

Commentaries An accompanying editorial pointed out that two previous studies reached different conclusions: “that relative to [intensity-modulated radiotherapy], proton therapy was associated with increased long-term bowel complications and with no statistically significant difference in urinary complications.” The different studies “defined complications using such different methodologies and billing codes that a comparison of effect estimates between the three studies is not possible,” according to the editorial writers, Justin E. Bekelman, MD, and Stephen M. Hahn, MD, of the Department of Radiation Oncology, Abramson Cancer Center, University of Pennsylvania in Philadelphia.

“Without studies to validate the surrogacy of claims-based endpoints, outcome misclassification could lead to false-negative or false-positive results.” they wrote. A randomized trial comparing proton therapy and intensity-modulated radiotherapy “would appear to be a good investment for patients and clinics,” they stated, adding, “the University of Pennsylvania and the Massachusetts General Hospital have partnered with other centers to conduct this randomized trial.” In another accompanying editorial, Theodore S. Lawrence, MD, PhD, and Mary Feng, MD, of the Department of Radiation Oncology, University of Michigan in Ann Arbor, also stressed the need for prospective clinical trials directly comparing proton radiotherapy and intensity-modulated radiotherapy. “Although it seems unlikely that proton therapy will be superior to … photons for prostate cancer, protons may be superior for tumors in which the elimination of the lowdose regions might decrease normal tissue injury (eg, lung cancers, when combined with chemotherapy),” they wrote.

Yu JB, et al: J Natl Cancer Inst 105:2532, 2013. Bekelman JE, Hahn SM: J Natl Cancer Inst 105:6-7, 2013. Lawrence TS, Feng M: J Natl Cancer Inst 105:7-8, 2013.

LUNG CANCER E-mail Reminders to Providers May Improve Documentation of Code Status in Patients with Advanced Disease E-mail reminders to providers at the start of each new chemotherapy regimen may improve the rate and timing of code status documentation for patients with advanced lung cancer, according to a study in the Journal of Clinical Oncology. Jennifer S. Temel, MD, and colleagues from Massachusetts General Hospital in Boston reported the results of a two-phase study to “develop and assess the effect of electronic prompts to encourage oncology clinicians to document code status in the outpatient electronic health record of patients with advanced lung cancers.”

First Phase The first phase consisted of focus groups with oncology clinicians—one with physicians and one with nurses and nurse practitioners. The aim of the

meetings was to explore knowledge and practice related to code status in patients with incurable malignancies as well as to assess perceptions about the delivery, content, timing, and acceptability of an electronic prompt to document code status. “Oncology clinicians reported that conversations with patients regarding their resuscitation preferences primarily occur in the inpatient setting or at times of clinical deterioration, although most agreed this was not the optimal timing because of the level of stress experienced by patients and families in those circumstances,” the authors wrote. “Four main themes emerged regarding the delivery, timing, content, and acceptability of an electronic prompt to encourage discussion and documentation of resuscitation preferences in the outpatient setting,” they continued. “Specifically, the prompts ideally should (1) be brief and delivered early in the course of disease, (2) identify clearly the relevant patient, (3) contain minimal clinical information, and (4) be sent close to the time of the patient’s clinic visit. Additionally, clinicians felt that e-mail reminders were more acceptable than a ‘popup’ on the [electronic health record] or a ‘hard stop’ that prevents clinicians from ordering chemotherapy and interferes with their workflow,” the researchers reported. “Informed by these themes, we developed two succinct e-mail prompts that were delivered in tandem with each new line of chemotherapy.”

Second Phase In the second phase, clinical documentation of code status in the electronic health record of 100 patients with incurable lung cancer who agreed to participate in the study was compared to documentation of 100 consecutive historical controls who began therapy for incurable lung cancer at least 1 year before the start of the study. E-mail prompts were sent to the clinical team caring for the patient (physician, nurse practitioner, and oncology fellow). “The first e-mail prompt was sent on the morning of the outpatient appointment immediately after the visit at which the patient provided written informed consent for the study,” the investigators explained. “Subsequent e-mail prompts were sent on the day of the outpatient appointment immediately after the start of each new line of

chemotherapy (either oral or IV) until a code status was documented in the [electronic health record] code status module or the patient was referred to hospice or died.” At 1-year follow-up, 33 of 98 (33.7%) study participants had a code status documented in the outpatient electronic health record compared with 12 of 83 (14.5%) historical controls (P = .003), the researchers reported. The majority in both groups had a documented code status listed as DNR/DNI (do not resuscitate/do not intubate). “Mean See Page 61 time to code status documentation was significantly shorter” among the study participants: 8.6 vs 10.5 months for controls (P = .004). Deferring or delaying conversations about preferences for end-of-life care “has negative implications both for patients with cancer and society as a whole,” the authors wrote. “Specifically, patients with advanced cancer who do not recall discussing their [end-of-life] care goals are significantly more likely to receive aggressive medical care, initiate hospice services later in the course of disease, and lack a documented code status. Alternatively, patients who report having these conversations have significantly lower health-care costs in the final week of life, when the majority of health-care expenditures occur.”

‘Long Way to Go’ The results of the study represent an improvement, “but we still have a long way to go,” wrote Jamie H. Von Roenn, MD, of Feinberg School of Medicine, Northwestern University, Chicago, in an editorial accompanying the article. “Because we all tend to do what is most comfortable on the basis of our training, it is not surprising that many oncologists prefer to delay the often difficult conversations regarding code status or hospice care until there are no nonpalliative treatment options remaining,” she added. “A systematic review and meta-analysis of the efficacy of communication skills training in oncology concluded that skills training is a promising approach to change this communication behavior. This training is essential.” n

Temel JS, et al: J Clin Oncol January 2, 2013 (early release online). Von Roenn, JH: J Clin Oncol January 2, 2013 (early release online).

The ASCO Post | FEBRUARY 1, 2013

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Letters to the Editor

More Thoughts on Rationing Cancer Care

read the article about “The Ethics of Rationing Cancer Care” with interest (The ASCO Post, Dec 15, 2012). The issue of rationing (or rational) care has likely been debated since Hippocrates. Yet the topic has become a focus of acute interest with the current fiscal crises fac-

ing countries around the world. Cancer consumes 5% of all medical costs and 10% of Medicare spending. For advanced noncurable cancer, there are many high-cost, marginal-benefit therapeutic options whose judicious use could help solve the burgeoning

severe fiscal crises. At a recent tumor board meeting at our institution, the question was asked, “When is cancer care excessive?” The response from a primary care physician was, “When the care deprives resources from ‘more useful’ care like prenatal

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care, or when research and drug costs deprive resources better applied toward lifesaving drugs like antibiotics.”

See Page 61

‘Skin in the Game’ Prioritizing health-care spending and weighing the cost-benefit of treatments makes eminent sense. With the limited success of noncurative treatments in improving quality and length of life, decisions to opt for such treatments should be shared by patient and family. Family members should also be involved in sharing the patient’s costs. Thus, patient and family can weigh for themselves the costs against perceived benefits (aka “skin in the game”). In one possible model, well-proven, continued on page 67

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News

Lung Cancer Screening Guidelines continued from page 2

Principal elements of the clinicianpatient discussion should include the following: Benefit: Low-dose CT has been shown to effectively reduce lung cancer mortality. Limitations: Low-dose CT does not detect all lung cancers and does not guarantee early cancer detection; not all patients who have lung cancer identified by Low-dose CT will avoid death. Harms: Low-dose CT confers a significant percentage of false-positive results, which will require additional testing and, in some cases, an invasive procedure to determine whether an

Rationing Cancer Care continued from page 66

effective palliative measures might be fully covered by insurance. The patient’s shared cost of second-line cancer therapy could be determined at 20% (as an example). The shared cost of third-line therapy might be 30%, and the shared cost of fourth-line therapy might be 40%. Making the patient and family increasingly vested with the effectiveness of therapy would reduce the use of cancer drugs for marginal benefit, as well as reduce the cost of these agents.

Nondrug Costs Cost control of drugs is not the only concern. Specialized surgical and nonsurgical procedures may be similarly evaluated. For example, stereotactic radiosurgery may be the optimum therapy for a solitary

abnormality that is picked up is lung cancer or some other incidental noncancer finding. It is rare that patients with a false-positive experience have major complications from subsequent diagnostic workup. Eligible patients should make the screening decision together with their clinicians; together they can clarify the personal values needed in effective decision-making. Patients must be willing to weigh the reduced risk of dying that screening offers with the risks and costs associated with a lowdose CT. Clinicians should not discuss low-dose CT with patients who do not meet those criteria. Further, since few payers cover the initial lowdose CT, clinicians who offer screen-

ing must help patients determine how they will ultimately pay for the test.

brain metastasis, but it is considered third-line therapy for a case involving nine brain lesions. Overutilization of various other expensive diagnostic and therapeutic technologies could also be evaluated and better defined. With the patient and family’s greater involvement, the individual oncologist would not be anguished in denying tests and treatments with marginal benefits. Yet the family and patient can have the satisfaction of determining whether “every option has been exhausted” for their loved one. The oncologic community (like the developers of National Comprehensive Cancer Network guidelines) would be charged with better defining which therapies are considered first, second, and third line. Scientific rationalization of cost and extent of

benefit will also encourage physicians to think specifically of therapeutic benefits and other alternatives. Thus, we can provide patients the optimum value and benefits of “evidence-based medicine” as well as “comparative effectiveness research.”

Conclusions The National Lung Screening Trial has demonstrated that there is an opportunity to reduce deaths from lung cancer in high-risk groups of current and former smokers. Clinicians now face the challenge of integrating riskassessment into their discussions with patients. To that end, it is incumbent on cancer control organizations to devote resources toward preparing clinicians in identifying patients who are eligible for lowdose CT. Whether community-based lung cancer screening with low-dose CT will achieve the benefits observed in the

Need for Specialty Leadership While it is important to evaluate cost-benefit of cancer care, the field of oncology needs to take a fundamental look at what drives the cost of cancer care services, technologies, products, utilization, and reimbursement. This involves our specialty leaders looking at the structural component of the cost of drugs (business practice, research, production, marketing), technology (manufacturing of diagnostic and therapeutic radiology equipment and utilization), and practice patterns (geographic patterns of care, including

NLST awaits further research. n

Disclosure: Among the authors of the screening guidelines, Dr. Christopher R. Flowers has received consulting fees from Celgene Corporation; Spectrum; Seattle Genetics, Inc; OptumRx; Clinical Care Options; and Education Concepts Group. He has performed contracted research for Millennium Pharmaceuticals, Celgene Corporation, Spectrum, Gilead Pharmaceuticals, and Janssen Pharmaceuticals. Dr. G. Scott Gazelle is a consultant to GE Healthcare. Dr. Douglas K. Kelsey is employed by Eli Lilly and Company. Other authors reported no potential conflicts of interest.

Reference 1. Wender R, Fontham ETH, Barrera E Jr, et al: American Cancer Society lung cancer screening guidelines. CA Cancer J Clin. January 11, 2013 (early release online).

self-referral). Hopefully, such an evaluation will curtail the health-care marketing wars and medical technology arms race (and resulting overutilization) that has gripped many regions of the country. Regional and local patterns of care (Surveillance, Epidemiology and End Results data and billing data) could be used to address issues of waste, redundancy, and overutilization on the part of all stakeholders (patients, doctors, hospitals, insurance carriers). We should not make health care a political issue. But if the medical profession does not address these selfcreated problems, the fiscal stability of the country is at stake, and the political debate becomes inevitable. n —Gilbert A. Lawrence, MD, DMRT, FRCR Radiation Oncology, Faxton Hospital Utica, New York

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